CA2929715A1 - Methods for inhibiting tie2 kinase useful in the treatment of cancer - Google Patents
Methods for inhibiting tie2 kinase useful in the treatment of cancer Download PDFInfo
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- CA2929715A1 CA2929715A1 CA2929715A CA2929715A CA2929715A1 CA 2929715 A1 CA2929715 A1 CA 2929715A1 CA 2929715 A CA2929715 A CA 2929715A CA 2929715 A CA2929715 A CA 2929715A CA 2929715 A1 CA2929715 A1 CA 2929715A1
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to methods of inhibiting TIE2 kinase useful in the treatment of tumor growth, invasiveness, intravasation, dissemination, metastasis, and immunosuppression. Specifically, the invention relates to methods of using 1-(3-tert-butyl-1-(quinolin-6-yl)-1Hpyrazol- 5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea and salts thereof of Formula I.
Description
USEFUL IN THE TREATMENT OF CANCER
Description of the Text File Submitted Electronically [0001] The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: A computer readable format copy of the Sequence Listing (filename: DECP 066 00W0 SeqList ST25.txt, date recorded: November 7, 2013, file size 6 kilobytes).
Field of the Invention
Description of the Text File Submitted Electronically [0001] The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: A computer readable format copy of the Sequence Listing (filename: DECP 066 00W0 SeqList ST25.txt, date recorded: November 7, 2013, file size 6 kilobytes).
Field of the Invention
[0002] The present invention relates to methods of inhibiting TIE2 kinase useful in the treatment of tumor growth, tumor invasiveness, tumor intravasation, tumor dissemination, tumor metastasis, and tumor immunotolerance. Specifically, the invention relates to methods of using compositions of Formula I herein described as potent inhibitors of TIE2 for treating breast cancer growth, invasiveness, intravasation dissemination, metastasis, and immunotolerance.
Background of the Invention
Background of the Invention
[0003] Tunica interna endothelial cell kinase-2 (TIE2) is largely restricted to expression in endothelial cells of the vasculature, and in a subset of bone marrow derived TIE2 expressing monocytes (TEMs). TIE2 is the receptor for angiopoietin 1 (ANG1), angiopoietin 2 (ANG2), and angiopoietin 4 (ANG4) and this signaling system plays an important role in both angiogenesis (sprouting of new vessels from existing vessels) and vasculogenesis (de novo new vessel formation). TEMs are a subset of circulating monocytes and tissue macrophages that have proangiogenic and provasculogenic activity in tumor models (De Palma MD et al, Cancer Cell 2005; 8:211-226). TIE2 inhibition decreases the ability of TEMs to associate with blood vessels (Mazzieri R, Cancer Cell 2011; 19:512-526) and markedly decreases the proangiogenic activity of this macrophage subset (De Palma M, Clin Cancer Res 2011; 17(16):5226-5232).
[0004] Cytotoxic chemotherapy, radiation therapy, and anti-angiogenic treatments damage the tumor-associated vasculature thus leading to a hypoxic tumor environment.
The hypoxic tumor environment leads to rebound tumor vascularization by activating an angiogenic switch from the vascular endothelial growth factor (VEGF)NEGFR2 pathway to the pathway in vascular endothelial cells. The recruitment of pro-vasculogenic TEMs from the bone marrow to these hypoxic tumor sites facilitates this revascularization by the association of TEMs with endothelial cells within the tumor microenvironment. TEMs and TIE2-expressing endothelial cells are thus believed to play an important role in the revascularization of tumors after these treatments, leading to progression due to the growth of residual tumor cells (De Palma M, et al. Trends Immunol 2007; 28:519-524).
The hypoxic tumor environment leads to rebound tumor vascularization by activating an angiogenic switch from the vascular endothelial growth factor (VEGF)NEGFR2 pathway to the pathway in vascular endothelial cells. The recruitment of pro-vasculogenic TEMs from the bone marrow to these hypoxic tumor sites facilitates this revascularization by the association of TEMs with endothelial cells within the tumor microenvironment. TEMs and TIE2-expressing endothelial cells are thus believed to play an important role in the revascularization of tumors after these treatments, leading to progression due to the growth of residual tumor cells (De Palma M, et al. Trends Immunol 2007; 28:519-524).
[0005] TIE2 is also a mediator of osteoclast differentiation, and TIE2 inhibition led to decreased osteolytic bone invasion and decreased tumor growth in the 4T1 mouse breast cancer model (Dales JP, et al. Int J Oncol 2003; 22:391-397 ). Beyond the physiologic expression of TIE2 on endothelial, monocyte/macrophage, and osteoclast cells of the tumor microenvironment, TIE2 has also been demonstrated to be present on breast cancer cells. Tumor cell expression of TIE2 was associated with an elevated risk of metastatic disease and an independent predictor of prognosis on multivariate analysis (Min Y, et al. Cancer Res 2010; 70:2918-2828).
[0006] Significantly, a subset of TIE2-expressing tissue macrophages are located within specialized vascular structures known as tumor microenvironment for metastases (TMEMs).
Recent observations have linked TIE2-expressing macrophages within TMEM
structures as being essential for extravasation of breast cancer cells into the vascular circulation and subsequent dissemination to distal metastatic sites (Condeelis J, Pollard JW.
Cell 2006; 124:263-6; Ginter PS, et al. Cancer Res 2012; 72(24 Suppl):Abstract #P6-02-04). Thus inhibition of TIE2, and of the macrophages within TMEM structures, may lead to a decrease in new metastases.
Recent observations have linked TIE2-expressing macrophages within TMEM
structures as being essential for extravasation of breast cancer cells into the vascular circulation and subsequent dissemination to distal metastatic sites (Condeelis J, Pollard JW.
Cell 2006; 124:263-6; Ginter PS, et al. Cancer Res 2012; 72(24 Suppl):Abstract #P6-02-04). Thus inhibition of TIE2, and of the macrophages within TMEM structures, may lead to a decrease in new metastases.
[0007] TIE2-expressing tissue macrophages (TEMs) have recently been demonstrated to play a role in breast cancer immunotolerance. TEMs from breast tumors are able to suppress tumor-specific immune responses. Specifically, suppressive functions of TEMs are similarly driven by TIE2 and VEGFR kinase activity. TEMs isolated from breast cancer tissue can function as antigen-presenting cells that elicit only a weak proliferation of T cells. Blocking TIE2 and VEGFR kinase activity induced TEMs to change their phenotype into cells with features of myeloid dendritic cells with robust antigen-presentation.
Immunosuppressive activity of TEMs is also associated with high CD86 surface expression and extensive engagement of T
regulatory cells in breast tumors. TIE2 and VEGFR kinase activities were required to maintain high CD86 surface expression levels and to convert T cells into immunosuppressive regulatory cells (Ibberson M, et al. Clin Cancer Res 2013; 19:3439-3449).
Immunosuppressive activity of TEMs is also associated with high CD86 surface expression and extensive engagement of T
regulatory cells in breast tumors. TIE2 and VEGFR kinase activities were required to maintain high CD86 surface expression levels and to convert T cells into immunosuppressive regulatory cells (Ibberson M, et al. Clin Cancer Res 2013; 19:3439-3449).
[0008] The polyoma middle-T antigen (PyMT) syngeneic mouse breast cancer model utilizes the mouse mammary tumor virus (MMTV) promoter, a breast specific promoter, to express PyMT in mouse breast tissue. In this model, PyMT breast cancer cells are implanted in the mouse mammary fat pad, and these cancers metastasize and lead to the death of the mouse.
Unlike xenograft models, the PyMT model utilizes fully immunocompetent mice.
Metastasis in this model is known to be modulated by TIE2 expressing macrophages within TMEM
vascular structures. Thus, there is a need for new treatments for diseases assocaited with TIE2.
Summary of the Invention
Unlike xenograft models, the PyMT model utilizes fully immunocompetent mice.
Metastasis in this model is known to be modulated by TIE2 expressing macrophages within TMEM
vascular structures. Thus, there is a need for new treatments for diseases assocaited with TIE2.
Summary of the Invention
[0009] Methods of the present invention find utility in the inhibition TIE2 kinase. As a result of this inhibition the present invention is useful in the treatment or prophylaxis against of tumor growth, invasiveness, intravasation, dissemination, metastasis, and tumor immunotolerance. In particular, the invention relates to methods of using compositions of Formula I, described below, as potent inhibitors of TIE2 for treating breast cancer growth, invasiveness, intravasation, dissemination, metastasis, and immunotolerance:
N
N N N
H H F
CN.-*
H
= nHX
Nk /
Formula I
wherein n is an integer from 0 to 7;
X is the basic radical of a pharmaceutically acceptable salt;
provided that when n is 0, the composition of Formula I is the parent free base. In some embodiments, HX is absent whereby the structure of Formula I is the parent free base.
N
N N N
H H F
CN.-*
H
= nHX
Nk /
Formula I
wherein n is an integer from 0 to 7;
X is the basic radical of a pharmaceutically acceptable salt;
provided that when n is 0, the composition of Formula I is the parent free base. In some embodiments, HX is absent whereby the structure of Formula I is the parent free base.
[0010] The compositions of Formula I also find utility in other cancers wherein TIE2 expression, either in the tumor cell or in the tumor microenvironment, causes tumor progression by mechanisms mediating primary tumor growth, primary tumor invasiveness, tumor intravasation into the blood stream, tumor cell dissemination, tumor metastases to distal tissues, or tumor immunotolerance. Inhibition of TIE2 kinase by the composition of Formula I therefore finds utility in the treatment of cancer by inhibiting processes including primary tumor growth, primary tumor invasiveness, tumor intravasation into the blood stream, tumor cell dissemination, tumor metastases to distal tissues, or tumor immunotolerance.
[0011] TIE2 kinase has been shown to be causative of cancer progression in gliomas (Liu et al, Oncotarget (2010) 1: 700-709; Brunckhorst et al, Cancer Research (2010) 70: 7283-7293), melanomas (Helfrich et al, Clin Cancer Res (2009) 15: 1384-1392 ), ovarian cancer (Karlan et al, J. Clinical Oncology (2012) 30: 362-370), colorectal cancer (Ahmad et al, Cancer (2001) 92:
1138-1143; Hashizume et al, Cancer Research (2010) 70: 2213-2223), hepatocellular carcinoma (Matsubara et al, Hepatology (2013) 57: 1416-1425; Mitsuhashi et al, Hepatology (2003) 37:
1105-1113; Tanaka et al, J. Clin Invest (1999) 103: 341-345), and hematological cancers (Muller et al, Leukemia Research (2002) 26: 163-168; Hou et al, Leukemia Research (2008) 32: 904-912).
Brief Description of the Drawings
1138-1143; Hashizume et al, Cancer Research (2010) 70: 2213-2223), hepatocellular carcinoma (Matsubara et al, Hepatology (2013) 57: 1416-1425; Mitsuhashi et al, Hepatology (2003) 37:
1105-1113; Tanaka et al, J. Clin Invest (1999) 103: 341-345), and hematological cancers (Muller et al, Leukemia Research (2002) 26: 163-168; Hou et al, Leukemia Research (2008) 32: 904-912).
Brief Description of the Drawings
[0012] Figure 1 shows the inhibition of primary PyMT tumor growth using the composition of Formula II , paclitaxel, or a combination thereof.
[0013] Figure 2 shows the inhibition of PyMT tumor macrophage accumulation using the composition of Formula II, paclitaxel, or a combination thereof.
[0014] Figure 3 shows the inhibition of PyMT tumor TIE2-expressing cell accumulation using the composition of Formula II, paclitaxel, or a combination thereof.
[0015] Figure 4 shows the inhibition of lung metastases in the PyMT breast cancer model using the composition of Formula II, paclitaxel, or a combination thereof.
[0016] Figure 5 shows the inhibition of lung metastases in the PyMT breast cancer model comparing the activities of paclitaxel and the combination of paclitaxel and the composition of Formula II.
[0017] Figure 6 shows the inhibition of lung metastases in the PyMT breast cancer model using eribulin as a single agent or in combination with the composition of Formula II.
[0018] Figure 7 shows enzymatic and in vivo activities of eribulin as a single agent or in combination with the composition of Formula II.
Detailed Description of the Invention Definitions:
Detailed Description of the Invention Definitions:
[0019] The term "basic radical of a pharmaceutically acceptable salt" in compositions of Formula I include, without limitation, water-soluble and water-insoluble salts, such as substituted or unsubstituted benzenesulfonate , the acetate, amsonate (4,4-diaminostilbene-2, 2 -disulfonate), benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1 ,1 -methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts. Specific examples of the basic radicals include para-toluene sulfonate, triflate, and methanesulfonate.
[0020] The term "salt' refers to pharmaceutically acceptable salts
[0021] The term "pharmaceutically acceptable salt" also refers to a salt of the compositions of the present invention having an acidic functional group, such as a carboxylic acid functional group, and a base.
[0022] The term "treating" with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating can be curing, improving, or at least partially ameliorating the disorder.
[0023] The term "administer", "administering", or "administration" as used in this disclosure refers to either directly administering a composition or pharmaceutically acceptable salt of the compound or a composition to a subject, or administering a prodrug derivative or analog of the composition or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.
[0024] An "effective amount," when used in connection with medical uses is an amount that is effective for providing a measurable treatment, prevention, or reduction in the rate of pathogenesis of a disease of interest.
[0025] The present invention relates to methods of the treatment (blocking) or prophylaxis against tumor growth, invasiveness, intravasation, dissemination, metastasis, and tumor immunotolerance. The method comprises administering to a patient in need of treatment or reduction of prophylactic effects of these conditions an effective amount of a composition of Formula I herein described in a dosing regimen that regulates TIE2 inhibition.
[0026] The amount of composition described herein needed for achieving a therapeutic effect may be determined empirically in accordance with conventional procedures for the particular purpose. Generally, for administering therapeutic agents (e.g. compositions of Formulae I or II
(and/or additional agents) described herein) for therapeutic purposes, the therapeutic agents are given at a pharmacologically effective dose. A "pharmacologically effective amount,"
"pharmacologically effective dose," "therapeutically effective amount," or "effective amount"
refers to an amount sufficient to produce the desired physiological effect or amount capable of achieving the desired result, particularly for treating the disorder or disease. An effective amount as used herein would include an amount sufficient to, for example, delay the development of a symptom of the disorder or disease, alter the course of a symptom of the disorder or disease (e.g., slow the progression of a symptom of the disease), reduce or eliminate one or more symptoms or manifestations of the disorder or disease, and reverse a symptom of a disorder or disease. For example, administration of therapeutic agents to a patient suffering from cancer provides a therapeutic benefit not only when the underlying condition is eradicated or ameliorated, but also when the patient reports a decrease in the severity or duration of the symptoms associated with the disease, e.g., a decrease in tumor burden, a decrease in circulating tumor cells, an increase in progression free survival. Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is realized.
(and/or additional agents) described herein) for therapeutic purposes, the therapeutic agents are given at a pharmacologically effective dose. A "pharmacologically effective amount,"
"pharmacologically effective dose," "therapeutically effective amount," or "effective amount"
refers to an amount sufficient to produce the desired physiological effect or amount capable of achieving the desired result, particularly for treating the disorder or disease. An effective amount as used herein would include an amount sufficient to, for example, delay the development of a symptom of the disorder or disease, alter the course of a symptom of the disorder or disease (e.g., slow the progression of a symptom of the disease), reduce or eliminate one or more symptoms or manifestations of the disorder or disease, and reverse a symptom of a disorder or disease. For example, administration of therapeutic agents to a patient suffering from cancer provides a therapeutic benefit not only when the underlying condition is eradicated or ameliorated, but also when the patient reports a decrease in the severity or duration of the symptoms associated with the disease, e.g., a decrease in tumor burden, a decrease in circulating tumor cells, an increase in progression free survival. Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is realized.
[0027] In one embodiment of the invention, the composition of Formula I is 1-(3-tert-butyl-1 -(quino lin-6 -y1)- 1 H-pyrazol-5-y1)-3-(2-fluoro -4-(2-(methylc arb amoyl)pyri din-4-yloxy)phenyOurea para-toluene sulfonic acid salt of Formula II which is a potent inhibitor of TIE2, the receptor tyrosine kinase for angiopoietin ligands.
(:) IN
N N N
H H
410 F ...--H
NN/ s SO3H
Formula II
(:) IN
N N N
H H
410 F ...--H
NN/ s SO3H
Formula II
[0028] The compositions of Formula I find utility in cancers wherein TIE2 expression, either in the tumor cell or in the tumor microenvironment, causes tumor progression by mechanisms mediating primary tumor growth, primary tumor invasiveness, tumor intravasation into the blood stream, tumor cell dissemination, tumor metastases to distal tissues, or tumor immunotolerance.
Inhibition of TIE2 kinase by the composition of Formula I therefore finds utility in the treatment of cancer by inhibiting processes including primary tumor growth, primary tumor invasiveness, tumor intravasation into the blood stream, tumor cell dissemination, tumor metastases to distal tissues, or tumor immunotolerance.
Inhibition of TIE2 kinase by the composition of Formula I therefore finds utility in the treatment of cancer by inhibiting processes including primary tumor growth, primary tumor invasiveness, tumor intravasation into the blood stream, tumor cell dissemination, tumor metastases to distal tissues, or tumor immunotolerance.
[0029] Therapeutic concentrations of the compositions of Formula I block cells within the tumor microenvironment known to cause tumor growth, invasion, intravasation, dissemination, metastases, of tumor induced immunotolerance. Such cell types within the tumor microenvironment include TIE2-expressing monocytes, TIE2-expessing macrophages, and TIE2-expressing endothelial cells.
[0030] Tumors responsive to angiopoietin/TIE2 signaling include but are not limited to breast cancer, ovarian cancer, hepatocellular carcinoma, gliomas, colorectal cancer, and hematological malignancies.
[0031] In another embodiment, the composition of Formula I when the HX is absent is the free base compound 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylcarbamoyOpyridin-4-yloxy)phenyOurea having the structure:
Nisi \ 1 N el N
N N
H H F
H
N N /
Nisi \ 1 N el N
N N
H H F
H
N N /
[0032] The composition of Formula I may be administered as a single agent or in combination with other therapeutic agents known to treat cancers. Such other therapeutic agents include radiation therapy, anti-tubulin agents, DNA alkylating agents, DNA
synthesis-inhibiting agents, DNA intercalating agents, anti-estrogen agents, anti-androgens, steroids, anti-EGFR
agents, kinase inhibitors, topoisomerase inhibitors, Histone Deacetylase (HDAC) inhibitors, DNA methylation inhibitors, anti-HER2 agents, anti-angiogenic agents, proteasome inhibitors, thalidomide, lenalidomide, antibody-drug-conjugates (ADCs), immunomodulating agents, or cancer vaccines.
synthesis-inhibiting agents, DNA intercalating agents, anti-estrogen agents, anti-androgens, steroids, anti-EGFR
agents, kinase inhibitors, topoisomerase inhibitors, Histone Deacetylase (HDAC) inhibitors, DNA methylation inhibitors, anti-HER2 agents, anti-angiogenic agents, proteasome inhibitors, thalidomide, lenalidomide, antibody-drug-conjugates (ADCs), immunomodulating agents, or cancer vaccines.
[0033] Effective amounts, toxicity, and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to about 50% of the population) and the ED50 (the dose therapeutically effective in about 50% of the population). The dosage can vary depending upon the dosage form employed and the route of administration utilized. The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD50/ED50.
In some embodiments, compositions and methods that exhibit large therapeutic indices are preferred. A
therapeutically effective dose can be estimated initially from in vitro assays, including, for example, cell culture assays. Also, a dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 as determined in cell culture, or in an appropriate animal model. Levels of the described compositions in plasma can be measured, for example, by high performance liquid chromatography. The effects of any particular dosage can be monitored by a suitable bioassay. The dosage can be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.
In some embodiments, compositions and methods that exhibit large therapeutic indices are preferred. A
therapeutically effective dose can be estimated initially from in vitro assays, including, for example, cell culture assays. Also, a dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 as determined in cell culture, or in an appropriate animal model. Levels of the described compositions in plasma can be measured, for example, by high performance liquid chromatography. The effects of any particular dosage can be monitored by a suitable bioassay. The dosage can be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.
[0034] In certain embodiments, the prophylactic effect will result in a quantifiable change of at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 70%, or at least about 90%. In some embodiments, the effect will result in a quantifiable change of about 10%, about 20%, about 30%, about 50%, about 70%, or even about 90% or more.
Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is realized.
Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is realized.
[0035] When the compositions of Formulae I or II are used in combination with other anti-cancer agents, the other anti-cancer agent may be dosed independently of the dosing schedule of the composition of Formulae I or II. The other anti-cancer agent may be dosed at its previously established therapeutic dose and dosing schedule, or its dose and dosing schedule may be modified to optimize efficacy, safety or tolerability when used in combination with the compositions of Formulae I or II.
[0036] Further, any compositions of Formulae I or II (and/or additional agents) described herein can be administered to a subject as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle. Such compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration.
[0037] Pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical excipients can be, for example, saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In one embodiment, the pharmaceutically acceptable excipients are sterile when administered to a subject. Water is a useful excipient when any agent described herein is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, specifically for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Any agent described herein, if desired, can also comprise minor amounts of wetting or emulsifying agents, or pH buffering agents.
[0038] The compositions of Formula I may be used in combination with other agents including chemotherapeutic agents, targeted therapeutics, biological agents, or radiotherapy.
[0039] The compositions of Formula I may be used in combination with chemotherapeutic agents including but not limited to anti-tubulin agents (paclitaxel, paclitaxel protein-bound particles for injectable suspension, eribulin, docetaxel, ixabepilone, vincristine), vinorelbine, DNA-alkylating agents (including cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, temozolomide), DNA intercalating agents (including doxorubicin, pegylated liposomal doxorubicin, daunorubicin, idarubicin, and epirubicin), 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-aza cytadine, gemcitabine and methotrexate.
[0040] The compositions of Formula I may be used in combination with kinase inhibitors including but not limited to erlotinib, gefitinib, lapatanib, everolimus, temsirolimus, LY2835219, LEE011, PD 0332991, crizotinib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, axitinib, dasatinib, imatinib, nilotinib, vemurafenib, dabrafenib, trametinib, idelalisib, and quizartinib.
[0041] The compositions of Formula I may be used in combination with anti-estrogen agents including but not limited to tamoxifen, fulvestrant, anastrozole, letrozole, and exemestane.
[0042] The compositions of Formula I may be used in combination with anti-androgen agents including but not limited to abiraterone acetate, enzalutamide, nilutamide, bicalutamide, flutamide, cyproterone acetate.
[0043] The compositions of Formula I may be used in combination with steroid agents including but not limited to prednisone and dexamethazone.
[0044] The compositions of Formula I may be used in combination with topoisomerase I
inhibitors including but not limited to irinotecan, camptothecin, and topotecan.
inhibitors including but not limited to irinotecan, camptothecin, and topotecan.
[0045] The compositions of Formula I may be used in combination with topoisomerase II
inhibitors including but not limited to etoposide, etoposide phosphate, and mitoxantrone.
inhibitors including but not limited to etoposide, etoposide phosphate, and mitoxantrone.
[0046] The compositions of Formula I may be used in combination with Histone Deacetylase (HDAC) inhibitors including but not limited to vorinostat, romidepsin, panobinostat, valproic acid, and belinostat.
[0047] The compositions of Formula I may be used in combination with DNA
methylation inhibitors including but not limited to DZNep and 5-aza-2'-deoxycytidine.
methylation inhibitors including but not limited to DZNep and 5-aza-2'-deoxycytidine.
[0048] The compositions of Formula I may be used in combination with proteasome inhibitors including but not limited to bortezomib and carfilzomib.
[0049] The compositions of Formula I may be used in combination with thalidomide, lenalidomide and pomalidomide.
[0050] The compositions of Formula I may be used in combination with biological agents including but not limited to trastuzumab, ado-trastuzumab, pertuzumab, cetuximab, panitumumab, ipilimumab, anti-PD-1 agents including labrolizumab and nivolumab, anti-PD-L1 agents including MPDL3280A, anti-angiogenic agents including bevacizumab and aflibercept, and antibody-drug-conjugates (ADCs) including brentuximab vedotin and trastuzumab emtansine.
[0051] The compositions of Formula I may be used in combination with radiotherapy.
[0052] The compositions of Formula I may be used in combination with therapeutic vaccines including but not limited to sipuleucel-T.
[0053] In some embodiments, the composition of Formula I or Formula II can be used in combination with one or more of the other agents described herein.
Methods for blocking primary breast tumor growth and invasiveness:
Methods for blocking primary breast tumor growth and invasiveness:
[0054] A first aspect of the invention relates to a method of blocking primary breast tumor growth and invasiveness which comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment.
[0055] In one embodiment of this aspect of the invention, the dosing regimen of the composition of Formula I is a daily dosing administration.
[0056] In another embodiment of this aspect of the invention the dosing regimen of the composition of Formula I is a daily dosing administration. The intermittent non-daily dosing regimen may include, without limitation, alternate daily dosing, every third-day dosing, twice weekly dosing, or once weekly dosing.
[0057] In another embodiment of this aspect of the invention, a suitable dosing regimen of the composition of Formula I includes administration twice weekly, once weekly, or alternate weekly.
[0058] In another embodiment of this aspect of the invention, the dosing regimen of the composition of Formula I is twice weekly or once weekly.
[0059] In other embodiments of this aspect of the invention, the dosing regimen of the composition of Formula I is administration twice weekly.
[0060] In yet another embodiment of the invention, the method of blocking primary breast tumor growth and invasiveness comprises administering a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment in combination with one or more agents taken from an anti-tubulin agent, a DNA alkylating agent, a DNA
synthesis-inhibiting agent, a DNA intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor or an anti-angiogenic agent.
synthesis-inhibiting agent, a DNA intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor or an anti-angiogenic agent.
[0061] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises administering a composition of Formula I in combination with paclitaxel.
[0062] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises administering a composition of Formula I in combination with paclitaxel protein-bound particles for injectable suspension.
[0063] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises administering a composition of Formula I in combination with docetaxel.
[0064] In another embodiment of this aspect of the invention, a method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with eribulin.
[0065] In another embodiment of this aspect of the invention, a method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with ixabepilone.
[0066] In another embodiment of this aspect of the invention, a method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with vinorelbine.
[0067] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with capecitabine.
[0068] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with gemcitabine.
[0069] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a compositionof Formula I in combination with 5-fluorouracil.
[0070] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with methotrexate.
[0071] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with cyclophosphamide.
[0072] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with cisplatin.
[0073] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with carboplatin.
[0074] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises administering of a composition of Formula I in combination with doxorubicin.
[0075] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises administering of a composition of Formula I in combination with pegylated liposomal doxorubicin.
[0076] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises administering of a compositionof Formula I in combination with epirubicin.
[0077] In yet another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with tamoxifen.
[0078] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with fulvestrant.
[0079] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with anastrozole.
[0080] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with letrozole.
[0081] \In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with exemestane.
[0082] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with trastuzumab.
[0083] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with ado-trastuzumab emtansine.
[0084] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises administering a composition of Formula I in combination with pertuzumab.
[0085] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with lapatinib.
[0086] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with everolimus.
[0087] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with temsirolimus.
[0088] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with the CDK4/6 inhibitor LY2835219.
[0089] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with the CDK4/6 inhibitor LEE011.
[0090] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with the CDK4/6 inhibitor PD 0332991.
[0091] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with bevacizumab.
[0092] Another aspect of the invention relates to a method of blocking primary breast tumor growth and invasiveness which comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, wherein the composition of Formula I is administered in an intermittent non-daily dosing regimen. In some embodiments, the intermittent non-daily dosing regimen, includes alternate daily dosing, every third daily dosing, twice weekly dosing, and once weekly dosing.
[0093] In another embodiment of this aspect of the invention, a method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, wherein the composition of Formula I is administered twice weekly, once weekly, or alternate weekly.
[0094] In another embodiment of this aspect of the invention, a method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, wherein the composition of Formula I is administered twice weekly or once weekly.
[0095] In another embodiment of this aspect of the invention, a method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, wherein the composition of Formula I is administered twice weekly.
[0096] In another embodiment of this aspect of the invention, a method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment wherein the composition of Formula I is administered in combination with one or more agents taken from an anti-tubulin agent, a DNA alkylating agent, a DNA synthesis-inhibiting agent, a DNA
intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor or an anti-angiogenic agent.
intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor or an anti-angiogenic agent.
[0097] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises administering a composition of Formula I in combination with paclitaxel.
[0098] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises administering a composition of Formula I in combination with paclitaxel protein-bound particles for injectable suspension.
[0099] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises administering a composition of Formula I in combination with docetaxel.
[0100] In another embodiment of this aspect of the invention, a method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with eribulin.
[0101] In another embodiment of this aspect of the invention, a method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with ixabepilone.
[0102] In another embodiment of this aspect of the invention, a method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with vinorelbine.
[0103] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with capecitabine.
[0104] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with gemcitabine.
[0105] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with 5-fluorouracil.
[0106] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with methotrexate.
[0107] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with cyclophosphamide.
[0108] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with cisplatin.
[0109] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with carboplatin.
[0110] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises administering of a composition of Formula I in combination with doxorubicin.
[0111] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises administering of a composition of Formula I in combination with pegylated liposomal doxorubicin.
[0112] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises administering of a composition of Formula I in combination with epirubicin.
[0113] In yet another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with tamoxifen.
[0114] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with fulvestrant.
[0115] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with anastrozole.
[0116] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with letrozole.
[0117] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with exemestane.
[0118] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with trastuzumab.
[0119] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with ado-trastuzumab emtansine.
[0120] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises administering a composition of Formula I in combination with pertuzumab.
[0121] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with lapatinib.
[0122] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with everolimus.
[0123] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with temsirolimus.
[0124] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LY2835219.
[0125] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LEE011.
[0126] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor PD 0332991.
[0127] In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with bevacizumab.
Methods for blocking breast cancer intravasation, dissemination and metastasis:
Methods for blocking breast cancer intravasation, dissemination and metastasis:
[0128] In yet another aspect of the invention a method of blocking breast cancer intravasation, dissemination and metastasis is provided which comprises administering to patient in need thereof an effective amount of a composition of Formula I sufficient to block TIE2 kinase in the tumor microenvironment.
[0129] In one embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering to patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment.
[0130] In another embodiment of this aspect of the invention, the dosing regimen sufficient to block breast cancer intravasation, dissemination and metastasis comprises the daily administration of a composition of Formula I.
[0131] In another embodiment of this aspect of the invention, the dosing regimen of a composition of Formula I is administered in an intermittent non-daily dosing manner, including alternate daily dosing, every third daily dosing, twice weekly dosing, or once weekly dosing.
[0132] In another embodiment of this aspect of the invention, the dosing regimen of a composition of Formula I is administered twice weekly, once weekly, or alternate weekly.
[0133] In another embodiment of this aspect of the invention, the dosing regimen of a composition of Formula I is twice weekly or once weekly administration.
[0134] In another embodiment of this aspect of the invention, the dosing regimen a composition of Formula I is administered twice weekly.
[0135] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment in combination with one or more agents taken from an anti-tubulin agent, a DNA alkylating agent, a DNA synthesis-inhibiting agent, a DNA
intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor or an anti-angiogenic agent.
intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor or an anti-angiogenic agent.
[0136] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with paclitaxel.
[0137] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with paclitaxel protein-boundn particles for injectable suspension.
[0138] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with docetaxel.
[0139] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with eribulin.
[0140] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises adminstering a composition of Formula I in combination with ixabepilone.
[0141] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises adminstering a composition of Formula I in combination with vinorelbine.
[0142] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with capecitabine.
[0143] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with gemcitabine.
[0144] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with 5-fluorouracil.
[0145] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with methotrexate.
[0146] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with cyclophosphamide.
[0147] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with cisplatin.
[0148] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with carboplatin.
[0149] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with doxorubicin.
[0150] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with epirubicin.
[0151] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with tamoxifen.
[0152] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with fulvestrant.
[0153] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with anastrozole.
[0154] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with letrozole.
[0155] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with exemestane.
[0156] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with trastuzumab.
[0157] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with ado-trastuzumab emtansine.
[0158] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with pertuzumab.
[0159] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with lapatinib.
[0160] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with everolimus.
[0161] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with temsirolimus.
[0162] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with the CDK4/6 inhibitor LY2835219.
[0163] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with the CDK4/6 inhibitor LEE011.
[0164] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with the CDK4/6 inhibitor PD 0332991.
[0165] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with bevacizumab.
[0166] In another aspect of the invention, a method of blocking breast cancer intravasation, dissemination and metastasis comprises administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, wherein the dosing regimen of the composition of Formula I is administered as intermittent non-daily dosing.
In some embodiments, the alternate daily dosing includes every third daily dosing, twice weekly dosing, or once weekly dosing.
In some embodiments, the alternate daily dosing includes every third daily dosing, twice weekly dosing, or once weekly dosing.
[0167] In one embodiment of this aspect of the invention, a method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, with the dosing regimen of the composition of Formula I being administered twice weekly, once weekly, or alternate weekly.
[0168] In another embodiment of this aspect of the invention, a method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, with the dosing regimen of the composition of Formula I being administered twice weekly or once weekly.
[0169] In another embodiment of this aspect of the invention, a method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, with the dosing regimen of the composition of Formula I being administered twice weekly.
[0170] In another embodiment of this aspect of the invention, a method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment administered in combination with one or more agents taken from an anti-tubulin agent, a DNA
alkylating agent, a DNA synthesis-inhibiting agent, a DNA intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor or an anti-angiogenic agent.
alkylating agent, a DNA synthesis-inhibiting agent, a DNA intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor or an anti-angiogenic agent.
[0171] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with paclitaxel.
[0172] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with paclitaxel protein-bound particles for injectable suspension.
[0173] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with docetaxel.
[0174] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with eribulin.
[0175] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with ixabepilone.
[0176] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with vinorelbine.
[0177] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with capecitabine.
[0178] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with gemcitabine.
[0179] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with 5-fluorouracil.
[0180] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with methotrexate.
[0181] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with cyclophosphamide.
[0182] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with cisplatin.
[0183] In another embodiment of of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with carboplatin.
[0184] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering of a composition of Formula I in combination with doxorubicin.
[0185] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering of a composition of Formula I in combination with pegylated liposomal doxorubicin.
[0186] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering of a composition of Formula I in combination with epirubicin.
[0187] In yet another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with tamoxifen.
[0188] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with fulvestrant.
[0189] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with anastrozole.
[0190] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with letrozole.
[0191] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with exemestane.
[0192] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with trastuzumab.
[0193] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with ado-trastuzumab emtansine.
[0194] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with pertuzumab.
[0195] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with lapatinib.
[0196] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with everolimus.
[0197] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with temsirolimus.
[0198] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LY2835219.
[0199] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LEE011.
[0200] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor PD 0332991.
[0201] In another embodiment of this aspect of the invention, the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with bevacizumab.
Methods for blocking breast cancer immunotolerance:
Methods for blocking breast cancer immunotolerance:
[0202] Another aspect of the invention relates to a method of blocking breast cancer immunotolerance. The method comprises administering to a patient in need thereof an effective amount of a composition of Formula I. In one embodiment, the dosing regimen of the salt is sufficient to block TIE2 kinase in the tumor microenvironment that mediates immunotolerance.
[0203] In one embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment that mediates immunotolerance.
[0204] In one embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I daily.
[0205] In another embodiment of this aspect of the invention,the composition of Formula I
is administered in an intermittent non-daily manner. In some embodiments, the intermittent non-daily manner includes alternate daily dosing, every third daily dosing, twice weekly dosing, or once weekly dosing.
is administered in an intermittent non-daily manner. In some embodiments, the intermittent non-daily manner includes alternate daily dosing, every third daily dosing, twice weekly dosing, or once weekly dosing.
[0206] In another embodiment of this aspect of the invention, administration of the composition of Formula I is twice weekly, once weekly, or alternate weekly.
[0207] In another embodiment of this aspect of the invention, the composition of Formula I
is administered twice weekly or once weekly.
is administered twice weekly or once weekly.
[0208] In another embodiment of this aspect of the invention, the composition of Formula I
is administered twice weekly.
is administered twice weekly.
[0209] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment in combination with one or more agents taken from an anti-tubulin agent, a DNA alkylating agent, a DNA synthesis-inhibiting agent, a DNA
intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor, an anti-angiogenic agent, or an immunomodulating agent.
intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor, an anti-angiogenic agent, or an immunomodulating agent.
[0210] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with paclitaxel.
[0211] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with paclitaxel protein-bound particles for injectable suspension.
[0212] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with docetaxel.
[0213] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with eribulin.
[0214] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with ixabepilone.
[0215] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with vinorelbine.
[0216] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with capecitabine.
[0217] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with gemcitabine.
[0218] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with 5-fluorouracil.
[0219] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with 5-methotrexate.
[0220] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with cyclophosphamide.
[0221] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with cisplatin.
[0222] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with carboplatin.
[0223] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises administering of a composition of Formula I
in combination with doxorubicin.
in combination with doxorubicin.
[0224] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises administering of a composition of Formula I
in combination with pegylated liposomal doxorubicin.
in combination with pegylated liposomal doxorubicin.
[0225] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises administering of a composition of Formula I
in combination with epirubicin.
in combination with epirubicin.
[0226] In yet another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with tamoxifen.
[0227] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with fulvestrant.
[0228] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with anastrozole.
[0229] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with letrozole.
[0230] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with exemestane.
[0231] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with trastuzumab.
[0232] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with ado-trastuzumab emtansine.
[0233] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with pertuzumab.
[0234] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with lapatinib.
[0235] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with everolimus.
[0236] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with temsirolimus.
[0237] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LY2835219.
[0238] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LEE011.
[0239] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor PD 0332991.
[0240] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with bevacizumab.
[0241] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with an anti-CTLA-4 agent.
[0242] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with ipilimumab.
[0243] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with an anti-PD-1 agent.
[0244] In another embodiment of this aspect of the invention, a method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with lambrolizumab.
[0245] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with an anti-PD L-1 agent.
[0246] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with MPDL3280A.
Methods for blocking breast cancer immunotolerance:
Methods for blocking breast cancer immunotolerance:
[0247] In another aspect of the invention, a method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, wherein the dosing regimen of the composition of Formula I is administered in an intermittent non-daily dosing manner, including alternate daily dosing, every third daily dosing, twice weekly dosing, or once weekly dosing.
[0248] In one embodiment of this aspect of the invention, a method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, wherein the composition of Formula I is administered twice weekly, once weekly, or alternate weekly.
[0249] In another embodiment of this aspect of the invention, a method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, wherein the composition of Formula I is administered twice weekly or once weekly.
[0250] In another embodiment of this aspect of the invention, a method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, wherein the composition of Formula I is administered twice weekly.
[0251] In another embodiment of this aspect of the invention, a method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment administered in combination with one or more agents taken from an anti-tubulin agent, a DNA alkylating agent, a DNA synthesis-inhibiting agent, a DNA intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor, an anti-angiogenic agent, or an immunomodulating agent.
[0252] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with paclitaxel.
[0253] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with paclitaxel protein-bound particles for injectable suspension.
[0254] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with docetaxel.
[0255] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with eribulin.
[0256] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with ixabepilone.
[0257] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with vinorelbine.
[0258] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with capecitabine.
[0259] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with gemcitabine.
[0260] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with 5-fluorouracil.
[0261] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with methotrexate.
[0262] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with cyclophosphamide.
[0263] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with cisplatin.
[0264] In another embodiment of of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with carboplatin.
[0265] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises administering of a composition of Formula I
in combination with doxorubicin.
in combination with doxorubicin.
266 PCT/US2013/069005 [0266] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises administering of a composition of Formula I
in combination with pegylated liposomal doxorubicin.
in combination with pegylated liposomal doxorubicin.
[0267] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises administering of a composition of Formula I
in combination with epirubicin.
in combination with epirubicin.
[0268] In yet another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with tamoxifen.
[0269] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with fulvestrant.
[0270] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with anastrozole.
[0271] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with letrozole.
[0272] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with exemestane.
[0273] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with trastuzumab.
[0274] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a a composition of Formula I in combination with ado-trastuzumab emtansine.
[0275] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with pertuzumab.
[0276] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with lapatinib.
[0277] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with everolimus.
[0278] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with temsirolimus.
[0279] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LY2835219.
[0280] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LEE011.
[0281] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor PD 0332991.
[0282] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with bevacizumab.
[0283] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with an anti-CTLA-4 agent.
[0284] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with ipilimumab.
[0285] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with an anti-PD-1 agent.
[0286] In another embodiment of this aspect of the invention, a method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with lambrolizumab.
[0287] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with an anti-PD L-1 agent.
[0288] In another embodiment of this aspect of the invention, the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with MPDL3280A.
Methods for increasing overall survival in breast cancer patients:
Methods for increasing overall survival in breast cancer patients:
[0289] Another aspect of the invention relates to a method of increasing overall survival in breast cancer patients compriseing administering to a patient in need thereof an effective amount of a composition of Formula I. In one embodiment, the dosing regimen is sufficient to block TIE2 kinase in the tumor microenvironment .
[0290] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises a dosing regimen wherein the composition of Formula I administered daily.
[0291] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises a composition of Formula I in a dosing regimen administered in an intermittent non-daily manner, including alternate daily dosing, every third daily dosing, twice weekly dosing, or once weekly dosing.
[0292] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises a composition of Formula I in a dosing regimen administered twice weekly, once weekly, or alternate weekly.
[0293] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients, the dosing regimen of a composition of Formula I is administered twice weekly or once weekly.
[0294] In another embodiment of this aspect of the invention, the dosing regimen of a composition of Formula I is administered only twice weekly.
[0295] Another embodiment of this aspect of the invention relates to the method of increasing overall survival in breast cancer patients which comprises administering a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment in combination with one or more agents taken from an anti-tubulin agent, a DNA alkylating agent, a DNA synthesis-inhibiting agent, a DNA intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor, an anti-angiogenic agent, or an immunomodulating agent.
[0296] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with paclitaxel.
[0297] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with paclitaxel protein-bound particles for injectable suspension.
[0298] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with docetaxel.
[0299] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with eribulin.
[0300] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with ixabepilone.
[0301] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with vinorelbine.
[0302] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with capecitabine.
[0303] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with gemcitabine.
[0304] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with 5-fluorouracil.
[0305] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with methotrexate.
[0306] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with cyclophosphamide.
[0307] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with cisplatin.
[0308] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with carboplatin.
[0309] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises administering of a composition of Formula I
in combination with doxorubicin.
in combination with doxorubicin.
[0310] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises administering of a composition of Formula I
in combination with pegylated liposomal doxorubicin.
in combination with pegylated liposomal doxorubicin.
[0311] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises administering of a composition of Formula I
in combination with epirubicin.
in combination with epirubicin.
[0312] In yet another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with tamoxifen.
[0313] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with fulvestrant.
[0314] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with anastrozole.
[0315] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with letrozole.
[0316] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with exemestane.
[0317] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with trastuzumab.
[0318] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with ado-trastuzumab emtansine.
[0319] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with pertuzumab.
[0320] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with lapatinib.
[0321] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with everolimus.
[0322] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with temsirolimus.
[0323] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LY2835219.
[0324] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LEE011.
[0325] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor PD 0332991.
[0326] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with bevacizumab.
[0327] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with an anti-CTLA-4 agent.
[0328] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with ipilimumab.
[0329] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with an anti-PD-1 agent.
[0330] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with lambrolizumab.
[0331] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with an anti- anti-PD L-1 agent.
In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I
in combination with MPDL3280A.
Methods for increasing overall survival in breast cancer patients:
In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I
in combination with MPDL3280A.
Methods for increasing overall survival in breast cancer patients:
[0332] In another aspect of the invention, a method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, wherein a dosing regimen of the composition of Formula I is intermittent non-daily dosing administration, including alternate daily dosing, every third daily dosing, twice weekly dosing, or once weekly dosing.
[0333] In one embodiment of this aspect of the invention, a method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, wherein a dosing regimen of the composition of Formula I is twice weekly, once weekly, or alternate weekly, administration.
[0334] In another embodiment of this aspect of the invention, a method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, wherein a dosing regimen of the composition of Formula I is twice weekly or once weekly administration.
[0335] In another embodiment of this aspect of the invention, a method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, with a dosing regimen of the composition of Formula I is twice weekly administration.
[0336] In another embodiment of this aspect of the invention, a method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment administered in combination with one or more agents taken from an anti-tubulin agent, a DNA
alkylating agent, a DNA synthesis-inhibiting agent, a DNA intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor, an anti-angiogenic agent, or an immunomodulating agent.
alkylating agent, a DNA synthesis-inhibiting agent, a DNA intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor, an anti-angiogenic agent, or an immunomodulating agent.
[0337] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients administering a composition of Formula I in combination with paclitaxel.
[0338] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with paclitaxel protein-bound particles for injectable suspension.
[0339] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with docetaxel.
[0340] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with eribulin.
[0341] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with ixabepilone.
[0342] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with vinorelbine.
[0343] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with capecitabine.
[0344] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with gemcitabine.
[0345] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with 5-fluorouracil.
[0346] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with methotrexate.
[0347] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with cyclophosphamide.
[0348] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with cisplatin.
[0349] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with carboplatin.
[0350] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises administering of a composition of Formula I
in combination with doxorubicin.
in combination with doxorubicin.
[0351] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises administering of a composition of Formula I
in combination with pegylated liposomal doxorubicin.
in combination with pegylated liposomal doxorubicin.
[0352] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises administering of a composition of Formula I
in combination with epirubicin.
in combination with epirubicin.
[0353] In yet another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with tamoxifen.
[0354] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with fulvestrant.
[0355] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with anastrozole.
[0356] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with letrozole.
[0357] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with exemestane.
[0358] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with trastuzumab.
[0359] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with ado-trastuzumab emtansine.
[0360] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with pertuzumab.
[0361] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with lapatinib.
[0362] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with everolimus.
[0363] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with temsirolimus.
[0364] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LY2835219.
[0365] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LEE011.
[0366] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor PD 0332991.
[0367] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with bevacizumab.
[0368] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with an anti-CTLA-4 agent.
[0369] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with ipilimumab.
[0370] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with an anti-PD-1 agent.
[0371] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with lambrolizumab.
[0372] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with an anti- anti-PD L-1 agent.
[0373] In another embodiment of this aspect of the invention, the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with MPDL3280A.
Methods for treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor:
Methods for treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor:
[0374] Another aspect of the invention relates to a method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor, comprising administering to a patient in need thereof and effective amount of a composition of Formula I, a dosing regimen of the composition of Formula I is sufficient to block TIE2 kinase in the tumor microenvironment.
[0375] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment.
[0376] In another embodiment of this aspect of the invention, a method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, with a dosing regimen of the composition of Formula I being administered daily.
[0377] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment, with a dosing regimen of the composition of Formula I administered in an intermittent non-daily manner, including alternate daily dosing, every third daily dosing, twice weekly dosing, or once weekly dosing.
[0378] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen administered twice weekly, once weekly, or alternate weekly.
[0379] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection comprises the administration of a composition of Formula I in a dosing regimen administered twice weekly or once weekly.
[0380] In another embodiment of this aspect of the invention, the dosing regimen of a composition of Formula I is administered twice weekly.
[0381] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection comprises the administration of a composition of Formula I in dosing regimen sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages in combination with one or more agents taken from an anti-tubulin agent, a DNA alkylating agent, a DNA synthesis-inhibiting agent, a DNA
intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor, an anti-angiogenic agent, or an immunomodulating agent.
intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor, an anti-angiogenic agent, or an immunomodulating agent.
[0382] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with paclitaxel.
[0383] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with paclitaxel protein-bound particles for injectable suspension.
[0384] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with docetaxel.
[0385] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with eribulin.
[0386] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with ixabepilone.
[0387] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with vinorelbine.
[0388] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with capecitabine.
[0389] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with gemcitabine.
[0390] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with 5-fluorouracil.
[0391] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with methotrexate.
[0392] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with cyclophosphamide.
[0393] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with cisplatin.
[0394] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with carboplatin.
[0395] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering of a composition of Formula I in combination with doxorubicin.
[0396] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering of a composition of Formula I in combination with pegylated liposomal doxorubicin.
[0397] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering of a composition of Formula I in combination with epirubicin.
[0398] In yet another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with tamoxifen.
[0399] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with fulvestrant.
[0400] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with anastrozole.
[0401] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with letrozole.
[0402] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with exemestane.
[0403] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with trastuzumab.
[0404] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with ado-trastuzumab emtansine.
[0405] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with pertuzumab.
[0406] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with lapatinib.
[0407] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with everolimus.
[0408] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with temsirolimus.
[0409] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LY2835219.
[0410] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LEE011.
[0411] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor PD 0332991.
[0412] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with bevacizumab.
[0413] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with an anti-CTLA-4 agent.
[0414] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with ipilimumab.
[0415] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with an anti-PD-1 agent.
[0416] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with lambrolizumab.
[0417] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with an anti- anti-PD
L-1 agent.
L-1 agent.
[0418] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with MPDL3280A.
Methods for treating breast cancer patients in a neoadjuvant setting prior to surgical resection:
Methods for treating breast cancer patients in a neoadjuvant setting prior to surgical resection:
[0419] In another aspect of the invention, a method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, with a dosing regimen of the composition of Formula I administered as intermittent non-daily dosing, including alternate daily dosing, every third daily dosing, twice weekly dosing, or once weekly dosing.
[0420] In one embodiment of this aspect of the invention, a method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, with a dosing regimen of the composition of Formula I
administered twice weekly, once weekly, or alternate weekly.
administered twice weekly, once weekly, or alternate weekly.
[0421] In another embodiment of this aspect of the invention, a method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, with a dosing regimen of the composition of Formula I
administered twice weekly or once weekly.
administered twice weekly or once weekly.
[0422] In another embodiment of this aspect of the invention, a method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, with a dosing regimen of the composition of Formula I
administered twice weekly.
administered twice weekly.
[0423] In another embodiment of this aspect of the invention, a method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment administered in combination with one or more
[0424] agents taken from an anti-tubulin agent, a DNA alkylating agent, a DNA synthesis-inhibiting agent, a DNA intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor, an anti-angiogenic agent, or an immunomodulating agent.
[0425] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with paclitaxel.
[0426] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with paclitaxel protein-bound particles for injectable suspension.
[0427] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with docetaxel.
[0428] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with eribulin.
[0429] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with ixabepilone.
[0430] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with vinorelbine.
[0431] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with capecitabine.
[0432] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with gemcitabine.
[0433] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with 5-fluorouracil.
[0434] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with 5-methotrexate.
[0435] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with cyclophosphamide.
[0436] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with cisplatin.
[0437] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with carboplatin.
[0438] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering of a composition of Formula I in combination with doxorubicin.
[0439] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering of a composition of Formula I in combination with pegylated liposomal doxorubicin.
[0440] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering of a composition of Formula I in combination with epirubicin.
[0441] In yet another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with tamoxifen.
[0442] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with fulvestrant.
[0443] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with anastrozole.
[0444] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with letrozole.
[0445] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with exemestane.
[0446] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with trastuzumab.
[0447] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with ado-trastuzumab emtansine.
[0448] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with pertuzumab.
[0449] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with lapatinib.
[0450] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with everolimus.
[0451] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with temsirolimus.
[0452] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LY2835219.
[0453] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LEE011.
[0454] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor PD 0332991.
[0455] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with bevacizumab.
[0456] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with an anti-CTLA-4 agent.
[0457] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with ipilimumab.
[0458] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with an anti-PD-1 agent.
[0459] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with lambrolizumab.
[0460] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with an anti- anti-PD
L-1 agent.
L-1 agent.
[0461] In another embodiment of this aspect of the invention, the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with MPDL3280A.
[0462] Another aspect of the invention relates to a method of treating ovarian cancer as TIE2 pathway signaling has been shown to contribute to ovarian cancer progression (Karlan et al, J.
Clinical Oncology (2012) 30: 362-370). The method comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment.In one embodiment of this aspect of the invention, a composition of Formula I is administered as a single agent.
Clinical Oncology (2012) 30: 362-370). The method comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment.In one embodiment of this aspect of the invention, a composition of Formula I is administered as a single agent.
[0463] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with paclitaxel + carboplatin, doxetaxel +
carboplatin, paclitaxel +
cisplatin, or other taxane + platinum drug regimens.
carboplatin, paclitaxel +
cisplatin, or other taxane + platinum drug regimens.
[0464] Another aspect of the invention relates to a method of treating hepatocellular carcinoma as TIE2 pathway signaling has been shown to contribute to hepatocellular cancer progression and as a diagnostic marker (Matsubara et al, Hepatology (2013) 57:
1416-1425;
Mitsuhashi et al, Hepatology (2003) 37: 1105-1113; Tanaka et al, J. Clin Invest (1999) 103: 341-345). The method comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor mi cro environment .
1416-1425;
Mitsuhashi et al, Hepatology (2003) 37: 1105-1113; Tanaka et al, J. Clin Invest (1999) 103: 341-345). The method comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor mi cro environment .
[0465] In one embodiment of this aspect of the invention, a composition of Formula I is administered as a single agent.
[0466] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with a kinase inhibitor including sorafenib, crizotinib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, or axitinib.
[0467] Another aspect of the invention relates to a method of treating glioma as TIE2 pathway signaling has been shown to contribute to glioma cancer progression (Liu et al, Oncotarget (2010) 1: 700-709; Brunckhorst et al, Cancer Research (2010) 70:
7283-7293). The method comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor mi cro environment .
7283-7293). The method comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor mi cro environment .
[0468] In one embodiment of this aspect of the invention, a composition of Formula I is administered as a single agent.
[0469] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with radiotherapy.
[0470] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with temozolomide therapy.
[0471] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with radiotherapy and temozolomide therapy.
[0472] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with bevacizumab therapy.
[0473] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with radiotherapy and bevacizumab therapy.
[0474] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with temozolomide therapy and bevacizumab therapy.
[0475] Another aspect of the invention relates to a method of treating melanoma as TIE2 pathway signaling has been shown to contribute to melanoma progression (Helfrich et al, Clin Cancer Res (2009) 15: 1384-1392; Peinado et al, Nature Medicine (2012) 18: 883-891). The method comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor mi cro environment .
[0476] In one embodiment of this aspect of the invention, a composition of Formula I is administered as a single agent.
[0477] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with vemurafenib.
[0478] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with dabrafenib.
[0479] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with dabrafenib and trametinib.
[0480] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with temozolomide.
[0481] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with dacarbazine.
[0482] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with ipilimumab.
[0483] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with labrolizumab or nivolumab.
[0484] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with MPDL3280A.
[0485] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with imatinib.
[0486] Another aspect of the invention relates to a method of treating colorectal cancer as TIE2 pathway signaling has been shown to contribute to colorectal cancer progression (Ahmad et al, Cancer (2001) 92: 1138-1143; Hashizume et al, Cancer Research (2010) 70: 2213-2223).
The method comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor mi cro environment .
The method comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor mi cro environment .
[0487] In one embodiment of this aspect of the invention, a composition of Formula I is administered as a single agent.
[0488] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with mFOLFOX6 therapy (oxaplatin + leucovorin + 5-fluorouracil).
[0489] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with mFOLFOX6 therapy and bevacizumab.
[0490] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with mFOLFOX6 therapy and panitumumab.
[0491] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with mFOLFOX6 therapy and cetuximab.
[0492] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with capecitabine.
[0493] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with capecitabine and bevacizumab.
[0494] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with FOLFIRI therapy (irinotecan + leucovorin + 5-fluorouracil).
[0495] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with FOLFIRI therapy and bevacizumab.
[0496] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with FOLFIRI therapy and aflibercept.
[0497] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with FOLFIRI therapy and cetuximab.
[0498] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with FOLFIRI therapy and panitumumab.
[0499] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with panitumumab.
[0500] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with panitumumab and irinotecan.
[0501] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with cetuximab.
[0502] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with cetuximab and irinotecan.
[0503] Another aspect of the invention relates to a method of treating acute myeloid leukemia as TIE2 pathway signaling has been shown to contribute to acute myeloid leukemia progression (Muller et al, Leukemia Research (2002) 26: 163-168; Hou et al, Leukemia Research (2008) 32: 904-912). The method comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment.
[0504] In one embodiment of this aspect of the invention, a composition of Formula I is administered as a single agent.
[0505] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with daunorubicin and cytarabine.
[0506] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with idarubicin and cytarabine.
[0507] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with mitoxantrone and cytarabine.
[0508] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with cytarabine.
[0509] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with 5-azacytabine.
[0510] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with decitabine.
[0511] In another embodiment of this aspect of the invention, a composition of Formula I is administered in combination with quizartinib.
[0512] Another aspect of the invention relates to a method of treating cancer. The method comprises administering an effective amount of a composition of Formula I to a patient in need thereof. In one embodiment the patient overexpresses Tunica interna endothelial cell kinase 2 (TIE2) and the cancer is selected from breast cancer, colorectal cancer, hepatocellular carcinoma, head and neck cancer, bladder cancer, ovarian cancer, gliomas, angiosarcomas, melanomas, or acute myeloid leukemia.
[0513] In certain embodiments of the invention of the treatment regimen, the composition of Formula I is administered at a frequency of daily.
[0514] In other embodiments of the invention of the treatment regimen, the composition of Formula I is administered at a frequency of non-daily intermittent.
[0515] In other embodiments of the invention of the treatment regimen, the composition of Formula I is administered at a frequency of three times weekly.
[0516] In other embodiments of the invention of the treatment regimen, the composition of Formula I is administered at a frequency of two times weekly.
[0517] In other embodiments of the invention of the treatment regimen, the composition of Formula I is administered at a frequency of one time weekly.
[0518] In other embodiments of the invention of the treatment regimen, the composition of Formula I is administered at a frequency of one time every two weeks.
[0519] In other embodiments the cancer is metastatic, triple negative breast cancer (estrogen receptor negative, progesterone receptor negative, HER2 negative).
[0520] In other embodiments the cancer is estrogen positive (ER) and HER2 receptor kinase negative (HER2-) breast cancer.
[0521] In other embodiments the cancer is inflammatory breast cancer.
[0522] In another embodiment, the method comprises the treatment of preventing or reducing one or more of primary tumor growth, tumor invasiveness, cancer intravasation, cancer dissemination, metastasis, and tumor immunotolerance. In certain embodiments the method increases patient survival rates.
Formulations, Administration, Dosing, and Treatment Regimens
Formulations, Administration, Dosing, and Treatment Regimens
[0523] The present invention includes the described salts of Formulae I
and/or II (and/or additional agents) in various formulations. Any composition (and/or additional agents) described herein can take the form of solutions, suspensions, emulsion, drops, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
In one embodiment, the composition is in the form of a capsule (see, e.g., U.S. Patent No.
5,698,155). Other examples of suitable pharmaceutical excipients are described in Remington 's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed. 1995), incorporated herein by reference.
and/or II (and/or additional agents) in various formulations. Any composition (and/or additional agents) described herein can take the form of solutions, suspensions, emulsion, drops, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
In one embodiment, the composition is in the form of a capsule (see, e.g., U.S. Patent No.
5,698,155). Other examples of suitable pharmaceutical excipients are described in Remington 's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed. 1995), incorporated herein by reference.
[0524] Where necessary, the salts herein described can also include a solubilizing agent.
Also, the agents can be delivered with a suitable vehicle or delivery device as known in the art.
Combination therapies outlined herein can be co-delivered in a single delivery vehicle or delivery device. Compositions for administration can optionally include a local anesthetic such as, for example, lignocaine to lessen pain at the site of the injection.
Also, the agents can be delivered with a suitable vehicle or delivery device as known in the art.
Combination therapies outlined herein can be co-delivered in a single delivery vehicle or delivery device. Compositions for administration can optionally include a local anesthetic such as, for example, lignocaine to lessen pain at the site of the injection.
[0525] In one embodiment, the salts of Formulae I and/or II (and/or additional agents) described herein is formulated in accordance with routine procedures as a composition adapted for a mode of administration.
[0526] In certain embodiments, routes of administration include, for example: intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectally, by inhalation, or topically, particularly to the ears, nose, eyes, or skin. In some embodiments, the administering is effected orally or by parenteral injection. The mode of administration can be left to the discretion of the practitioner, and depend in-part upon the site of the medical condition. In most instances, administration results in the release of any agent described herein into the bloodstream.
[0527] In specific embodiments, it may be desirable to administer locally to the area in need of treatment or blocking.
[0528] In one embodiment, the salts (and/or additional agents) described herein is formulated in accordance with routine procedures as a composition adapted for oral administration to humans. Compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example. Orally administered compositions can comprise one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. Moreover, where in tablet or pill form, the compositions can be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically active driving the salt of Formula I or II (and/or additional agents) described herein are also suitable for orally administered compositions. In these latter platforms, fluid from the environment surrounding the capsule is imbibed by the driving composition, which swells to displace the agent or agent composition through an aperture. These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations. A time-delay material such as glycerol monostearate or glycerol stearate can also be useful. Oral compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment, the excipients are of pharmaceutical grade. Suspensions, in addition to the active compositions, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, etc., and mixtures thereof.
[0529] Dosage forms suitable for parenteral administration (e.g.
intravenous, intramuscular, intraperitoneal, subcutaneous and intra-articular injection and infusion) include, for example, solutions, suspensions, dispersions, emulsions, and the like. They may also be manufactured in the form of sterile solid compositions (e.g. lyophilized composition), which can be dissolved or suspended in sterile injectable medium immediately before use. They may contain, for example, suspending or dispersing agents known in the art.
intravenous, intramuscular, intraperitoneal, subcutaneous and intra-articular injection and infusion) include, for example, solutions, suspensions, dispersions, emulsions, and the like. They may also be manufactured in the form of sterile solid compositions (e.g. lyophilized composition), which can be dissolved or suspended in sterile injectable medium immediately before use. They may contain, for example, suspending or dispersing agents known in the art.
[0530] The dosage of the salt of Formulae I and/or II (and/or additional agents) described herein as well as the dosing schedule can depend on various parameters, including, but not limited to, the disease being treated, the subject's general health, and the administering physician's discretion. Any agent described herein, can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of an additional therapeutic agent, to a subject in need thereof. In various embodiments any agent described herein is administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, or 11 hours to 12 hours apart.
[0531] The dosage of the salt of Formula I or II (and/or additional agents) described herein can depend on several factors including the severity of the condition, whether the condition is to be treated or prevented, and the age, weight, and health of the subject to be treated. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of a therapeutic) information about a particular subject may affect dosage used.
Furthermore, the exact individual dosages can be adjusted somewhat depending on a variety of factors, including the specific combination of the agents being administered, the time of administration, the route of administration, the nature of the formulation, the rate of excretion, the particular disease being treated, the severity of the disorder, and the anatomical location of the disorder. Some variations in the dosage can be expected.
Furthermore, the exact individual dosages can be adjusted somewhat depending on a variety of factors, including the specific combination of the agents being administered, the time of administration, the route of administration, the nature of the formulation, the rate of excretion, the particular disease being treated, the severity of the disorder, and the anatomical location of the disorder. Some variations in the dosage can be expected.
[0532] Generally, when orally administered to a mammal, the dosage of any composition of Formula I (and/or additional agents) described herein may be 0.001 mg/kg/day to 100 mg/kg/day, 0.01 mg/kg/day to 50 mg/kg/day, or 0.1 mg/kg/day to 10 mg/kg/day.
When orally administered to a human, the dosage of any agent described herein is normally 0.001 mg to 1500 mg per day, 1 mg to 600 mg per day, or 5 mg to 30 mg per day. In some embodiments, the dosage of the salt (or agent) ranges from 57 mg to 1200 mg per day. In other embodiments, the dosage of the agents or salt ranges from 100 mg to 200 mg per day.
When orally administered to a human, the dosage of any agent described herein is normally 0.001 mg to 1500 mg per day, 1 mg to 600 mg per day, or 5 mg to 30 mg per day. In some embodiments, the dosage of the salt (or agent) ranges from 57 mg to 1200 mg per day. In other embodiments, the dosage of the agents or salt ranges from 100 mg to 200 mg per day.
[0533] For administration of the salts of Formulae I or II (and/or additional agents) described herein by parenteral injection, the dosage is normally 0.1 mg to 250 mg per day, 1 mg to 20 mg per day, or 3 mg to 5 mg per day. Injections may be given up to four times daily. Generally, when orally or parenterally administered, the dosage of any agent described herein is normally 0.1 mg to 1500 mg per day, or 0.5 mg to 10 mg per day, or 0.5 mg to 5 mg per day. A dosage of up to 3000 mg per day can be administered.
[0534] Administration of the salts (and/or additional agents) described herein can, independently, be one to four times daily. Specifically, administration of the salt can be once a day at a dosing regimen of the salt is from about 50 mg to 1500 mg. Suitable daily dosage for the prophylactic effects sought is 57-1200 mg/day. If administered twice daily, a suitable dosage is 100 mg to 200mg of the salt. Administration of the salt may also be intermittently non-daily.
In particular, administration of the salt may be done one to four times per month or one to six times per year or once every two, three, four or five years. In certain embodiments administration of the salt is done weekly or bi-weekly. When administered weekly or bi-weekly, a suitable salt dosing regimen ranges from 50-200 mg/ per administration. In certain weekly or bi-weekly administrations, dosage is 200-400 mg/ per administration. Yet other mode of weekly or bi-weekly administration include 400-500 mg/ per administration, 500-600 mg/ per administration, 600-700 mg/ per administration, 700-800 mg/ per administration, 800-900 mg/
per administration, 900-1000 mg/ per administration, 1000-1100 mg/ per administration, or 1100-1200 mg/ per administration. Administration can be for the duration of one day or one month, two months, three months, six months, one year, two years, three years, and may even be for the life of the subject. Chronic, long-term administration will be indicated in many cases.
The dosage may be administered as a single dose or divided into multiple doses. In general, the desired dosage should be administered at set intervals for a prolonged period, usually at least over several weeks or months, although longer periods of administration of several months or years or more may be needed.
Examples Example 1. Biochemical inhibition of unphosphorylated TIE2 (uTIE2) by 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea Biochemical assay for uTIE2 (Seq. ID No. 1)
In particular, administration of the salt may be done one to four times per month or one to six times per year or once every two, three, four or five years. In certain embodiments administration of the salt is done weekly or bi-weekly. When administered weekly or bi-weekly, a suitable salt dosing regimen ranges from 50-200 mg/ per administration. In certain weekly or bi-weekly administrations, dosage is 200-400 mg/ per administration. Yet other mode of weekly or bi-weekly administration include 400-500 mg/ per administration, 500-600 mg/ per administration, 600-700 mg/ per administration, 700-800 mg/ per administration, 800-900 mg/
per administration, 900-1000 mg/ per administration, 1000-1100 mg/ per administration, or 1100-1200 mg/ per administration. Administration can be for the duration of one day or one month, two months, three months, six months, one year, two years, three years, and may even be for the life of the subject. Chronic, long-term administration will be indicated in many cases.
The dosage may be administered as a single dose or divided into multiple doses. In general, the desired dosage should be administered at set intervals for a prolonged period, usually at least over several weeks or months, although longer periods of administration of several months or years or more may be needed.
Examples Example 1. Biochemical inhibition of unphosphorylated TIE2 (uTIE2) by 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea Biochemical assay for uTIE2 (Seq. ID No. 1)
[0535] Activity of uTIE2 kinase was determined by following the production of ADP from the kinase reaction through coupling with the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler et al. Science (2000) 289: 1938-1942). In this assay, the oxidation of NADH
(thus the decrease at A340nm) was continuously monitored spectrophotometrically. The reaction mixture (100 L) contained TIE2 (SignalChem) (5.6 nM), BSA (0.004% (w/v)), polyEY (1.5 mg/ml), MgC12 (15 mM), DTT (0.5 mM), pyruvate kinase (4 units), lactate dehydrogenase (7 units), phosphoenol pyruvate (1 mM), and NADH (0.28 mM) and ATP (1.5 mM) in 90 mM Tris buffer containing 0.2% octyl-glucoside and 1% DMSO, pH 7.5. The inhibition reaction was started by mixing serial diluted test composition with the above reaction mixture. The absorption at 340 nm was monitored continuously for 6 hours at 30 C on a plate reader (BioTek). The reaction rate was calculated using the 5 to 6 h time frame.
Percent inhibition was obtained by comparison of reaction rate with that of a control (i.e. with no test composition). IC50 values were calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using software routines as implemented in the GraphPad Prism software package. The composition 1 -(3-tert-buty1-1 -(quinolin-6-y1)- 1H-pyrazol-5-y1)-3 -(2 -fluoro-4-(2 -(methylcarbamoyOpyridin-4-yloxy)phenyOurea para-toluene sulfonic acid salt (compound 1 as described in figures) exhibited an IC50 value of 3.5 nM.
uTIE2 protein sequence used for screening (Seq. ID No. 1) QLKRANVQRRMAQAFQNVREEPAVQFNSGTLALNRKVKNNPDPTIYPVLDWNDIKFQ
DVIGEGNFGQVLKARIKKDGLRMDAAIKRMKEYASKDDHRDFAGELEVLCKLGHHPNI
INLLGACEHRGYLYLAIEYAPHGNLLDFLRKSRVLETDPAFAIANSTASTLSSQQLLHFA
ADVARGMDYLSQKQFIHRDLAARNILVGENYVAKIADFGLSRGQEVYVKKTMGRLPV
RWMAIESLNYSVYTTNSDVWSYGVLLWEIVSLGGTPYCGMTCAELYEKLPQGYRLEKP
LNCDDEVYDLMRQCWREKPYERPSFAQILVSLNRMLEERKTYVNTTLYEKFTYAGIDC
SAEEAA
Example 2. Biochemical inhibition of phosphorylated TIE2 (pTIE2) by 1-(3-tert-butyl-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea Biochemical assay for pTIE2 (Seq. ID No. 2)
(thus the decrease at A340nm) was continuously monitored spectrophotometrically. The reaction mixture (100 L) contained TIE2 (SignalChem) (5.6 nM), BSA (0.004% (w/v)), polyEY (1.5 mg/ml), MgC12 (15 mM), DTT (0.5 mM), pyruvate kinase (4 units), lactate dehydrogenase (7 units), phosphoenol pyruvate (1 mM), and NADH (0.28 mM) and ATP (1.5 mM) in 90 mM Tris buffer containing 0.2% octyl-glucoside and 1% DMSO, pH 7.5. The inhibition reaction was started by mixing serial diluted test composition with the above reaction mixture. The absorption at 340 nm was monitored continuously for 6 hours at 30 C on a plate reader (BioTek). The reaction rate was calculated using the 5 to 6 h time frame.
Percent inhibition was obtained by comparison of reaction rate with that of a control (i.e. with no test composition). IC50 values were calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using software routines as implemented in the GraphPad Prism software package. The composition 1 -(3-tert-buty1-1 -(quinolin-6-y1)- 1H-pyrazol-5-y1)-3 -(2 -fluoro-4-(2 -(methylcarbamoyOpyridin-4-yloxy)phenyOurea para-toluene sulfonic acid salt (compound 1 as described in figures) exhibited an IC50 value of 3.5 nM.
uTIE2 protein sequence used for screening (Seq. ID No. 1) QLKRANVQRRMAQAFQNVREEPAVQFNSGTLALNRKVKNNPDPTIYPVLDWNDIKFQ
DVIGEGNFGQVLKARIKKDGLRMDAAIKRMKEYASKDDHRDFAGELEVLCKLGHHPNI
INLLGACEHRGYLYLAIEYAPHGNLLDFLRKSRVLETDPAFAIANSTASTLSSQQLLHFA
ADVARGMDYLSQKQFIHRDLAARNILVGENYVAKIADFGLSRGQEVYVKKTMGRLPV
RWMAIESLNYSVYTTNSDVWSYGVLLWEIVSLGGTPYCGMTCAELYEKLPQGYRLEKP
LNCDDEVYDLMRQCWREKPYERPSFAQILVSLNRMLEERKTYVNTTLYEKFTYAGIDC
SAEEAA
Example 2. Biochemical inhibition of phosphorylated TIE2 (pTIE2) by 1-(3-tert-butyl-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea Biochemical assay for pTIE2 (Seq. ID No. 2)
[0536] Activity of pTIE2 kinase was determined by following the production of ADP from the kinase reaction through coupling with the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler et al. Science (2000) 289: 1938-1942). In this assay, the oxidation of NADH
(thus the decrease at A340nm) was continuously monitored spectrophotometrically. The reaction mixture (100 L) contained TIE2 (Life Technologies) (6 nM), BSA (0.004%
(w/v)), polyEY (1.5 mg/ml), MgC12 (15 mM), DTT (0.5 mM), pyruvate kinase (4 units), lactate dehydrogenase (7 units), phosphoenol pyruvate (1 mM), and NADH (0.28 mM) and ATP (1.5 mM) in 90 mM Tris buffer containing 0.2% octyl-glucoside and 1% DMSO, pH 7.5. The inhibition reaction was started by mixing serial diluted test composition with the above reaction mixture. The absorption at 340 nm was monitored continuously for 6 hours at 30 C on a plate reader (BioTek). The reaction rate was calculated using the 2 to 3 h time frame.
Percent inhibition was obtained by comparison of reaction rate with that of a control (i.e. with no test composition). IC50 values were calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using software routines as implemented in the GraphPad Prism software package. When tested the compositions 1 -(3 -tert-butyl- 1 -(quino lin-6 -y1)-1 H-pyrazo 1-5 -y1)-3 -(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea para-toluene sulfonic acid salt and 1-(3 -tert-butyl- 1 -(quino lin- 6-y1)- 1 H-pyrazol-5 -y1)-3 -(2 -fluoro- 4-(2 -(methylc arb amoyOpyri din-4-yloxy)phenyOurea bis-hydrochloric acid salt exhibited >50% inhibition of pTIE2 kinase at <0.1 iuM concentration. 1 -(3 -tert-butyl- 1 -(quinolin-6-y1)- 1 H-pyrazo 1-5 -y1)-3 -(2- fluoro- 4-(2 -(methylcarbamoyOpyridin-4-yloxy)phenyOurea para-toluene sulfonic acid salt exhibited an IC50 value of 4.2 nM. 1 -(3 -tert-butyl- 1 -(quinolin-6-y1)- 1 H-pyrazo 1-5 -y1)-3 -(2 -fluor -4- (2-(methylcarbamoyOpyridin-4-yloxy)phenyOurea bis-hydrochloric acid salt exhibited an IC50 value of 2.2 nM.
pTIE2 protein sequence used for screening (Seq. ID No. 2) PVLDWNDIKFQDVIGEGNFGQVLKARIKKDGLRMDAAIKRMKEYASKDDHRDFAGELE
VLCKLGHHPNIINLLGACEHRGYLYLAIEYAPHGNLLDFLRKSRVLETDPAFAIANSTAS
TLS S Q QLLHFAADVARGMDYL S QKQFIHRDLAARNILVGENYVAKIADF GL S RGQ EVY
VKKTMGRLPVRWMAIESLNYSVYTTNSDVWSYGVLLWEIVSLGGTPYCGMTCAELYE
KLPQGYRLEKPLNCDDEVYDLMRQCWREKPYERP SFAQILVSLNRMLEERKT
Example 3. Cellular inhibition of TIE2 in CHO cells by 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-flu oro-4-(2-(methylc arb amoyl)pyridin-4-yloxy)p he nyl)u re a CHO-K1 Cell Culture
(thus the decrease at A340nm) was continuously monitored spectrophotometrically. The reaction mixture (100 L) contained TIE2 (Life Technologies) (6 nM), BSA (0.004%
(w/v)), polyEY (1.5 mg/ml), MgC12 (15 mM), DTT (0.5 mM), pyruvate kinase (4 units), lactate dehydrogenase (7 units), phosphoenol pyruvate (1 mM), and NADH (0.28 mM) and ATP (1.5 mM) in 90 mM Tris buffer containing 0.2% octyl-glucoside and 1% DMSO, pH 7.5. The inhibition reaction was started by mixing serial diluted test composition with the above reaction mixture. The absorption at 340 nm was monitored continuously for 6 hours at 30 C on a plate reader (BioTek). The reaction rate was calculated using the 2 to 3 h time frame.
Percent inhibition was obtained by comparison of reaction rate with that of a control (i.e. with no test composition). IC50 values were calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using software routines as implemented in the GraphPad Prism software package. When tested the compositions 1 -(3 -tert-butyl- 1 -(quino lin-6 -y1)-1 H-pyrazo 1-5 -y1)-3 -(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea para-toluene sulfonic acid salt and 1-(3 -tert-butyl- 1 -(quino lin- 6-y1)- 1 H-pyrazol-5 -y1)-3 -(2 -fluoro- 4-(2 -(methylc arb amoyOpyri din-4-yloxy)phenyOurea bis-hydrochloric acid salt exhibited >50% inhibition of pTIE2 kinase at <0.1 iuM concentration. 1 -(3 -tert-butyl- 1 -(quinolin-6-y1)- 1 H-pyrazo 1-5 -y1)-3 -(2- fluoro- 4-(2 -(methylcarbamoyOpyridin-4-yloxy)phenyOurea para-toluene sulfonic acid salt exhibited an IC50 value of 4.2 nM. 1 -(3 -tert-butyl- 1 -(quinolin-6-y1)- 1 H-pyrazo 1-5 -y1)-3 -(2 -fluor -4- (2-(methylcarbamoyOpyridin-4-yloxy)phenyOurea bis-hydrochloric acid salt exhibited an IC50 value of 2.2 nM.
pTIE2 protein sequence used for screening (Seq. ID No. 2) PVLDWNDIKFQDVIGEGNFGQVLKARIKKDGLRMDAAIKRMKEYASKDDHRDFAGELE
VLCKLGHHPNIINLLGACEHRGYLYLAIEYAPHGNLLDFLRKSRVLETDPAFAIANSTAS
TLS S Q QLLHFAADVARGMDYL S QKQFIHRDLAARNILVGENYVAKIADF GL S RGQ EVY
VKKTMGRLPVRWMAIESLNYSVYTTNSDVWSYGVLLWEIVSLGGTPYCGMTCAELYE
KLPQGYRLEKPLNCDDEVYDLMRQCWREKPYERP SFAQILVSLNRMLEERKT
Example 3. Cellular inhibition of TIE2 in CHO cells by 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-flu oro-4-(2-(methylc arb amoyl)pyridin-4-yloxy)p he nyl)u re a CHO-K1 Cell Culture
[0537] CHO-K1 cells (catalog #CCL-61) were obtained from the American Type Culture Collection (ATCC, Manassas, VA). Briefly, cells were grown in F 12K medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units/mL penicillin G, 100 lag/m1 streptomycin, and 0.29 mg/mL L-glutamine (Invitrogen, Carlsbad, CA) at 37 degrees Celsius, 5% CO2, and 95% humidity. Cells were allowed to expand until reaching 70-95% confluence at which point they were subcultured or harvested for assay use.
TIE2-transfected CHO K1 Phospho-TIE2 Western Blot Assay
TIE2-transfected CHO K1 Phospho-TIE2 Western Blot Assay
[0538] CHO K1 cells (1 x 105 cells/well) were added to a 24-well tissue-culture treated plate in 1 mL of RPMI1640 medium supplemented with 10% characterized fetal bovine serum and 1X
non-essential amino acids (Invitrogen, Carlsbad, CA). Cells were then incubated overnight at 37 degrees Celsius, 5% CO2, and 95% humidity. Medium was aspirated, and 0.5 mL of medium was added to each well. Transfection-grade plasmid DNA (TIE2 gene Gateway cloned into pcDNA3.2Tm/V5-DEST expression vector, Invitrogen, Carlsbad, CA) was diluted to 5 lag/mL in room temperature Opti-MEMO I Medium without serum (Invitrogen, Carlsbad, CA).
Two iaL of Lipofectamine LTX Reagent (Invitrogen, Carlsbad, CA) was added per 0.5 jag of plasmid DNA.
The tube was mixed gently and incubated for 25 minutes at room temperature to allow for DNA-Lipofectamine LTX complex formation. 100 iaL of the DNA-Lipofectamine LTX
complex was added directly to each well containing cells and mixed gently. Twenty-four hours post-transfection, medium containing DNA-Lipofectamine complexes was aspirated, cells were washed with PBS, and RPMI1640 medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), and 1X non-essential amino acids (Invitrogen, Carlsbad, CA) was added. Test composition (1 -(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro -4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyOurea para-toluene sulfonic acid salt) or DMSO was added to the wells (0.5% final DMSO concentration). The plates were then incubated for 4 hours at 37 degrees Celsius, 5% CO2, and 95% humidity. Following the incubation, the media was aspirated and the cells were washed with PBS. The cells were lysed using MPER
lysis buffer (Pierce, Rockford, IL) containing Halt Phosphatase and Protease Inhibitors (Pierce, Rockford, IL) and Phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO) at 4 C for 10 minutes with shaking. Cleared lysates were separated by SDS-PAGE on a 4-12% Novex NuPage Bis-Tris gel (Invitrogen, Carlsbad, CA) and then transferred to PVDF (Invitrogen, Carlsbad, CA). After transfer, the PVDF membrane was blocked with BSA (Santa Cruz Biotechnology, Santa Cruz, CA) and then probed with an antibody for phospho-TIE2 (Cell Signaling Technology, Beverly, MA). A secondary anti-rabbit antibody conjugated to horseradish peroxidase (Cell Signaling Technology, Beverly, MA) was used to detect phospho-TIE2. ECL Plus (GE
Healthcare, Piscataway, NJ), a substrate for horseradish peroxidase that generates a fluorescent product, was added. Fluorescence was detected using a Storm 840 phosphorimager (GE
Healthcare, Piscataway, NJ) in fluorescence mode. The 160 kDa phospho-TIE2 band was quantified using ImageQuant software (GE Healthcare, Piscataway, NJ). Data was analyzed using Prism software (GraphPad Software, San Diego, CA) to calculate IC50 values. The composition 1-(3-tert-butyl-1-(quino lin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro -4-(2-(methylc arb amoyl)pyri din-4-yloxy)phenyOurea para-toluene sulfonic acid salt exhibited an IC50 value of 2.0 nM.
Example 4. Cellular inhibition of TIE2 in CHO cells after inhibitor wash-out by 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea CHO-K1 Cell Culture
non-essential amino acids (Invitrogen, Carlsbad, CA). Cells were then incubated overnight at 37 degrees Celsius, 5% CO2, and 95% humidity. Medium was aspirated, and 0.5 mL of medium was added to each well. Transfection-grade plasmid DNA (TIE2 gene Gateway cloned into pcDNA3.2Tm/V5-DEST expression vector, Invitrogen, Carlsbad, CA) was diluted to 5 lag/mL in room temperature Opti-MEMO I Medium without serum (Invitrogen, Carlsbad, CA).
Two iaL of Lipofectamine LTX Reagent (Invitrogen, Carlsbad, CA) was added per 0.5 jag of plasmid DNA.
The tube was mixed gently and incubated for 25 minutes at room temperature to allow for DNA-Lipofectamine LTX complex formation. 100 iaL of the DNA-Lipofectamine LTX
complex was added directly to each well containing cells and mixed gently. Twenty-four hours post-transfection, medium containing DNA-Lipofectamine complexes was aspirated, cells were washed with PBS, and RPMI1640 medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), and 1X non-essential amino acids (Invitrogen, Carlsbad, CA) was added. Test composition (1 -(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro -4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyOurea para-toluene sulfonic acid salt) or DMSO was added to the wells (0.5% final DMSO concentration). The plates were then incubated for 4 hours at 37 degrees Celsius, 5% CO2, and 95% humidity. Following the incubation, the media was aspirated and the cells were washed with PBS. The cells were lysed using MPER
lysis buffer (Pierce, Rockford, IL) containing Halt Phosphatase and Protease Inhibitors (Pierce, Rockford, IL) and Phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO) at 4 C for 10 minutes with shaking. Cleared lysates were separated by SDS-PAGE on a 4-12% Novex NuPage Bis-Tris gel (Invitrogen, Carlsbad, CA) and then transferred to PVDF (Invitrogen, Carlsbad, CA). After transfer, the PVDF membrane was blocked with BSA (Santa Cruz Biotechnology, Santa Cruz, CA) and then probed with an antibody for phospho-TIE2 (Cell Signaling Technology, Beverly, MA). A secondary anti-rabbit antibody conjugated to horseradish peroxidase (Cell Signaling Technology, Beverly, MA) was used to detect phospho-TIE2. ECL Plus (GE
Healthcare, Piscataway, NJ), a substrate for horseradish peroxidase that generates a fluorescent product, was added. Fluorescence was detected using a Storm 840 phosphorimager (GE
Healthcare, Piscataway, NJ) in fluorescence mode. The 160 kDa phospho-TIE2 band was quantified using ImageQuant software (GE Healthcare, Piscataway, NJ). Data was analyzed using Prism software (GraphPad Software, San Diego, CA) to calculate IC50 values. The composition 1-(3-tert-butyl-1-(quino lin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro -4-(2-(methylc arb amoyl)pyri din-4-yloxy)phenyOurea para-toluene sulfonic acid salt exhibited an IC50 value of 2.0 nM.
Example 4. Cellular inhibition of TIE2 in CHO cells after inhibitor wash-out by 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea CHO-K1 Cell Culture
[0539] CHO-K1 cells (catalog #CCL-61) were obtained from the American Type Culture Collection (ATCC, Manassas, VA). Briefly, cells were grown in F 12K medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units/mL penicillin G, 100 jug/m1 streptomycin, and 0.29 mg/mL L-glutamine (Invitrogen, Carlsbad, CA) at 37 degrees Celsius, 5% CO2, and 95% humidity. Cells were allowed to expand until reaching 70-95% confluence at which point they were subcultured or harvested for assay use.
TIE2-transfected CHO K1 Phospho-TIE2 Western Blot Composition Washout Assay
TIE2-transfected CHO K1 Phospho-TIE2 Western Blot Composition Washout Assay
[0540] CHO K1 cells (1 x 105 cells/well) were added to a 24-well tissue-culture treated plate in 1 mL of RPMI1640 medium supplemented with 10% characterized fetal bovine serum and 1X
non-essential amino acids (Invitrogen, Carlsbad, CA). Cells were then incubated overnight at 37 degrees Celsius, 5% CO2, and 95% humidity. Medium was aspirated, and 0.5 mL of medium was added to each well. Transfection-grade plasmid DNA (TIE2 gene Gateway cloned into pcDNA3.2Tm/V5-DEST expression vector, Invitrogen, Carlsbad, CA) was diluted to 5 g/mL in room temperature Opti-MEMO I Medium without serum (Invitrogen, Carlsbad, CA).
Two L of Lipofectamine LTX Reagent (Invitrogen, Carlsbad, CA) was added per 0.5 ng of plasmid DNA.
The tube was mixed gently and incubated for 25 minutes at room temperature to allow for DNA-Lipofectamine LTX complex formation. 100 1._, of the DNA-Lipofectamine LTX
complex was added directly to each well containing cells and mixed gently. Approximately 18-24 hours post-transfection, medium containing DNA-Lipofectamine complexes was aspirated, cells were washed with PBS, and RPMI1640 medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), and 1X non-essential amino acids (Invitrogen, Carlsbad, CA) was added. Test composition (1 -(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro -4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyOurea para-toluene sulfonic acid salt) or DMSO was added to the wells (0.5% final DMSO concentration). The plates were then incubated for 2 hours at 37 degrees Celsius, 5% CO2, and 95% humidity. Following the incubation, the media was aspirated and the cells were washed three times with 1 mL media to wash out free composition.
Next, 1 mL fresh media was added and cells were incubated for specific times points prior to lysis (i.e., 0, 1, 2, 4, 6, and 24 hours). The cells were lysed using MPER
lysis buffer (Pierce, Rockford, IL) containing Halt Phosphatase and Protease Inhibitors (Pierce, Rockford, IL) and Phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO) at 4 C for 10 minutes with shaking.
Cleared lysates were separated by SDS-PAGE on a 4-12% Novex NuPage Bis-Tris gel (Invitrogen, Carlsbad, CA) and then transferred to PVDF (Invitrogen, Carlsbad, CA). After transfer, the PVDF membrane was blocked with BSA (Santa Cruz Biotechnology, Santa Cruz, CA) and then probed with an antibody for phospho-TIE2 (Cell Signaling Technology, Beverly, MA). A secondary anti-rabbit antibody conjugated to horseradish peroxidase (Cell Signaling Technology, Beverly, MA) was used to detect phospho-TIE2 ECL Plus (GE
Healthcare, Piscataway, NJ), a substrate for horseradish peroxidase that generates a fluorescent product, was added. Fluorescence was detected using a Storm 840 phosphorimager (GE
Healthcare, Piscataway, NJ) in fluorescence mode. PVDF membranes were stripped and then re-probed with total TIE2 antibody (Santa Cruz Biotechnology, Inc., Dallas, TX) as above. The 160 kDa phospho-TIE2 and total TIE2 bands were quantified using ImageQuant software (GE Healthcare, Piscataway, NJ). Phospho-TIE2 levels were normalized to total TIE2 levels, and data was plotted using Prism software (GraphPad Software, San Diego, CA). When incubated with transfected CHO K1 cells for 2 hours at 0.1 IVI ¨ 1 IVI prior to being washed out, Composition 1-(3-tert-buty1-1-(quino lin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylc arb amoyOpyri din-4-yloxy)phenyOurea para-toluene sulfonic acid salt disclosed herein exhibited >50% inhibition of phospho-TIE2 levels for >24 hours.
Example 5. Cellular inhibition of TIE2 in HUVEC cells by 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluo ro-4-(2-(methylc arb a moyl)pyridin-4-yloxy)p he nyl)u re a HUVEC Cell Culture
non-essential amino acids (Invitrogen, Carlsbad, CA). Cells were then incubated overnight at 37 degrees Celsius, 5% CO2, and 95% humidity. Medium was aspirated, and 0.5 mL of medium was added to each well. Transfection-grade plasmid DNA (TIE2 gene Gateway cloned into pcDNA3.2Tm/V5-DEST expression vector, Invitrogen, Carlsbad, CA) was diluted to 5 g/mL in room temperature Opti-MEMO I Medium without serum (Invitrogen, Carlsbad, CA).
Two L of Lipofectamine LTX Reagent (Invitrogen, Carlsbad, CA) was added per 0.5 ng of plasmid DNA.
The tube was mixed gently and incubated for 25 minutes at room temperature to allow for DNA-Lipofectamine LTX complex formation. 100 1._, of the DNA-Lipofectamine LTX
complex was added directly to each well containing cells and mixed gently. Approximately 18-24 hours post-transfection, medium containing DNA-Lipofectamine complexes was aspirated, cells were washed with PBS, and RPMI1640 medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), and 1X non-essential amino acids (Invitrogen, Carlsbad, CA) was added. Test composition (1 -(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro -4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyOurea para-toluene sulfonic acid salt) or DMSO was added to the wells (0.5% final DMSO concentration). The plates were then incubated for 2 hours at 37 degrees Celsius, 5% CO2, and 95% humidity. Following the incubation, the media was aspirated and the cells were washed three times with 1 mL media to wash out free composition.
Next, 1 mL fresh media was added and cells were incubated for specific times points prior to lysis (i.e., 0, 1, 2, 4, 6, and 24 hours). The cells were lysed using MPER
lysis buffer (Pierce, Rockford, IL) containing Halt Phosphatase and Protease Inhibitors (Pierce, Rockford, IL) and Phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO) at 4 C for 10 minutes with shaking.
Cleared lysates were separated by SDS-PAGE on a 4-12% Novex NuPage Bis-Tris gel (Invitrogen, Carlsbad, CA) and then transferred to PVDF (Invitrogen, Carlsbad, CA). After transfer, the PVDF membrane was blocked with BSA (Santa Cruz Biotechnology, Santa Cruz, CA) and then probed with an antibody for phospho-TIE2 (Cell Signaling Technology, Beverly, MA). A secondary anti-rabbit antibody conjugated to horseradish peroxidase (Cell Signaling Technology, Beverly, MA) was used to detect phospho-TIE2 ECL Plus (GE
Healthcare, Piscataway, NJ), a substrate for horseradish peroxidase that generates a fluorescent product, was added. Fluorescence was detected using a Storm 840 phosphorimager (GE
Healthcare, Piscataway, NJ) in fluorescence mode. PVDF membranes were stripped and then re-probed with total TIE2 antibody (Santa Cruz Biotechnology, Inc., Dallas, TX) as above. The 160 kDa phospho-TIE2 and total TIE2 bands were quantified using ImageQuant software (GE Healthcare, Piscataway, NJ). Phospho-TIE2 levels were normalized to total TIE2 levels, and data was plotted using Prism software (GraphPad Software, San Diego, CA). When incubated with transfected CHO K1 cells for 2 hours at 0.1 IVI ¨ 1 IVI prior to being washed out, Composition 1-(3-tert-buty1-1-(quino lin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylc arb amoyOpyri din-4-yloxy)phenyOurea para-toluene sulfonic acid salt disclosed herein exhibited >50% inhibition of phospho-TIE2 levels for >24 hours.
Example 5. Cellular inhibition of TIE2 in HUVEC cells by 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluo ro-4-(2-(methylc arb a moyl)pyridin-4-yloxy)p he nyl)u re a HUVEC Cell Culture
[0541] HUVEC (Human umbilical vein endothelial cells; Catalog #CRL-1730) cells were obtained from the American Type Culture Collection (ATCC, Manassas, VA).
Briefly, cells were grown in EGM-2 (Lonza, Walkersville, MD) at 37 degrees Celsius, 5%CO2, and 95%
humidity. Cells were allowed to expand until reaching 90-95% saturation at which point they were subcultured or harvested for assay use.
HUVEC Phospho-TIE2 Western Blot Assay
Briefly, cells were grown in EGM-2 (Lonza, Walkersville, MD) at 37 degrees Celsius, 5%CO2, and 95%
humidity. Cells were allowed to expand until reaching 90-95% saturation at which point they were subcultured or harvested for assay use.
HUVEC Phospho-TIE2 Western Blot Assay
[0542] HUVEC cells (2.5 x 105 cells/well) were added to a 24-well tissue-culture treated plate in 1 mL of EGM-2 culture medium (Lonza, Walkersville, MD). Cells were then incubated overnight at 37 degrees Celsius, 5% CO2, and 95% humidity. Media was then aspirated and 1 mL EBM-2 basal medium (Lonza, Walkersville, MD) supplemented with 2% FBS
(Invitrogen, Carlsbad, CA) was added. Test composition or DMSO was added to the wells (0.5%
final DMSO concentration). The plates were then incubated for 4 hours at 37 degrees Celsius, 5%
CO2, and 95% humidity. During the incubation, histidine-tagged angiopoietin 1 (ANG1) growth factor (R&D Systems, Minneapolis, MN) was added to a anti-polyhistidine antibody (R&D
Systems, Minneapolis, MN) for 30 minutes at room temperature to generate multimers of ANG1.
Following the four hour incubation of composition, cells were stimulated with 800 ng/mL of the ANG l/anti-polyhistidine antibody complex mixture for 15 minutes. The media was aspirated and the cells were washed with PBS. The cells were lysed using MPER lysis buffer (Pierce, Rockford, IL) containing Halt Phosphatase and Protease Inhibitors (Pierce, Rockford, IL) and Phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO) at 4 C for 10 minutes with shaking.
Cleared lysates were separated by SDS-PAGE on a 4-12% Novex NuPage Bis-Tris gel (Invitrogen, Carlsbad, CA) and then transferred to PVDF (Invitrogen, Carlsbad, CA). After transfer, the PVDF membrane was blocked with BSA (Santa Cruz Biotechnology, Santa Cruz, CA) and then probed with an antibody for phospho-TIE2 (Cell Signaling Technology, Beverly, MA). A secondary anti-rabbit antibody conjugated to horseradish peroxidase (Cell Signaling Technology, Beverly, MA) was used to detect phospho-TIE2. ECL Plus (GE
Healthcare, Piscataway, NJ), a substrate for horseradish peroxidase that generates a fluorescent product, was added. Fluorescence was detected using a Storm 840 phosphorimager (GE
Healthcare, Piscataway, NJ) in fluorescence mode. The 160 kDa phospho-TIE2 band was quantified using ImageQuant software (GE Healthcare, Piscataway, NJ). Data was analyzed using Prism software (GraphPad Software, San Diego, CA) to calculate IC50 values. The composition 1-(3-tert-butyl-1-(quino lin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro -4-(2-(methylc arb amoyl)pyri din-4-yloxy)phenyOurea para-toluene sulfonic acid salt disclosed herein exhibited an IC50 value of 0.018 nM.
Example 6. Inhibition of angiopoietin 1 (ANGI) or angiopoietin 2 (ANG2) stimulated capillary tube formation by 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylca rb am oyl)pyridin-4-yloxy)p he nyl)u re a HMVEC Cell Culture
(Invitrogen, Carlsbad, CA) was added. Test composition or DMSO was added to the wells (0.5%
final DMSO concentration). The plates were then incubated for 4 hours at 37 degrees Celsius, 5%
CO2, and 95% humidity. During the incubation, histidine-tagged angiopoietin 1 (ANG1) growth factor (R&D Systems, Minneapolis, MN) was added to a anti-polyhistidine antibody (R&D
Systems, Minneapolis, MN) for 30 minutes at room temperature to generate multimers of ANG1.
Following the four hour incubation of composition, cells were stimulated with 800 ng/mL of the ANG l/anti-polyhistidine antibody complex mixture for 15 minutes. The media was aspirated and the cells were washed with PBS. The cells were lysed using MPER lysis buffer (Pierce, Rockford, IL) containing Halt Phosphatase and Protease Inhibitors (Pierce, Rockford, IL) and Phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO) at 4 C for 10 minutes with shaking.
Cleared lysates were separated by SDS-PAGE on a 4-12% Novex NuPage Bis-Tris gel (Invitrogen, Carlsbad, CA) and then transferred to PVDF (Invitrogen, Carlsbad, CA). After transfer, the PVDF membrane was blocked with BSA (Santa Cruz Biotechnology, Santa Cruz, CA) and then probed with an antibody for phospho-TIE2 (Cell Signaling Technology, Beverly, MA). A secondary anti-rabbit antibody conjugated to horseradish peroxidase (Cell Signaling Technology, Beverly, MA) was used to detect phospho-TIE2. ECL Plus (GE
Healthcare, Piscataway, NJ), a substrate for horseradish peroxidase that generates a fluorescent product, was added. Fluorescence was detected using a Storm 840 phosphorimager (GE
Healthcare, Piscataway, NJ) in fluorescence mode. The 160 kDa phospho-TIE2 band was quantified using ImageQuant software (GE Healthcare, Piscataway, NJ). Data was analyzed using Prism software (GraphPad Software, San Diego, CA) to calculate IC50 values. The composition 1-(3-tert-butyl-1-(quino lin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro -4-(2-(methylc arb amoyl)pyri din-4-yloxy)phenyOurea para-toluene sulfonic acid salt disclosed herein exhibited an IC50 value of 0.018 nM.
Example 6. Inhibition of angiopoietin 1 (ANGI) or angiopoietin 2 (ANG2) stimulated capillary tube formation by 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylca rb am oyl)pyridin-4-yloxy)p he nyl)u re a HMVEC Cell Culture
[0543] HMVEC (Human microvascular endothelial cells; Catalog #PCS-110-010) cells were obtained from the American Type Culture Collection (ATCC, Manassas, VA).
Briefly, cells were grown in EGM-2 MV (Lonza, Walkersville, MD) at 37 degrees Celsius, 5%
CO2, and 95%
humidity. Cells were allowed to expand until reaching 90-95% saturation at which point they were subcultured or harvested for assay use.
HMVEC Capillary Tube Formation Assay
Briefly, cells were grown in EGM-2 MV (Lonza, Walkersville, MD) at 37 degrees Celsius, 5%
CO2, and 95%
humidity. Cells were allowed to expand until reaching 90-95% saturation at which point they were subcultured or harvested for assay use.
HMVEC Capillary Tube Formation Assay
[0544] HMVEC cells (1.5 x 104 cells/well) mixed with test composition or DMSO control and the appropriate growth factor (ANG1 or ANG2) or control were added to a 96-well tissue-culture treated plate coated with growth-factor reduced Matrigel in 0.1 mL of EBM-2 basal medium (Lonza, Walkersville, MD). Cells were then incubated for 18 hours at 37 degrees Celsius, 5% CO2, and 95% humidity. Media was then gently aspirated and wells were gently washed with 0.1 mL EBM-2 basal medium. Media was again aspirated and 1 iuM
Calcein AM
solution (Invitrogen, Carlsbad, CA) in basal medium was added to each well to fluorescently label live cells. Cells were then incubated for 30 minutes at 37 degrees Celsius, 5% CO2, and 95% humidity. Media was aspirated and wells were gently washed with phosphate-buffered saline twice. Images of each well were acquired with a fluorescent microscope and processed using ImagePro Analyzer (Media Cybernetics, Inc., Rockville, MD) using an automated macro that measures total capillary tube length. Data was analyzed using Prism software (GraphPad Software, San Diego, CA) to calculate IC50 values. The composition 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyOurea para-toluene sulfonic acid salt disclosed herein exhibited an IC50 value of 6.9 nM
for inhibition of ANG1-stimulated HMVEC capillary tube formation. The composition of Formula I
disclosed herein exhibited an IC50 value of 34 nM for inhibition of ANG2-stimulated HMVEC capillary tube formation.
Example 7. Inhibition of in vivo primary tumor growth and invasiveness in the murine PyMT breast cancer model by 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea as a single agent and in combination with paclitaxel PyMT syngeneic breast cancer model primary tumor growth
Calcein AM
solution (Invitrogen, Carlsbad, CA) in basal medium was added to each well to fluorescently label live cells. Cells were then incubated for 30 minutes at 37 degrees Celsius, 5% CO2, and 95% humidity. Media was aspirated and wells were gently washed with phosphate-buffered saline twice. Images of each well were acquired with a fluorescent microscope and processed using ImagePro Analyzer (Media Cybernetics, Inc., Rockville, MD) using an automated macro that measures total capillary tube length. Data was analyzed using Prism software (GraphPad Software, San Diego, CA) to calculate IC50 values. The composition 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyOurea para-toluene sulfonic acid salt disclosed herein exhibited an IC50 value of 6.9 nM
for inhibition of ANG1-stimulated HMVEC capillary tube formation. The composition of Formula I
disclosed herein exhibited an IC50 value of 34 nM for inhibition of ANG2-stimulated HMVEC capillary tube formation.
Example 7. Inhibition of in vivo primary tumor growth and invasiveness in the murine PyMT breast cancer model by 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea as a single agent and in combination with paclitaxel PyMT syngeneic breast cancer model primary tumor growth
[0545] The PyMT syngeneic breast cancer implant mouse model was used to evaluate in vivo activity of compound 1. Briefly, 1 x 106 cells (dissociated from PyMT tumor fragments) in 0.1 mL total volume were implanted into the fourth mammary fat pad on the left side of female mice (FVB/NJ, JAXWEST:RB05 mice from Jackson Labs). A total of 10 mice were implanted in each group. Molecular Imaging, Inc.'s Animal Care and Use Committee approved all the experimental protocols and conducted experiments in compliance with all the laws, regulations and guidelines of the National Institutes of Health (NIH). Treatment was initiated by oral administration (gavage) of Compound 1 twice daily or vehicle (0.4%
hydroxypropylmethylcellulose in water) and/or intravenous administration (IV) of paclitaxel every five days or vehicle (10% ethanol, 10% Cremophor EL and 80% saline) according to individual body weight on the day of treatment at 0.2 mL per 20 g when tumor size reached approximately 850 mg.
Animals were dosed for 21 days. Body weights and tumor measurements were recorded three times weekly. Tumor burden (mg) was estimated from caliper measurements by the formula for the volume of a prolate ellipsoid assuming unit density as:
Tumor burden (mg) = (L x W2)/2, where L and W are the respective orthogonal tumor length and width measurements (mm),In the PyMT model, both Compound 1 and paclitaxel groups evidenced tumor growth inhibition. Compound 1 in combination with paclitaxel demonstrated additive activity (Figure 1). These data evidence in vivo activity by Compound 1 and show correlation to enzymatic and cell data.
Example 8. Inhibition of in vivo primary tumor macrophage accumulation in the murine PyMT breast cancer model by 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea as a single agent and in combination with paclitaxel PyMT syngeneic breast cancer model primary tumor macrophage accumulation
hydroxypropylmethylcellulose in water) and/or intravenous administration (IV) of paclitaxel every five days or vehicle (10% ethanol, 10% Cremophor EL and 80% saline) according to individual body weight on the day of treatment at 0.2 mL per 20 g when tumor size reached approximately 850 mg.
Animals were dosed for 21 days. Body weights and tumor measurements were recorded three times weekly. Tumor burden (mg) was estimated from caliper measurements by the formula for the volume of a prolate ellipsoid assuming unit density as:
Tumor burden (mg) = (L x W2)/2, where L and W are the respective orthogonal tumor length and width measurements (mm),In the PyMT model, both Compound 1 and paclitaxel groups evidenced tumor growth inhibition. Compound 1 in combination with paclitaxel demonstrated additive activity (Figure 1). These data evidence in vivo activity by Compound 1 and show correlation to enzymatic and cell data.
Example 8. Inhibition of in vivo primary tumor macrophage accumulation in the murine PyMT breast cancer model by 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea as a single agent and in combination with paclitaxel PyMT syngeneic breast cancer model primary tumor macrophage accumulation
[0546] The PyMT syngeneic breast cancer implant mouse model was used to evaluate in vivo activity of compound 1. Briefly, 1 x 106 cells (dissociated from PyMT tumor fragments) in 0.1 mL total volume were implanted into the fourth mammary fat pad on the left side of female mice (FVB/NJ, JAXWEST:RB05 mice from Jackson Labs). A total of 10 mice were implanted in each group. Molecular Imaging, Inc.'s Animal Care and Use Committee approved all the experimental protocols and conducted experiments in compliance with all the laws, regulations and guidelines of the National Institutes of Health (NIH). Treatment was initiated by oral administration (gavage) of Compound 1 twice daily or vehicle (0.4%
hydroxypropylmethylcellulose in water) and/or intravenous administration (IV) of paclitaxel every five days or vehicle (10% ethanol, 10% Cremophor EL and 80% saline) according to individual body weight on the day of treatment at 0.2 mL per 20 g when tumor size reached approximately 850 mg.
Animals were dosed for 21 days. Body weights and tumor measurements were recorded three times weekly.
hydroxypropylmethylcellulose in water) and/or intravenous administration (IV) of paclitaxel every five days or vehicle (10% ethanol, 10% Cremophor EL and 80% saline) according to individual body weight on the day of treatment at 0.2 mL per 20 g when tumor size reached approximately 850 mg.
Animals were dosed for 21 days. Body weights and tumor measurements were recorded three times weekly.
[0547] At the end of study, tumors were excised and placed in formalin. Formalin-fixed tumor samples were then placed in paraffin blocks. Formalin fixed-paraffin embedded tissue slides were deparaffinized with xylene and hydrated to distilled water through a graduated series of alcohol rinses. Antigenic retrieval was performed using Dako's PT Link Module with a Tris/EDTA buffer target retrieval solution at 95 C for 20 minutes. Once the slides cooled down, they were loaded onto a Dako AutostainerPlusLink for immunohistochemical staining at room temperature with F4/80 and CD31 antibodies, to stain for macrophages and endothelial cells, respectively. Endogenous peroxidase and alkaline phosphatase activity in the tissues was quenched with a Dual Endogenous Enzyme Block solution (Dako, S2003) for 5 minutes. Non-specific protein binding was blocked with serum free Protein Block (Dako, X0909) for 5 minutes. The rat anti mouse CD31 primary antibody was then incubated on the experimental tissue sections for 30 minutes at an immunogenic concentration of 1:100. The primary antibody was then conjugated with a rabbit anti rat immunoglobulin secondary antibody (Dako, E0468).
The secondary antibody was then amplified with a goat anti rabbit peroxidase labeled polymer (Dako, K4003) for 30 minutes. Enzymatic staining was developed with substrate-chromogen DAB+ (Dako, K3468) for 5 minutes. Excess rat IgG components were further blocked with Rodent Block Rat (Biocare Medical, RBR962H) for 5 minutes. The rat anti mouse F4/80 primary antibody was incubated on the experimental tissue sections for 30 minutes. The F4/80 was then conjugated with a rabbit anti rat immunoglobulin secondary antibody (Dako, E0468). The secondary antibody was then amplified with a goat anti rabbit alkaline phosphatase labeled polymer, (Biocare RALP525) for 30 minutes. Enzymatic staining was developed with substrate chromogen WARP Red (Biocare WR806). The counter staining was performed with automation hematoxylin for 10 minutes. The tissue slides were then air dried and cleared to xylene for glass cover slipping. Slides were scored for F4/80 staining using a scale of 0, no visible staining; 1, weak staining; 2, moderate staining; 3 strong staining.In the PyMT model, Compound 1 evidenced a decrease in macrophage accumulation at the primary tumor, whereas paclitaxel did not decrease macrophage accumulation. Compound 1 in combination with paclitaxel demonstrated similar activity to Compound 1 single-agent treatment (Figure 2).
These data evidence in vivo activity by Compound 1 and show correlation to enzymatic and cell data.
Example 9. Inhibition of in vivo primary tumor TIE2 cell accumulation in the murine PyMT breast cancer model by 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea as a single agent and in combination with paclitaxel PyMT syngeneic breast cancer model primary tumor macrophage accumulation
The secondary antibody was then amplified with a goat anti rabbit peroxidase labeled polymer (Dako, K4003) for 30 minutes. Enzymatic staining was developed with substrate-chromogen DAB+ (Dako, K3468) for 5 minutes. Excess rat IgG components were further blocked with Rodent Block Rat (Biocare Medical, RBR962H) for 5 minutes. The rat anti mouse F4/80 primary antibody was incubated on the experimental tissue sections for 30 minutes. The F4/80 was then conjugated with a rabbit anti rat immunoglobulin secondary antibody (Dako, E0468). The secondary antibody was then amplified with a goat anti rabbit alkaline phosphatase labeled polymer, (Biocare RALP525) for 30 minutes. Enzymatic staining was developed with substrate chromogen WARP Red (Biocare WR806). The counter staining was performed with automation hematoxylin for 10 minutes. The tissue slides were then air dried and cleared to xylene for glass cover slipping. Slides were scored for F4/80 staining using a scale of 0, no visible staining; 1, weak staining; 2, moderate staining; 3 strong staining.In the PyMT model, Compound 1 evidenced a decrease in macrophage accumulation at the primary tumor, whereas paclitaxel did not decrease macrophage accumulation. Compound 1 in combination with paclitaxel demonstrated similar activity to Compound 1 single-agent treatment (Figure 2).
These data evidence in vivo activity by Compound 1 and show correlation to enzymatic and cell data.
Example 9. Inhibition of in vivo primary tumor TIE2 cell accumulation in the murine PyMT breast cancer model by 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea as a single agent and in combination with paclitaxel PyMT syngeneic breast cancer model primary tumor macrophage accumulation
[0548] The PyMT syngeneic breast cancer implant mouse model was used to evaluate in vivo activity of compound 1. Briefly, 1 x 106 cells (dissociated from PyMT tumor fragments) in 0.1 mL total volume were implanted into the fourth mammary fat pad on the left side of female mice (FVB/NJ, JAXWEST:RB05 mice from Jackson Labs). A total of 10 mice were implanted in each group. Molecular Imaging, Inc.'s Animal Care and Use Committee approved all the experimental protocols and conducted experiments in compliance with all the laws, regulations and guidelines of the National Institutes of Health (NIH). Treatment was initiated by oral administration (gavage) of Compound 1 twice daily or vehicle (0.4%
hydroxypropylmethylcellulose in water) and/or intravenous administration (IV) of paclitaxel every five days or vehicle (10% ethanol, 10% Cremophor EL and 80% saline) according to individual body weight on the day of treatment at 0.2 mL per 20 g when tumor size reached approximately 850 mg.
Animals were dosed for 21 days. Body weights and tumor measurements were recorded three times weekly.
hydroxypropylmethylcellulose in water) and/or intravenous administration (IV) of paclitaxel every five days or vehicle (10% ethanol, 10% Cremophor EL and 80% saline) according to individual body weight on the day of treatment at 0.2 mL per 20 g when tumor size reached approximately 850 mg.
Animals were dosed for 21 days. Body weights and tumor measurements were recorded three times weekly.
[0549] At the end of study, tumors were excised and placed in formalin.
Formalin-fixed tumor samples were then placed in paraffin blocks. The experimental formalin fixed-paraffin embedded tissue slides were deparaffinized with xylene and hydrated to distilled water through a graduated series of alcohol rinses. Antigenic retrieval was performed using Dako's PT Link Module with a Citrate pH 6 buffer target retrieval solution at 95 C for 20 minutes. Once the slides cooled down, they were loaded onto a Dako AutostainerPlusLink for immunohistochemical staining at room temperature with both TIE2 and CD31 antibodies.
Endogenous peroxidase and alkaline phosphatase activity in the tissues was quenched with a Dual Endogenous Enzyme Block solution (Dako, S2003) for 5 minutes. Non-specific protein binding was blocked with serum free Protein Block (Dako, X0909) for 5 minutes.
The rat anti mouse CD31 primary antibody was then incubated on the experimental tissue sections for 30 minutes at an immunogenic concentration of 1:100. The primary antibody was then conjugated with a rabbit anti rat immunoglobulin secondary antibody (Dako, E0468). The secondary antibody was then amplified with a goat anti rabbit peroxidase labeled polymer (Dako, K4003) for 30 minutes. Enzymatic staining was developed with substrate-chromogen DAB+
(Dako, K3468) for 5 minutes. Excess protein components were further blocked with Protein Block (Dako, X0909) for 5 minutes. The rabbit anti TIE2 primary antibody was incubated on the experimental tissue sections for 30 minutes. The TIE2 antibody was then conjugated with an alkaline phosphatase labeled goat anti rabbit polymer for 30 minutes.
Enzymatic staining was developed with substrate chromogen WARP Red (Biocare WR806). The counter staining was performed with automation hematoxylin for 10 minutes. The tissue slides were then air dried and cleared to xylene for glass cover slipping. Slides were scored for TIE2 staining using a scale of 0, no visible staining; 1, weak staining; 2, moderate staining; 3 strong staining.In the PyMT
model, Compound 1 evidenced a decrease in TIE2-expressing cell accumulation at the primary tumor, whereas paclitaxel did not decrease TIE2-expressing cell accumulation.
Compound 1 in combination with paclitaxel demonstrated enhanced activity compared to Compound 1 single-agent treatment (Figure 3). These data evidence in vivo activity by Compound 1 and show correlation to enzymatic and cell data.
Example 10. Inhibition of in vivo lung metastases in the murine PyMT breast cancer model by 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea as a single agent and in combination with paclitaxel PyMT syngeneic breast cancer model lung metastasis evaluation
Formalin-fixed tumor samples were then placed in paraffin blocks. The experimental formalin fixed-paraffin embedded tissue slides were deparaffinized with xylene and hydrated to distilled water through a graduated series of alcohol rinses. Antigenic retrieval was performed using Dako's PT Link Module with a Citrate pH 6 buffer target retrieval solution at 95 C for 20 minutes. Once the slides cooled down, they were loaded onto a Dako AutostainerPlusLink for immunohistochemical staining at room temperature with both TIE2 and CD31 antibodies.
Endogenous peroxidase and alkaline phosphatase activity in the tissues was quenched with a Dual Endogenous Enzyme Block solution (Dako, S2003) for 5 minutes. Non-specific protein binding was blocked with serum free Protein Block (Dako, X0909) for 5 minutes.
The rat anti mouse CD31 primary antibody was then incubated on the experimental tissue sections for 30 minutes at an immunogenic concentration of 1:100. The primary antibody was then conjugated with a rabbit anti rat immunoglobulin secondary antibody (Dako, E0468). The secondary antibody was then amplified with a goat anti rabbit peroxidase labeled polymer (Dako, K4003) for 30 minutes. Enzymatic staining was developed with substrate-chromogen DAB+
(Dako, K3468) for 5 minutes. Excess protein components were further blocked with Protein Block (Dako, X0909) for 5 minutes. The rabbit anti TIE2 primary antibody was incubated on the experimental tissue sections for 30 minutes. The TIE2 antibody was then conjugated with an alkaline phosphatase labeled goat anti rabbit polymer for 30 minutes.
Enzymatic staining was developed with substrate chromogen WARP Red (Biocare WR806). The counter staining was performed with automation hematoxylin for 10 minutes. The tissue slides were then air dried and cleared to xylene for glass cover slipping. Slides were scored for TIE2 staining using a scale of 0, no visible staining; 1, weak staining; 2, moderate staining; 3 strong staining.In the PyMT
model, Compound 1 evidenced a decrease in TIE2-expressing cell accumulation at the primary tumor, whereas paclitaxel did not decrease TIE2-expressing cell accumulation.
Compound 1 in combination with paclitaxel demonstrated enhanced activity compared to Compound 1 single-agent treatment (Figure 3). These data evidence in vivo activity by Compound 1 and show correlation to enzymatic and cell data.
Example 10. Inhibition of in vivo lung metastases in the murine PyMT breast cancer model by 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea as a single agent and in combination with paclitaxel PyMT syngeneic breast cancer model lung metastasis evaluation
[0550] The PyMT syngeneic breast cancer implant mouse model was used to evaluate in vivo activity of compound 1. Briefly, 1 x 106 cells (dissociated from PyMT tumor fragments) in 0.1 mL total volume were implanted into the fourth mammary fat pad on the left side of female mice (FVB/NJ, JAXWEST:RB05 mice from Jackson Labs). A total of 10 mice were implanted in each group. Molecular Imaging, Inc.'s Animal Care and Use Committee approved all the experimental protocols and conducted experiments in compliance with all the laws, regulations and guidelines of the National Institutes of Health (NIH). Treatment was initiated by oral administration (gavage) of Compound 1 twice daily or vehicle (0.4%
hydroxypropylmethylcellulose in water) and/or intravenous administration (IV) of paclitaxel every five days or vehicle (10% ethanol, 10% Cremophor EL and 80% saline) according to individual body weight on the day of treatment at 0.2 mL per 20 g when tumor size reached approximately 850 mg.
Animals were dosed for 21 days. Body weights and tumor measurements were recorded three times weekly.
hydroxypropylmethylcellulose in water) and/or intravenous administration (IV) of paclitaxel every five days or vehicle (10% ethanol, 10% Cremophor EL and 80% saline) according to individual body weight on the day of treatment at 0.2 mL per 20 g when tumor size reached approximately 850 mg.
Animals were dosed for 21 days. Body weights and tumor measurements were recorded three times weekly.
[0551] At the end of study, lung tissues were excised and placed in formalin. Formalin-fixed lung samples were then placed in paraffin blocks. Each lung block had three slides with two levels per slide cut and stained with Hematoxylin and Eosin. Metastatic lung nodules were counted via microscopy.In the PyMT model, both Compound 1 and paclitaxel evidenced a similar decrease in lung metastasis. Compound 1 in combination with paclitaxel demonstrated additive activity compared to single-agent treatments (Figure 4). These data evidence in vivo activity by Compound 1 and show correlation to enzymatic and cell data.
Example 11. Inhibition of in vivo lung metastases in the murine PyMT breast cancer model by 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea dosed intermittently (non-daily) in combination with paclitaxel PyMT syngeneic breast cancer model lung metastasis evaluation
Example 11. Inhibition of in vivo lung metastases in the murine PyMT breast cancer model by 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea dosed intermittently (non-daily) in combination with paclitaxel PyMT syngeneic breast cancer model lung metastasis evaluation
[0552] The PyMT syngeneic breast cancer implant mouse model was used to evaluate in vivo activity of compound 1. Briefly, 1 x 106 cells (dissociated from PyMT tumor fragments and stored frozen in cell-freezing medium) in 0.1 mL total volume were implanted into the fourth mammary fat pad on the left side of female mice (FVB/NJ, JAXWEST:RB05 mice from Jackson Labs). A total of three mice were implanted in each group. Molecular Imaging, Inc.'s Animal Care and Use Committee approved all the experimental protocols and conducted experiments in compliance with all the laws, regulations and guidelines of the National Institutes of Health (NIH). Treatment was initiated by oral administration (gavage) of Compound 1 twice weekly or vehicle (0.4% hydroxypropylmethylcellulose in water) and/or intravenous administration (IV) of paclitaxel every five days or vehicle (10% ethanol, 10% Cremophor EL and 80%
saline) according to individual body weight on the day of treatment at 0.2 mL per 20 g when tumor size reached approximately 600 mg. Animals were dosed for 12 days. Body weights and tumor measurements were recorded three times weekly.
saline) according to individual body weight on the day of treatment at 0.2 mL per 20 g when tumor size reached approximately 600 mg. Animals were dosed for 12 days. Body weights and tumor measurements were recorded three times weekly.
[0553] At the end of study, lung tissues were excised and placed in formalin. Formalin-fixed lung samples were then placed in paraffin blocks. Each lung block had three slides with two levels per slide cut and stained with Hematoxylin and Eosin. Metastatic lung nodules were counted via microscopy.In the PyMT model, paclitaxel evidenced a decrease in lung metastasis.
Compound 1 in combination with paclitaxel demonstrated additive activity compared to single-agent treatment (Figure 5). These data evidence in vivo activity by Compound 1 and show correlation to enzymatic and cell data.
Example 12. Inhibition of in vivo lung metastases in the murine PyMT breast cancer model by 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea dosed intermittently (non-daily) in combination with eribulin PyMT syngeneic breast cancer model lung metastasis evaluation
Compound 1 in combination with paclitaxel demonstrated additive activity compared to single-agent treatment (Figure 5). These data evidence in vivo activity by Compound 1 and show correlation to enzymatic and cell data.
Example 12. Inhibition of in vivo lung metastases in the murine PyMT breast cancer model by 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea dosed intermittently (non-daily) in combination with eribulin PyMT syngeneic breast cancer model lung metastasis evaluation
[0554] The PyMT syngeneic breast cancer implant mouse model was used to evaluate in vivo activity of compound 1. Briefly, 1 x 106 cells (dissociated from PyMT tumor fragments and stored frozen in cell-freezing medium) in 0.1 mL total volume were implanted into the fourth mammary fat pad on the left side of female mice (FVB/NJ, JAXWEST:RB05 mice from Jackson Labs). A total of three mice were implanted in each group. Molecular Imaging, Inc.'s Animal Care and Use Committee approved all the experimental protocols and conducted experiments in compliance with all the laws, regulations and guidelines of the National Institutes of Health (NIH). Treatment was initiated by oral administration (gavage) of Compound 1 twice weekly or vehicle (0.4% hydroxypropylmethylcellulose in water) and/or intravenous administration (IV) of eribulin three times weekly or vehicle (80% saline) according to individual body weight on the day of treatment at 0.2 mL per 20 g when tumor size reached approximately 600 mg. Animals were dosed for 12 days. Body weights and tumor measurements were recorded three times weekly.
[0555] At the end of study, lung tissues were excised and placed in formalin. Formalin-fixed lung samples were then placed in paraffin blocks. Each lung block had three slides with two levels per slide cut and stained with Hematoxylin and Eosin. Metastatic lung nodules were counted via microscopy.In the PyMT model, eribulin evidenced a decrease (or increase at low dose) in lung metastasis. Compound 1 in combination with eribulin demonstrated additive activity compared to single-agent treatment (Figure 6). These data evidence in vivo activity by Compound 1 and show correlation to enzymatic and cell data.
Example 13. Increase in overall survival in the murine PyMT breast cancer model by 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea dosed intermittently (non-daily) in combination with eribulin PyMT syngeneic breast cancer model survival evaluation
Example 13. Increase in overall survival in the murine PyMT breast cancer model by 1-(3-tert-buty1-1-(quinolin-6-y1)-1H-pyrazol-5-y1)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea dosed intermittently (non-daily) in combination with eribulin PyMT syngeneic breast cancer model survival evaluation
[0556] The PyMT syngeneic breast cancer implant mouse model was used to evaluate in vivo activity of compound 1. Briefly, 1 x 106 cells (dissociated from PyMT tumor fragments and stored frozen in cell-freezing medium) in 0.1 mL total volume were implanted into the fourth mammary fat pad on the left side of female mice (FVB/NJ, JAXWEST:RB05 mice from Jackson Labs). A total of ten mice were implanted in each group. Molecular Imaging, Inc.'s Animal Care and Use Committee approved all the experimental protocols and conducted experiments in compliance with all the laws, regulations and guidelines of the National Institutes of Health (NIH). Treatment was initiated by oral administration (gavage) of Compound 1 once or twice weekly or vehicle (0.4% hydroxypropylmethylcellulose in water) and/or intravenous administration (IV) of eribulin three times weekly or vehicle (80% saline) according to individual body weight on the day of treatment at 0.2 mL per 20 g when tumor size reached approximately 850 mg. Tumors were then resected three days after treatment began. Animals were then dosed for the duration of the survival experiment. Body weights and tumor measurements were recorded three times weekly. In the PyMT model, eribulin at 0.1 mg/kg evidenced no increase in survival. Compound 1 in combination with eribulin demonstrated significant increases in survival (Figure 7). These data evidence in vivo activity by Compound 1 and show correlation to enzymatic and cell data.
[0557] The present invention is not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention.
Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.
EQUIVALENTS
Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.
EQUIVALENTS
[0558] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.
Claims (219)
1. A method of blocking primary breast tumor growth and invasiveness comprising administering to a patient in need thereof an effective amount of a composition of Formula I
wherein n is an integer from 0 to 7;
X is the basic radical of a pharmaceutically acceptable salt;
provided that when n is 0, the composition of Formula I is the parent free base;
in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment.
wherein n is an integer from 0 to 7;
X is the basic radical of a pharmaceutically acceptable salt;
provided that when n is 0, the composition of Formula I is the parent free base;
in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment.
2. The method of claim 1, wherein the dosing regimen is administered daily.
3. The method of claim 1, wherein the dosing regimen is intermittent non-daily dosing, alternate daily dosing, every third daily dosing, twice weekly dosing, or once weekly dosing.
4. The method of claim 1, wherein the dosing regimen is twice weekly, once weekly, or on an alternately weekly dosing.
5. The methods of any of claims 1-4, wherein the composition of Formula I
is used in combination with one or more agents taken from an anti-tubulin agent, a DNA alkylating agent, a DNA
synthesis-inhibiting agent, a DNA intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor, or an anti-angiogenic agent.
is used in combination with one or more agents taken from an anti-tubulin agent, a DNA alkylating agent, a DNA
synthesis-inhibiting agent, a DNA intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor, or an anti-angiogenic agent.
6. The methods of any of claims 1-4, wherein the composition of Formula I
is used in combination with paclitaxel.
is used in combination with paclitaxel.
7. The methods of any of claims 1-4, wherein the composition of Formula I
is used in combination with paclitaxel protein-bound particles for injectable suspension.
is used in combination with paclitaxel protein-bound particles for injectable suspension.
8. The methods of any of claims 1-4, wherein the compound of Formula I is used in combination with eribulin.
9. The methods of any of claims 1-4, wherein the composition of Formula I
is used in combination with ixabepilone.
is used in combination with ixabepilone.
10. The methods of any of claims 1-4, wherein the composition of Formula I is used in combination with vinorelbine.
11. The methods of any of claims 1-4, wherein the composition of Formula I is used in combination with capecitabine.
12. The methods of any of claims 1-4, wherein the composition of Formula I is used in combination with gemcitabine.
13. The methods of any of claims 1-4, wherein the composition of Formula I is used in combination with 5-fluorouracil.
14. The methods of any of claims 1-4, wherein the composition of Formula I is used in combination with methotrexate.
15. The methods of any of claims 1-4, wherein the composition of Formula I is used in combination with cyclophosphamide.
16. The methods of any of claims 1-4, wherein the composition of Formula I is used in combination with cisplatin.
17. The methods of any of claims 1-4, wherein the composition of Formula I is used in combination with carboplatin.
18. The methods of any of claims 1-4, wherein the composition of Formula I is used in combination with doxorubicin.
19. The methods of any of claims 1-4, wherein the composition of Formula I is used in combination with pegylated liposomal doxorubicin.
20. The methods of any of claims 1-4, wherein the composition of Formula I is used in combination with epirubicin.
21. The methods of any of claims 1-4, wherein the composition of Formula I is used in combination with tamoxifen.
22. The methods of any of claims 1-4, wherein the composition of Formula I is used in combination with fulvestrant.
23. The methods of any of claims 1-4, wherein the composition of Formula I is used in combination with anastrozole.
24. The methods of any of claims 1-4, wherein the composition of Formula I is used in combination with letrozole.
25. The methods of any of claims 1-4, wherein the composition of Formula I is used in combination with exemestane.
26. The methods of any of claims 1-4, wherein the composition of Formula I is used in combination with trastuzumab.
27. The methods of any of claims 1-4, wherein the composition of Formula I is used in combination with ado-trastuzumab emtansine.
28. The methods of any of claims 1-4, wherein the composition of Formula I is used in combination with pertuzumab.
29. The methods of any of claims 1-4, wherein the composition of Formula I is used in combination with lapatinib.
30. The methods of any of claims 1-4, wherein the composition of Formula I is used in combination with everolimus.
31. The methods of any of claims 1-4, wherein the composition of Formula I is used in combination with temsirolimus.
32. The methods of any of claims 1-4, wherein the composition of Formula I is used in combination with the CDK4/6 inhibitor LY2835219.
33. The methods of any of claims 1-4, wherein the composition of Formula I is used in combination with the CDK4/6 inhibitor LEE011.
34. The methods of any of claims 1-4, wherein the composition of Formula I is used in combination with the CDK4/6 inhibitor PD 0332991.
35. The methods of any of claims 1-4, wherein the composition of Formula I is used in combination with bevacizumab.
36. The methods of any of claims 1-35, wherein the composition is the composition of Formula II.
37. The methods of any of claims 1-36, wherein the composition of Formula I or Formula II is used in combination with more than one of the other agents identified in claims 6-35.
38. A method of blocking breast cancer intravasation, dissemination and metastasis, comprising administering to a patient in need thereof an effective amount of a composition of Formula I
wherein n is an integer from 0 to 7;
X is the basic radical of a pharmaceutically acceptable salt;
provided that when n is 0, the composition of Formula I is the parent free base, in a dosing regimen sufficient to block TIE2 kinase in tumor microenvironment expressing macrophages.
wherein n is an integer from 0 to 7;
X is the basic radical of a pharmaceutically acceptable salt;
provided that when n is 0, the composition of Formula I is the parent free base, in a dosing regimen sufficient to block TIE2 kinase in tumor microenvironment expressing macrophages.
39. The method of claim 38, wherein the dosing regimen of is administered daily.
40. The method of claim 38, wherein the dosing regimen is intermittent non-daily dosing, alternate daily dosing, every third daily dosing, twice weekly dosing, or once weekly dosing.
41. The method of claim 38, wherein the dosing regimen is twice weekly, once weekly, or on an alternately weekly dosing.
42. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with one or more agents taken from an anti-tubulin agent, a DNA
alkylating agent, a DNA synthesis-inhibiting agent, DNA intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor, or an anti-angiogenic agent.
is used in combination with one or more agents taken from an anti-tubulin agent, a DNA
alkylating agent, a DNA synthesis-inhibiting agent, DNA intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor, or an anti-angiogenic agent.
43. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with paclitaxel.
is used in combination with paclitaxel.
44. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with paclitaxel protein-bound particles for injectable suspension.
is used in combination with paclitaxel protein-bound particles for injectable suspension.
45. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with eribulin.
is used in combination with eribulin.
46. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with ixabepilone.
is used in combination with ixabepilone.
47. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with vinorelbine.
is used in combination with vinorelbine.
48. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with capecitabine.
is used in combination with capecitabine.
49. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with gemcitabine.
is used in combination with gemcitabine.
50. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with 5-fluorouracil.
is used in combination with 5-fluorouracil.
51. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with methotrexate.
is used in combination with methotrexate.
52. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with cyclophosphamide.
is used in combination with cyclophosphamide.
53. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with cisplatin.
is used in combination with cisplatin.
54. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with carboplatin.
is used in combination with carboplatin.
55. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with doxorubicin.
is used in combination with doxorubicin.
56. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with pegylated liposomal doxorubicin.
is used in combination with pegylated liposomal doxorubicin.
57. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with epirubicin.
is used in combination with epirubicin.
58. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with tamoxifen.
is used in combination with tamoxifen.
59. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with fulvestrant.
is used in combination with fulvestrant.
60. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with anastrozole.
is used in combination with anastrozole.
61. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with letrozole.
is used in combination with letrozole.
62. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with exemestane.
is used in combination with exemestane.
63. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with trastuzumab.
is used in combination with trastuzumab.
64. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with ado-trastuzumab emtansine.
is used in combination with ado-trastuzumab emtansine.
65. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with pertuzumab.
is used in combination with pertuzumab.
66. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with lapatinib.
is used in combination with lapatinib.
67. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with everolimus.
is used in combination with everolimus.
68. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with temsirolimus.
is used in combination with temsirolimus.
69. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with the CDK4/6 inhibitor LY2835219.
is used in combination with the CDK4/6 inhibitor LY2835219.
70. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with the CDK4/6 inhibitor LEE011.
is used in combination with the CDK4/6 inhibitor LEE011.
71. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with the CDK4/6 inhibitor PD 0332991.
is used in combination with the CDK4/6 inhibitor PD 0332991.
72. The methods of any of claims 38-41, wherein the composition of Formula I
is used in combination with bevacizumab.
is used in combination with bevacizumab.
73. The methods of any of claims 38-72, wherein the composition is the composition of Formula II.
74. The methods of any of claims 38-73, wherein the composition of Formula I
or Formula II is used in combination with more than one of the other agents identified in claims 43-72.
or Formula II is used in combination with more than one of the other agents identified in claims 43-72.
75. A method of blocking breast cancer immunotolerance, comprising administering to a patient in need thereof an effective amount of the composition of Formula I
wherein n is an integer from 0 to 7;
X is the basic radical of a pharmaceutically acceptable salt;
provided that when n is 0, the composition of Formula I is the parent free base, in a dosing regimen sufficient to block TIE2 kinase in tumor microenvironment expressing macrophages that mediate immunotolerance.
wherein n is an integer from 0 to 7;
X is the basic radical of a pharmaceutically acceptable salt;
provided that when n is 0, the composition of Formula I is the parent free base, in a dosing regimen sufficient to block TIE2 kinase in tumor microenvironment expressing macrophages that mediate immunotolerance.
76. A method of claim 75, wherein the dosing regimen is administered daily.
77. A method of claim 75, wherein the dosing regimen is intermittent non-daily dosing, alternate daily dosing, every third daily dosing, twice weekly dosing, or once weekly dosing.
78. A method of claim 75, wherein the dosing regimen is twice weekly, once weekly, or on an alternately weekly regimen.
79. The methods of any of claims 75-78, wherein the composition of Formula I
is used in combination with one or more agents taken from an anti-tubulin agent, a DNA
alkylating agent, a DNA synthesis-inhibiting agent, a DNA intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor, an anti-angiogenic agent, or an immunomodulating agent.
is used in combination with one or more agents taken from an anti-tubulin agent, a DNA
alkylating agent, a DNA synthesis-inhibiting agent, a DNA intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor, an anti-angiogenic agent, or an immunomodulating agent.
80. The methods of any of claims 75-78, wherein the composition of Formula I
is used in combination with paclitaxel.
is used in combination with paclitaxel.
81. The methods of any of claims 75-78, wherein the composition of Formula I
is used in combination with paclitaxel protein-bound particles for injectable suspension.
is used in combination with paclitaxel protein-bound particles for injectable suspension.
82. The methods of any of claims 75-78, wherein the composition of Formula I
is used in combination with eribulin.
is used in combination with eribulin.
83. The methods of any of claims 75-78, wherein the composition of Formula I
is used in combination with ixabepilone.
is used in combination with ixabepilone.
84. The methods of any of claims 75-78, wherein the composition of Formula I
is used in combination with vinorelbine.
is used in combination with vinorelbine.
85. The methods of any of claims 75-78, wherein the composition of Formula I
is used in combination with capecitabine.
is used in combination with capecitabine.
86. The methods of any of claims 75-78, wherein the composition of Formula I
is used in combination with gemcitabine.
is used in combination with gemcitabine.
87. The methods of any of claims 75-78, wherein the composition of Formula I
is used in combination with 5-fluorouracil.
is used in combination with 5-fluorouracil.
88. The methods of any of claims 75-78, wherein the composition of Formula I
is used in combination with methotrexate.
is used in combination with methotrexate.
89. The methods of any of claims 75-78, wherein the composition of Formula I
is used in combination with cyclophosphamide.
is used in combination with cyclophosphamide.
90. The methods of any of claims 75-78, wherein the composition of Formula I
is used in combination with cisplatin.
is used in combination with cisplatin.
91. The methods of any of claims 75-78, wherein the composition of Formula I
is used in combination with carboplatin.
is used in combination with carboplatin.
92. The methods of any of claims 75-78, wherein the composition of Formula I
is used in combination with doxorubicin.
is used in combination with doxorubicin.
93. The methods of any of claims 75-78, wherein the composition of Formula I
is used in combination with pegylated liposomal doxorubicin.
is used in combination with pegylated liposomal doxorubicin.
94. The methods of any of claims 75-78, wherein the composition of Formula I
is used in combination with epirubicin.
is used in combination with epirubicin.
95. The methods of any of claims 75-78, wherein the composition of Formula I
is used in combination with tamoxifen.
is used in combination with tamoxifen.
96. The methods of any of claims 75-78, wherein the composition of Formula I
is used in combination with fulvestrant.
is used in combination with fulvestrant.
97. The methods of any of claims 75-78, wherein the composition of Formula I
is used in combination with anastrozole.
is used in combination with anastrozole.
98. The methods of any of claims 75-78, wherein the composition of Formula I
is used in combination with letrozole.
is used in combination with letrozole.
99. The methods of any of claims 75-78, wherein the composition of Formula I
is used in combination with exemestane.
is used in combination with exemestane.
100. The methods of any of claims 75-78, wherein the composition of Formula I is used in combination with trastuzumab.
101. The methods of any of claims 75-78, wherein the composition of Formula I is used in combination with ado-trastuzumab emtansine.
102. The methods of any of claims 75-78, wherein the composition of Formula I is used in combination with pertuzumab.
103. The methods of any of claims 75-78, wherein the composition of Formula I is used in combination with lapatinib.
104. The methods of any of claims 75-78, wherein the composition of Formula I is used in combination with everolimus.
105. The methods of any of claims 75-78, wherein the composition of Formula I is used in combination with temsirolimus.
106. The methods of any of claims 75-78, wherein the composition of Formula I is used in combination with the CDK4/6 inhibitor LY2835219.
107. The methods of any of claims 75-78, wherein the composition of Formula I is used in combination with the CDK4/6 inhibitor LEE011.
108. The methods of any of claims 75-78, wherein the composition of Formula I is used in combination with the CDK4/6 inhibitor PD 0332991.
109. The methods of any of claims 75-78, wherein the composition of Formula I is used in combination with bevacizumab.
110 . The methods of any of claims 75-78, wherein the composition of Formula I is used in combination with an anti-CTLA-4 agent.
111. The methods of any of claims 75-78, wherein the composition of Formula I is used in combination with ipilimumab.
112. The methods of any of claims 75-78, wherein the composition of Formula I is used in combination with an anti-PD-1 agent.
113. The methods of any of claims 75-78, wherein the composition of Formula I is used in combination with lambrolizumab.
114. The methods of any of claims 75-78, wherein the composition of Formula I is used in combination with an anti-PD L-1 agent.
115 . The methods of any of claims 75-78, wherein the composition of Formula I is used in combination with MPDL3280A.
116. The methods of any of claims 75-115, wherein the composition is the composition of Formula II.
117. The methods of any of claims 75-116, wherein the composition of Formula I or Formula II is used in combination with more than one of the other agents identified in claims 80-115.
118. A method of increasing overall survival in breast cancer patients, comprising administering to a patient in need thereof an effective amount of the composition of Formula I
wherein n is an integer from 0 to 7;
X is the basic radical of a pharmaceutically acceptable salt;
provided that when n is 0, the composition of Formula I is the parent free base, in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment.
wherein n is an integer from 0 to 7;
X is the basic radical of a pharmaceutically acceptable salt;
provided that when n is 0, the composition of Formula I is the parent free base, in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment.
119. The method of claim 118, wherein the dosing regimen is administered daily.
120. The method of claim 118, wherein the dosing regimen is intermittent non-daily dosing, alternate daily dosing, every third daily dosing, twice weekly dosing, or once weekly dosing.
121. The method of claim 118, wherein the dosing regimen is twice weekly, once weekly, or on an alternately weekly regimen.
122. The methods of claims 118-121, wherein the composition of Formula I is used in combination with one or more agents taken from an anti-tubulin agent, a DNA
alkylating agent, a DNA synthesis-inhibiting agent, a DNA intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor, an anti-angiogenic agent, or an immunomodulating agent.
alkylating agent, a DNA synthesis-inhibiting agent, a DNA intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor, an anti-angiogenic agent, or an immunomodulating agent.
123. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with paclitaxel.
124. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with paclitaxel protein-bound particles for injectable suspension.
125. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with eribulin.
126. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with ixabepilone.
127. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with vinorelbine.
128. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with capecitabine.
129. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with gemcitabine.
130. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with 5-fluorouracil.
131. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with methotrexate.
132. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with cyclophosphamide.
133. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with cisplatin.
134. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with carboplatin.
135. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with doxorubicin.
136. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with pegylated liposomal doxorubicin.
137. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with epirubicin.
138. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with tamoxifen.
139. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with fulvestrant.
140. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with anastrozole.
141. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with letrozole.
142. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with exemestane.
143. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with trastuzumab.
144. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with ado-trastuzumab emtansine.
145. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with pertuzumab.
146. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with lapatinib.
147. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with everolimus.
148. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with temsirolimus.
149. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with the CDK4/6 inhibitor LY2835219.
150. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with the CDK4/6 inhibitor LEE011.
151. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with the CDK4/6 inhibitor PD 0332991.
152. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with bevacizumab.
153. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with an anti-CTLA-4 agent.
154. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with ipilimumab.
155. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with an anti-PD-1 agent.
156. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with lambrolizumab.
157. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with an anti-PD L-1 agent.
158. The methods of any of claims 118-121, wherein the composition of Formula I is used in combination with MPDL3280A.
159. The methods of any of claims 118-158, wherein the composition is the composition of Formula II.
160. The methods of any of claims 118-159, wherein the composition of Formula I or Formula II is used in combination with more than one of the other agents identified in claims 123-158.
161. A method of treating breast cancer patients in a neoadjuvant setting, comprising administering to a patient in need thereof an effective amount of the composition of Formula I
prior to surgical resection of tumor.
prior to surgical resection of tumor.
162. A method of claim 161, wherein the dosing regimen is administered daily.
163. A method of claim 161, wherein the dosing regimen is intermittent non-daily dosing, alternate daily dosing, every third daily dosing, twice weekly dosing, or once weekly dosing.
164. A method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor, comprising administering to a patient in need thereof an effective amount of the composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment, administering doses of the composition of Formula I twice weekly, once weekly, or on an alternately weekly regimen.
165. The methods of any of claims 161-164 wherein the composition of Formula I is used in combination with one or more agents taken from an anti-tubulin agent, a DNA
alkylating agent, a DNA synthesis-inhibiting agent, a DNA intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor, an anti-angiogenic agent, or an immunomodulating agent.
alkylating agent, a DNA synthesis-inhibiting agent, a DNA intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor, an anti-angiogenic agent, or an immunomodulating agent.
166. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with paclitaxel.
167. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with paclitaxel protein-bound particles for injectable suspension.
168. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with eribulin.
169. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with ixabepilone.
170. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with vinorelbine.
171. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with capecitabine.
172. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with gemcitabine.
173. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with 5-fluorouracil.
174. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with methotrexate.
175. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with cyclophosphamide.
176. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with cisplatin.
177. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with carboplatin.
178. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with doxorubicin.
179. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with pegylated liposomal doxorubicin.
180. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with epirubicin.
181. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with tamoxifen.
182. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with fulvestrant.
183. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with anastrozole.
184. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with letrozole.
185. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with exemestane.
186. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with trastuzumab.
187. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with ado-trastuzumab emtansine.
188. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with pertuzumab.
189. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with lapatinib.
190. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with everolimus.
191. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with temsirolimus.
192. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with the CDK4/6 inhibitor LY2835219.
193. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with the CDK4/6 inhibitor LEE011.
194. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with the CDK4/6 inhibitor PD 0332991.
195. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with bevacizumab.
196. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with an anti-CTLA-4 agent.
197. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with ipilimumab.
198. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with an anti-PD-1 agent.
199. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with lambrolizumab.
200. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with an anti-PD L-1 agent.
201. The methods of any of claims 161-164, wherein the composition of Formula I is used in combination with MPDL3280A.
202. The methods of any of claims 161-201, wherein the composition is the composition of Formula II.
203. The methods of any of claims 161-202, wherein the composition of Formula I or Formula II is used in combination with more than one of the other agents identified in claims 166-201.
204. A method of treating cancer, comprising administering an effective amount of a composition of Formula I:
wherein n is an integer from 0 to 7;
X is the basic radical of a pharmaceutically acceptable salt;
provided that when n is 0, the composition of Formula I is the parent free base, to a patient in need thereof, wherein the patient overexpresses tyrosine kinase with tunica interna endothelial cell kinase-2 (TIE2) and the cancer is selected from breast cancer, colorectal cancer, hepatocellular carcinoma, head and neck cancer, bladder cancer, ovarian cancer, gliomas, angiosarcomas, melanomas, or acute myeloid leukemia.
wherein n is an integer from 0 to 7;
X is the basic radical of a pharmaceutically acceptable salt;
provided that when n is 0, the composition of Formula I is the parent free base, to a patient in need thereof, wherein the patient overexpresses tyrosine kinase with tunica interna endothelial cell kinase-2 (TIE2) and the cancer is selected from breast cancer, colorectal cancer, hepatocellular carcinoma, head and neck cancer, bladder cancer, ovarian cancer, gliomas, angiosarcomas, melanomas, or acute myeloid leukemia.
205. The method of claim 204, wherein the composition of Formula I is administered in combination with one or more other agents.
206. The method of claims 204 or 205, wherein the composition of Formula I
is administered daily.
is administered daily.
207. The method of claims 204 or 205, wherein the composition of Formula I
is administered intermittent non-daily.
is administered intermittent non-daily.
208. The method of claims 204 or 205, wherein the composition of Formula I
is administered three times weekly.
is administered three times weekly.
209. The method of claims 204 or 205, wherein the composition of Formula I
is administered two times weekly.
is administered two times weekly.
210. The method of claims 204 or 205, wherein the composition of Formula I
is administered one time weekly.
is administered one time weekly.
211. The method of claims 204 or 205, wherein the composition of Formula I
is administered one time every two weeks.
is administered one time every two weeks.
212. The method of claims 1, 38, 75, 118, 161 204, or 205, wherein the cancer is triple negative breast cancer.
213. The method of claims 1, 38, 75, 118, 161, 204, and 205, wherein the cancer is estrogen positive (ER) and HER2 receptor kinase negative (HER2-) breast cancer.
214. The method of claims 1, 38, 75, 118, 161, 204, or 205, wherein the cancer is inflammatory breast cancer.
215. The method of claims 1, 38, 75, 118, 161, 204, or 205, wherein the breast cancer is metastatic.
216. The method of claims 204 or 205, wherein the treatment comprises preventing or reducing one or more of primary tumor growth, tumor invasiveness, cancer intravasation, cancer dissemination, metastasis, and tumor immunotolerance.
217. The method of claims 204 or 205, wherein the treatment comprises increasing patient survival rates.
218. The method of claim 205, wherein the other agent is one or more of paclitaxel, paclitaxel protein-bound particles for injectable suspension, eribulin, docetaxel, ixabepilone, vincristine, vinorelbine, cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, temozolomide, doxorubicin, pegylated liposomal doxorubicin, daunorubicin, idarubicin, and epirubicin, 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacytadine, gemcitabine, methotrexate, erlotinib, gefitinib, lapatinib, everolimus, temsirolimus, LY2835219, LEE011, PD 0332991, crizotinib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, axitinib, dasatinib, imatinib, nilotinib, vemurafenib, dabrafenib, trametinib, idelalisib, quizartinib, tamoxifen, fulvestrant, anastrozole, letrozole, exemestane, abiraterone acetate, enzalutamide, nilutamide, bicalutamide, flutamide, cyproterone acetate, prednisone, dexamethasone, irinotecan, camptothecin, topotecan, etoposide, etoposide phosphate, mitoxantrone, vorinostat, romidepsin, panobinostat, valproic acid, belinostat, DZNep 5-aza-2'-deoxycytidine, bortezomib, carfilzomib, thalidomide, lenalidomide, pomalidomide, trastuzumab, pertuzumab, cetuximab, panitumumab, ipilimumab, labrolizumab, nivolumab, MPDL3280A, bevacizumab, aflibercept, brentuximab vedotin, ado-trastuzumab emtansine, radiotherapy, and sipuleucel-T.
219. The method of claim 205, wherein the composition of Formula I is administered an adjuvant or neoadjuvant therapy.
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PCT/US2013/069005 WO2015069266A1 (en) | 2013-11-07 | 2013-11-07 | Methods for inhibiting tie2 kinase useful in the treatment of cancer |
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US8461179B1 (en) | 2012-06-07 | 2013-06-11 | Deciphera Pharmaceuticals, Llc | Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases |
KR20160070188A (en) * | 2013-11-07 | 2016-06-17 | 데시페라 파마슈티칼스, 엘엘씨. | Methods for inhibiting tie2 kinase useful in the treatment of cancer |
ES2710211T3 (en) | 2014-02-04 | 2019-04-23 | Pfizer | Combination of a PD-1 antagonist and a VEGFR inhibitor to treat cancer |
RU2714233C2 (en) | 2015-02-26 | 2020-02-13 | Мерк Патент Гмбх | Pd-1/pd-l1 inhibitors for treating cancer |
WO2016191401A1 (en) * | 2015-05-27 | 2016-12-01 | Albert Einstein College Of Medicine, Inc. | Tmem active test and uses thereof in diagnosis, prognosis and treatment of tumors |
CA2989586A1 (en) | 2015-06-16 | 2016-12-22 | Pfizer, Inc. | Pd-l1 antagonist combination treatments |
CN114191428A (en) | 2016-03-02 | 2022-03-18 | 卫材研究发展管理有限公司 | Eribulin-based antibody-drug conjugates and methods of use |
US10690673B2 (en) | 2016-03-29 | 2020-06-23 | Mayo Foundation For Medical Education And Research | Method of treating cancer metastasis by CDK 4/6 inhibitors |
TWI808055B (en) | 2016-05-11 | 2023-07-11 | 美商滬亞生物國際有限公司 | Combination therapies of hdac inhibitors and pd-1 inhibitors |
TWI794171B (en) | 2016-05-11 | 2023-03-01 | 美商滬亞生物國際有限公司 | Combination therapies of hdac inhibitors and pd-l1 inhibitors |
KR20190062515A (en) | 2016-10-06 | 2019-06-05 | 화이자 인코포레이티드 | Usage of Abelipab for the Treatment of Cancer |
US11040027B2 (en) | 2017-01-17 | 2021-06-22 | Heparegenix Gmbh | Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death |
CN106822128A (en) * | 2017-02-24 | 2017-06-13 | 南华大学附属第医院 | The new opplication of tyrosine kinase inhibitor DCC 2036 |
CN111818915B (en) | 2018-01-31 | 2024-05-24 | 德西费拉制药有限责任公司 | Combination therapy for the treatment of gastrointestinal stromal tumors |
CN110003181B (en) * | 2019-05-22 | 2020-08-28 | 北京凯恩梅格医药科技有限公司 | c-Met/HDAC double-target inhibitor based on crizotinib structure and synthetic method and application thereof |
TW202122085A (en) * | 2019-08-12 | 2021-06-16 | 美商迪賽孚爾製藥公司 | Methods for treating vascular malformations |
KR20220045189A (en) | 2019-08-12 | 2022-04-12 | 데시페라 파마슈티칼스, 엘엘씨. | How to treat gastrointestinal stromal tumors |
TW202122082A (en) | 2019-08-12 | 2021-06-16 | 美商迪賽孚爾製藥有限公司 | Methods of treating gastrointestinal stromal tumors |
CN112812109B (en) * | 2019-11-18 | 2022-06-21 | 中国科学院微生物研究所 | Compound DaP-01 and preparation method and application thereof |
JP2023509628A (en) | 2019-12-30 | 2023-03-09 | デシフェラ・ファーマシューティカルズ,エルエルシー | 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3- Composition of phenylurea |
EP4327827A3 (en) | 2019-12-30 | 2024-05-29 | Deciphera Pharmaceuticals, LLC | Amorphous kinase inhibitor formulations and methods of use thereof |
US11779572B1 (en) | 2022-09-02 | 2023-10-10 | Deciphera Pharmaceuticals, Llc | Methods of treating gastrointestinal stromal tumors |
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WO2011150198A1 (en) * | 2010-05-27 | 2011-12-01 | Ambit Biosciences Corporation | Azolyl urea compounds and methods of use thereof |
WO2012097021A1 (en) * | 2011-01-11 | 2012-07-19 | Glaxosmithkline Llc | Combination |
MX359664B (en) * | 2011-07-29 | 2018-10-05 | Univ Colorado Regents | Treatment of breast cancer. |
WO2013036232A2 (en) * | 2011-09-08 | 2013-03-14 | Deciphera Pharmaceuticals, Llc | Methods and compositions for the treatment of myeloproliferative diseases and other proliferative diseases |
US20130071403A1 (en) * | 2011-09-20 | 2013-03-21 | Vical Incorporated | Synergistic anti-tumor efficacy using alloantigen combination immunotherapy |
KR20160070188A (en) * | 2013-11-07 | 2016-06-17 | 데시페라 파마슈티칼스, 엘엘씨. | Methods for inhibiting tie2 kinase useful in the treatment of cancer |
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