WO2013082511A1 - Procédés pour surmonter la résistance tumorale aux antagonistes de vegf - Google Patents

Procédés pour surmonter la résistance tumorale aux antagonistes de vegf Download PDF

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WO2013082511A1
WO2013082511A1 PCT/US2012/067419 US2012067419W WO2013082511A1 WO 2013082511 A1 WO2013082511 A1 WO 2013082511A1 US 2012067419 W US2012067419 W US 2012067419W WO 2013082511 A1 WO2013082511 A1 WO 2013082511A1
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tumor
vegf
cells
csf
cancer
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PCT/US2012/067419
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WO2013082511A9 (fr
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Napoleone Ferrara
Vernon PHAN
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Genentech, Inc.
F. Hoffmann-La Roche Ag
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Publication of WO2013082511A1 publication Critical patent/WO2013082511A1/fr
Publication of WO2013082511A9 publication Critical patent/WO2013082511A9/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/243—Colony Stimulating Factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies

Definitions

  • the present invention relates generally to the field of molecular biology and clinical oncology.
  • the invention concerns compositions and methods effective for overcoming tumor resistance to treatment with VEGF antagonists.
  • angiogenesis which involves the formation of new blood vessels from preexisting endothelium, plays a significant role in the pathogenesis of a variety of disorders. These include solid tumors and metastasis, atherosclerosis, retrolental fibroplasia, hemangiomas, chronic inflammation, intraocular neovascular syndromes such as proliferative retinopathies, e.g., diabetic retinopathy, age-related macular degeneration (AMD), neovascular glaucoma, immune rejection of transplanted corneal tissue and other tissues, rheumatoid arthritis, and psoriasis.
  • proliferative retinopathies e.g., diabetic retinopathy, age-related macular degeneration (AMD), neovascular glaucoma, immune rejection of transplanted corneal tissue and other tissues, rheumatoid arthritis, and psoriasis.
  • AMD age-related macular degeneration
  • tumor angiogenesis appears to be crucial for the transition from hyperplasia to neoplasia, and for providing nourishment for the growth and metastasis of the tumor.
  • Neovascularization allows the tumor cells to acquire a growth advantage and proliferative autonomy compared to normal cells.
  • a tumor usually begins as a single aberrant cell which can proliferate only to a size of a few cubic millimeters due to the distance from available capillary beds, and it can stay 'dormant' without further growth and dissemination for a long period of time.
  • ERK/MAPK pathway is upregulated in 30% of all tumors and oncogenic activating mutations in K-Ras and B-Raf have been identified in 22% and 18% of all cancers respectively. It has been shown that inhibition of the ERK pathway, and in particular inhibition of MEK kinase activity, results in anti-metastatic effects largely due to a reduction of cell-cell contact and motility.
  • a method of inhibiting proliferation and migration of cells in tumor stroma comprising administering an effective amount of a MEK inhibitor to a human subject having a tumor that is resistant or refractory to treatment with a VEGF antagonist.
  • the cells in tumor stroma are derived from bone marrow, are of hematopoietic lineage or subsets thereof as decribed above.
  • the cells in tumor stroma are tumor-associated fibroblast cells.
  • the VEGF antagonist in the methods of the invention is an anti-VEGF antibody or functional fragment thereof, such as bevacizumab.
  • the MEK inhibitor useful in the methods of the invention is a small molecule compound or a pharmaceutically acceptable salt thereof.
  • the small molecule compound is selected from the group consisting of PD325901, PD-181461, AR Y142886 / AZD6244, ARRY-509, GDC0973 (XL518), GDC0987, JTP- 74057, AS-701255, AS-701173, AZD8330, ARRY162, ARRY300, RDEA436, E6201 , R04987655/R-7167, GSK1120212 and AS-703026.
  • the small molecule compound is an azetidine compound.
  • the human subject in the methods of the invention has been previously treated with chemotherapy, a VEGF antagonist or both.
  • the human subject has been previously treated with bevacizumab but the tumor therein has relapsed.
  • a combination therapy using bevacizumab and GDC-0973 is contemplated.
  • a combination therapy using anti-G-CSF antibody and bevacizumab is contemplated.
  • the invention provides a novel combination of a) a MEK inhibitor and b) a VEGF antagonist for concurrent, separate or sequential use in treating tumor. Also provided is a pharmaceutical preparation comprising an effective amount of the above combination and at least one pharmaceutically acceptable carrier.
  • FIG. 2 depicts the signaling mechanisms controlling G-CSF expression in cancer cells.
  • (2B) Enforced expression of mutant BRAF (V600E) induces G-CSF expression in 67NR cells. *p 0.0004.
  • (2C) MEK inhibitor (GDC-0973) inhibits ERK phosphorylation and G-CSF expression in 4T1 cells. *p ⁇ 0.002.
  • ELISA shows the effects of MEKi and Pi3K inhibitor LY294002 (Pi3Ki) on G-CSF release. *p ⁇ 0.001.
  • Figure 3 depicts growth factors that positively regulate G-CSF secretion in
  • FIG. 4 depicts effects of MEKi, anti-G-CSF, anti-VEGF antibodies and combinations thereof on 4T1 tumor growth.
  • (4A-B) MEKi reduces G-CSF and Bv8 levels in 4T1 tumor-bearing mice, *p ⁇ 0.001.
  • (4F) Reduced angiogenesis in 4T1 tumors treated with MEKi plus anti-VEGF, or anti-G-CSF plus anti-VEGF combination treatments. Treatment groups are indicated in the figure. Tumor sections were stained with anti-CD31 (red). Scale bar is lOOum.
  • (4G) Quantitative analysis of tumor vascular surface area. Whole tumor cross-sections were stained with CD31 and analyzed as described in Methods (n 4, *p ⁇ 0.05).
  • FIG. 5 depicts effects of MEKi, anti-G-CSF, anti-VEGF antibodies and combinations thereof on LLC tumor growth.
  • Figure 6 depicts effects of RAF and MEK inhibitors on G-CSF expression in cancer cells.
  • MEKi GDC-0973 inhibits G-CSF
  • RAFi GDC-0879 induces G-CSF in mouse lung cell lines with KRAS mutation.
  • D DMSO
  • P PI3Ki LY-294002 5uM
  • R RAFi GDC-0879 luM
  • GDC-0973 MEKi: O.OluM, O. luM and l .OuM
  • G-CSF release was analyzed by ELISA.
  • Ten different human cancer cell lines were analyzed for G-CSF release by ELISA.
  • AKT and ERK phosphorylations were assessed in total lysates.
  • Cells were treated with DMSO (D), PBKi LY-294002 5uM (P), RAFi GDC-0879 luM (R), or GDC-0973 (MEKi : O.OluM, O. luM and l .OuM) for 24hrs.
  • FIG. 7 depicts effects of MEKi, anti-VEGF antibody and combination thereof on LLC tumor growth.
  • MEKi plus anti-VEGF combination treatment reduces growth of LLC tumors by approximately 64% at day 26 when compared to either MEKi or anti- VEGF as a single agent.
  • Figure 8 shows a marked reduction in total white blood cells counts in the peripheral blood of the animals that received either the MEKi alone, or MEKi plus anti- VEGF combination treatments compared to controls (8A). Reduction in white blood cells was correlated with a decrease in Cdl lb + Ly6G + cells in peripheral blood and in G-CSF and Bv8 plasma levels in animals that received MEKi as a single agent or MEKi plus anti- VEGF (8B-D).
  • FIG. 9 illustrates results from an Anti-VEGF resistant PDAC allograft mouse model.
  • G-CSFR wild-type (G-CSFR +/+ ) or G-CSFR knockout (G-CSFR 7 ) mice were crossed with RAG2 knockout (RAG2 ⁇ ⁇ ) mice to generate G-CSFR /+ RAG2 ⁇ ⁇ and (G-CSFR ⁇ / ⁇ RAG2 ⁇ / ⁇ .
  • aRAG anti-Ragweed
  • aVEGF anti-VEGF
  • Figure 10 illustrates results from a Kras-driven PDAC GEMM. (10A)
  • Figure 12 illustrates effects of MEKi GDC-0973 on G-CSF release and neutrophil mobilization in a Kras-driven PDAC GEMM.
  • (12A) ELISA analysis of G-CSF release in PDAC mice after received MEKi GDC-0973 at different time points, as indicated. Each number corresponds to an animal (n 5/group).
  • (12B) Cytokines and growth factors changes in plasma were monitored by Luminex. Time points were analyzed at day 7 after MEKi GDC-0973 administration. Wildtype (Naive), PDAC treated with control (Vehicle) or MEKi GDC-0973, (n 5/group) *p ⁇ 0.05. Error bars indicate SD.
  • cancers that are amenable to treatment by the anti-G-CSF antibody, anti-Bv8-antibody, anti-PK l antibody or any combination thereof include breast cancer, colorectal cancer, rectal cancer, non-small cell lung cancer, glioblastoma, non-Hodgkins lymphoma (NHL), renal cell cancer, prostate cancer, melanoma, liver cancer, pancreatic cancer, soft-tissue sarcoma, kaposi's sarcoma, carcinoid carcinoma, head and neck cancer, ovarian cancer and multiple myeloma.
  • breast cancer colorectal cancer, rectal cancer, non-small cell lung cancer, glioblastoma, non-Hodgkins lymphoma (NHL), renal cell cancer, prostate cancer, melanoma, liver cancer, pancreatic cancer, soft-tissue sarcoma, kaposi's sarcoma, carcinoid carcinoma, head and neck cancer, ovarian cancer and multiple myelom
  • the cancer is selected from the group consisting of small cell lung cancer, gliblastoma, neuroblastomas, melanoma, breast carcinoma, gastric cancer, colorectal cancer (CRC), and hepatocellular carcinoma. Yet, in some embodiments, the cancer is selected from the group consisting of non-small cell lung cancer, colorectal cancer, renal cell cancer, ovarian cancer, prostate cancer, glioblastoma and breast carcinoma, including metastatic forms of those cancers.
  • Cancer cells Primary tumors are classified by the type of tissue from which they arise; metastatic tumors are classified by the tissue type from which the cancer cells are derived. Over time, the cells of a malignant tumor become more abnormal and appear less like normal cells. This change in the appearance of cancer cells is called the tumor grade and cancer cells are described as being well-differentiated, moderately-differentiated, poorly-differentiated, or undifferentiated. Well-differentiated cells are quite normal appearing and resemble the normal cells from which they originated. Undifferentiated cells are cells that have become so abnormal that it is no longer possible to determine the origin of the cells.
  • Epithelial cancers generally evolve from a benign tumor to a preinvasive stage
  • adenocarcinoma (PDAC) investigated in the present invention is a type of cancer resistant to anti-VEGF therapy.
  • a cancer refers to cancer, cancerous cells, or a tumor that initially responded to a cancer therapy comprising at least a VEGF antagonist, but eventually reinitiates growth despite ongoing cancer therapy.
  • a cancer is relapse tumor growth or relapse cancer cell growth where the number of cancer cells has not been significantly reduced, or has increased, or tumor size has not been significantly reduced, or has increased, or fails any further reduction in size or in number of cancer cells.
  • sensitizing tumor to treatment with a VEGF antagonist herein is meant a step by which the targeted tumor becomes more sensitive, vulnerable or susceptable to treatment with a VEGF antagonist than a non-sensitized tumor control.
  • Cells in tumor stroma refers to the cell population in stroma, the microenvironment surrounding and supporting a tumor.
  • the cell population in tumor stroma often comprises tumor-associated fibroblasts, pericytes, mesenchymal stem cells and inflammatory-imuune cells.
  • Some cells in tumor stroma are derived from bone marrow and are of hematopoietic lineage, including but not limited to, myeloid cells, granulocytes and neutropils.
  • VEGF -A is part of a gene family including VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F, and P1GF.
  • VEGF -A primarily binds to two high affinity receptor tyrosine kinases, VEGFR-1 (Flt-1) and VEGFR-2 (Flk-l/KDR), the latter being the major transmitter of vascular endothelial cell mitogenic signals of VEGF -A.
  • VEGFR-1 Flt-1
  • VEGFR-2 Flk-l/KDR
  • a "chemotherapeutic agent” refers to a chemical compound useful in the treatment of cancer.
  • chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine;
  • alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN®)
  • alkyl sulfonates such as busulfan, improsulfan and piposulfan
  • aziridines such as benzodopa, carboquone, meturedopa, and ure
  • celecoxib or etoricoxib proteosome inhibitor
  • proteosome inhibitor e.g. PS341
  • bortezomib VELCADE®
  • CCI-779 tipifarnib (Rl 1577); orafenib, ABT510
  • Bcl-2 inhibitor such as oblimersen sodium
  • Sustained-release preparations of MEK inhibitors may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a MEK inhibitor, which matrices are in the form of shaped articles, e.g., films, or microcapsules.
  • the aqueous phase of the cream base may include a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs.
  • MEKi, anti-G-CSF, combination of MEKi plus anti-VEGF or anti-G-CSF plus anti-VEGF treatment significantly reduced G-CSF and Bv8 levels (Figure 5A and 5B) compared to anti-ragweed or anti-VEGF treated groups.
  • Cdl lb + Ly6G + cells were significantly decreased in the peripheral blood (Figure 5C), accompanied by marked reduction in total white blood cell counts ( Figure 5D).
  • MEKi treatment resulted in approximately 50% inhibition in tumor growth, whereas anti-G-CSF resulted in approximately 25% inhibition compared to anti-ragweed control group (Figure 5E).
  • G-CSF RNA S.E. signaling pathway Detection
  • myofibroblast-like cell fractions (29) that are negative for CD31 were purified to exclude endothelial cell contamination from tumors. Antibody staining confirmed that these cells express aSMA and CD 105 and are negative for CD31. Incubation of aSMA+CD105+CD31- cells with FGFs resulted in G-CSF release in a MEK-dependent manner.

Abstract

La présente invention concerne d'une manière générale l'inhibition de la croissance tumorale. En particulier, l'invention concerne la prévention ou le traitement d'angiogenèse de tumeur et l'inhibition de la croissance tumorale dans des tumeurs résistant au traitement anti-VEGF, à l'aide d'inhibiteurs de MEK ou d'antagonistes de G-CSF, soit individuellement soit en combinaison avec un antagoniste de VEGF.
PCT/US2012/067419 2011-12-02 2012-11-30 Procédés pour surmonter la résistance tumorale aux antagonistes de vegf WO2013082511A1 (fr)

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Cited By (3)

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US9682154B2 (en) 2013-02-04 2017-06-20 Vascular Biogenics Ltd. Methods of inducing responsiveness to anti-angiogenic agent
WO2021108255A1 (fr) * 2019-11-25 2021-06-03 The Regents Of The University Of California Inhibiteurs de vegf à action prolongée pour néovascularisation intraoculaire
US11524053B2 (en) 2018-01-26 2022-12-13 The Regents Of The University Of California Methods and compositions for treatment of angiogenic disorders using anti-VEGF agents

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