WO2009064300A1 - Combinaisons d'inhibiteurs de hdac et de cytokines/facteurs de croissance - Google Patents

Combinaisons d'inhibiteurs de hdac et de cytokines/facteurs de croissance Download PDF

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WO2009064300A1
WO2009064300A1 PCT/US2007/084836 US2007084836W WO2009064300A1 WO 2009064300 A1 WO2009064300 A1 WO 2009064300A1 US 2007084836 W US2007084836 W US 2007084836W WO 2009064300 A1 WO2009064300 A1 WO 2009064300A1
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cancer
agent
hdac inhibitor
effective amount
agents
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PCT/US2007/084836
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English (en)
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William Matsui
Richard J. Jones
Carol A. Huff
B. Douglas Smith
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The Johns Hopkins University
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Priority to PCT/US2007/084836 priority Critical patent/WO2009064300A1/fr
Publication of WO2009064300A1 publication Critical patent/WO2009064300A1/fr

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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/204—IL-6
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • a therapeutically or prophylactically effective amount of an HDAC inhibitor and a therapeutically or prophylactically effective amount of a cytokine are provided herein.
  • kits for inhibiting the proliferation of cancer by contacting stem cells present in the cancer with a therapeutically or prophylactically effective amount of an HDAC inhibitor and a therapeutically or prophylactically effective amount of a cytokine.
  • kits for inducing terminal differentiation in cancer stem cells by contacting the cancer stem cells with a therapeutically or prophylactically effective amount of an HDAC inhibitor and a therapeutically or prophylactically effective amount of a cytokine.
  • compositions containing a therapeutically or prophylactically effective amount of an HDAC inhibitor and therapeutically or prophylactically effective amount of a cytokine are provided herein.
  • kits containing a therapeutically or prophylactically effective amount of an HDAC inhibitor and therapeutically or prophylactically effective amount of a cytokine are in the same dosage form. In other embodiments, the HDAC inhibitor and the cytokine are in different dosage forms. In some embodiments, the HDAC inhibitor is formulated into a first dosage form with a first color and the cytokine is formulated into a second dosage form with a second color.
  • the first and second colors can be the same or different.
  • Provided herein are methods for treating cancer containing circulating cancer stem cells by administering to a patient a therapeutically effective amount of an HDAC inhibitor.
  • Provided herein are methods for inhibiting the proliferation of a cancer by contacting at least one circulating cancer stem cell with an effective amount of an HDAC inhibitor.
  • the HDAC inhibitor is a Class I selective HDAC inhibitor.
  • the Class I selective HDAC is selected from MS-275 and MGCD-0103.
  • the HDAC inhibitor is a non-selective HDAC inhibitor, including but not limited to SAHA.
  • the cytokine is an interleukin.
  • the interleukin is selected from IL-2, IL-4, IL-6 and IL-7.
  • the cytokine is a growth factor.
  • the cytokine is a lineage-specific growth factor.
  • the growth factor is selected from G-CSF and GM-CSF.
  • the cancer is a solid tumor.
  • the cancer is a hematological malignancy.
  • the hematological malignancy is a B-cell malignancy.
  • the cancer is selected from multiple myeloma, acute myeloid leukemia, acute lymphoid leukemia, non-Hodgkin's lymphoma and Hodgkin's lymphoma.
  • the cancer cells are selected from cancer cells of multiple myeloma, acute myeloid leukemia, acute lymphoid leukemia, non-Hodgkin's lymphoma and Hodgkin's lymphoma.
  • the cancer stem cells are precursors to cancer cells selected from cancer cells of multiple myeloma, acute myeloid leukemia, acute lymphoid leukemia, non-Hodgkin's lymphoma and Hodgkin's lymphoma.
  • compositions, methods and kits described herein in addition to the
  • the patient is administered and/or the composition contains a therapeutically effective amount of an additional chemotherapeutic agent.
  • the additional chemotherapeutic agent is selected from a methyltransferase inhibitor, a selective RAR agonist, or a selective RXR agonist.
  • the methyltransferase inhibitor is 5-azacytidine.
  • the selective RXR agonist is bexarotene.
  • kits for selecting a cancer patient who is predicted to benefit from the therapeutic administration of an HDAC inhibitor and a cytokine comprising the steps of: (a) obtaining a sample from the patient; (b) isolating a predetermined population of cells from the blood sample using at least one of flow cytometry, fluorescence, activated cell sorting, panning, affinity column separation and magnetic selection; and (c) determining whether the isolated cells are ALDH + ; wherein the patient is predicted to benefit from therapeutic administration of an HDAC inhibitor and a cytokine when the isolated cells are
  • FIG. 1 illustrates the phenotypic differentiation of cancer stem cells by an HDAC inhibitor and a cytokine/growth factor.
  • FIG. 2 illustrates the inhibition of cancer stem cells by an HDAC inhibitor and a cytokine/growth factor.
  • the HDACs are a family including at least eighteen enzymes, grouped in three classes (Class I, II and III).
  • Class I HDACs include, but are not limited to, HADCs 1, 2, 3, 8 and 11.
  • Class I HDACs can be found in the nucleus and are believed to be involved with transcriptional control repressors.
  • Class II HDACs include, but are not limited to, HDACS 4, 5, 6, 7, and 9 and can be found in both the cytoplasm as well as the nucleus.
  • Class III HDACs are believed to be NAD dependent proteins and include, but are not limited to, members of the Sirtuin family of proteins. Non-limiting examples of sirtuin proteins include SIRT 1-7.
  • selective HDAC refers to an HDAC inhibitor that does not substantially interact with all three HDAC classes.
  • Class I selective HDAC refers to an HDAC inhibitor that does not substantially interact with a Class II HDAC or Class III HDAC.
  • cancer stem cell refers to cells that are precursors to mature cancer cells. In certain embodiments, mature cancer cells do not proliferate. In some embodiments, the cancer stem cells are resistant to cancer therapy that is effective for the mature cancer cells. In some embodiments, these cells have a high level of Aldehyde Dehydrogenase (ALDH hlgh ). In some embodiments, the cells are ALDH positive (ALDH + ). In some embodiments (e.g., in certain embodiments of multiple myeloma), the cancer stem cells are CD138 ncg and the mature cancer cells are CD138 + .
  • the cancer stem cells are CD15 ncg and the mature cancer cells are CD15 + .
  • the cancer stem cells are CD30 ncg and the mature cancer cells are CD30 + .
  • the cancer stem cells are CD19 + .
  • the cancer stem cells are CD20 + .
  • the cancer stem cells are CD27 + . In some embodiments (e.g., in certain embodiments of leukemia), the cancer stem cells are CD34 + . In some embodiments (e.g., in certain embodiments of Hodgkin's lymphoma and multiple myeloma), the cancer stem cells are CD38 ncg .
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non -human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • non -mammals include, but are not limited to, birds, fish and the like.
  • the mammal is a human.
  • treat include alleviating, abating or ameliorating a disease or condition symptoms, ameliorating the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
  • the terms further include achieving a therapeutic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder.
  • compositions include preventing additional symptoms, preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition and are intended to include prophylaxis.
  • the terms further include achieving a prophylactic benefit.
  • the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • the agents described herein may be administered in combination as simple mixtures as well as chemical hybrids.
  • An example of the latter is where the agent is covalently linked to a targeting carrier or to an active pharmaceutical. Covalent binding can be accomplished in many ways, such as, though not limited to, the use of a commercially available cross-linking agent.
  • the terms "pharmaceutical combination”, “administering an additional therapy”, “administering an additional therapeutic agent” and the like refer to a pharmaceutical therapy resulting from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that at least one of the agents described herein, and at least one co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that at least one of the agents described herein, and at least one co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with variable intervening time limits, wherein such administration provides effective levels of the two or more agents in the body of the patient.
  • cocktail therapies e.g. the administration of three or more active ingredients.
  • the terms "co-administration”, “administered in combination with” and their grammatical equivalents or the like are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times.
  • the agents described herein will be co-administered with other agents.
  • These terms encompass administration of two or more agents to an animal so that both agents and/or their metabolites are present in the animal at the same time. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and/or administration in a composition in which both agents are present.
  • the agents described herein and the other agent(s) are administered in a single composition.
  • the agents described herein and the other agent(s) are admixed in the composition.
  • an “effective amount”, “therapeutically effective amount” or “pharmaceutically effective amount” as used herein, refer to a sufficient amount of at least one agent being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising an agent as set forth herein required to provide a clinically significant decrease in a disease.
  • An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study.
  • administer refers to the methods that may be used to enable delivery of agents or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the agents and methods described herein, e.g., as discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In certain embodiments, the agents and compositions described herein are administered orally.
  • the term "acceptable” as used herein, with respect to a formulation, composition or ingredient, means having no persistent detrimental effect on the general health of the subject being treated.
  • pharmaceutically acceptable refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the agents described herein, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • carrier refers to relatively nontoxic chemical agents that facilitate the incorporation of an agent into cells or tissues.
  • pharmaceutically acceptable derivative or prodrug refers to any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of an agent, which, upon administration to a recipient, is capable of providing, either directly or indirectly, a agent of this invention or a pharmaceutically active metabolite or residue thereof.
  • Particularly favored derivatives or prodrugs are those that increase the bioavailability of the agents of this invention when such agents are administered to a patient (e.g., by allowing an orally administered agent to be more readily absorbed into blood) or which enhance delivery of the parent agent to a biological compartment (e.g., the brain or lymphatic system).
  • the terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect.
  • the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
  • An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
  • cancer treatment encompasses treatments such as surgery (such as cutting, abrading, ablating (by physical or chemical means or a combination of physical or chemical means), suturing, lasering or otherwise physically changing body tissues and organs), radiation therapy, administration of chemotherapeutic agents and combinations of any two or all of these methods. Combination treatments may occur sequentially or concurrently.
  • Treatments(s), such as radiation therapy and/or chemotherapy, that is administered prior to surgery is referred to as neoadjuvant therapy.
  • Treatments(s), such as radiation therapy and/or chemotherapy, administered after surgery is referred to herein as adjuvant therapy.
  • the chemotherapeutic agent is a cytotoxic agent, an antiproliferative, a targeting agent (such as kinase inhibitors and cell cycle regulators), or a biologic agent (such as cytokines, vaccines, viral agents, and other immunostimulants such as BCG, hormones, monocolonal antibodies and siRNA).
  • a targeting agent such as kinase inhibitors and cell cycle regulators
  • a biologic agent such as cytokines, vaccines, viral agents, and other immunostimulants such as BCG, hormones, monocolonal antibodies and siRNA.
  • Histone deacetylation is a characteristic feature of cancer cells. Histones are small proteins that are tightly complexed with DNA to form a nucleosome, which is further connected by linker DNA to form a solenoid. Histones extending from the nucleosomal core are enzymatically modified, affecting chromatin structure and gene expression. Specifically, histones are modified by histone deacetylases (HDACs) by removing an acetyl group.
  • HDACs histone deacetylases
  • tumor growth is mediated by specialized populations of cancer stem cells. The failure of certain agents to cure various types of cancer (e.g., multiple myeloma) indicates that some cancer stem cells are relatively resistant to these agents.
  • the present invention provides for compositions and methods for treating a patient suffering from cancer containing cancer stem cells by administering a therapeutically effective amount of an HDAC inhibitor whereby the number of cancer stem cells found circulating in a patient's blood is reduced.
  • the present invention provides for compositions and methods for inhibiting the proliferation of cancer cells by contacting cancer stem cells with an effective amount of a first agent and an effective amount of a second agent, wherein the first agent is an HDAC inhibitor.
  • the present invention provides for compositions and methods for inducing terminal differentiation in cancer stem cells by contacting the cancer stem cells with an effective amount of a first agent and an effective amount of a second agent, wherein the first agent is an HDAC inhibitor.
  • the process of inducing terminal differentiation involves a process of forced cell maturation, which causes the cancer stem cells to progressively lose their ability to proliferate for long periods of time.
  • the methods described herein include methods of inhibiting clonogenic cancer growth by contacting cancer stem cells of the cancer with an effective amount of an HDAC inhibitor.
  • the method of inhibiting clonogenic cancer cell growth includes methods of reducing the clonogenic cell growth by at least 50%.
  • clonogenic cancer cell growth is reduced by at least 60%, 70%, 75%, 80%, 85%, 90%, 95% or 99%.
  • the level of clonogenic cancer cell growth inhibition is determined based on a comparison of treated cancer stem cells to untreated cancer stem cells. In other embodiments, the level of clonogenic cancer growth inhibition is determined based on overall clonogenic cancer growth.
  • the HDAC inhibitor may be a Class I selective HDAC inhibitor.
  • the HDAC inhibitor inhibits at least one of HDAC-I, HDAC-2, HDAC-3, HDAC-8, or HDAC-11.
  • the first agent inhibits HDAC-I.
  • the HDAC inhibitor inhibits HDAC-2.
  • the HDAC inhibitor inhibits HDAC-3.
  • the HDAC inhibitor inhibits HDAC- 11.
  • the HDAC inhibitor inhibits HDAC-I, HDAC-2, HDAC-3 and HDAC-11.
  • the HDAC inhibitor is, by way of non -limiting example, MGCD-0103 (N- (2-amino-phenyl)-4-[(4-pyridin-3-yl-pyrimidin-2-ylamino)-methyl]-benzamide) and derivatives of MGCD- 0103, MS-275 (N-(2-aminophenyl)-4-(N-(pyridin-3-ylmethoxycarbonyl)aminomethyl) benzamide and derivatives of MS-275 (see, e.g., U.S. Patent No.
  • the HDAC inhibitor is MS-275.
  • the HDAC inhibitor is a non-selective HDAC inhibitor.
  • the non-selective HDAC inhibitor is, by way of non-limiting example, N'-hydroxy-N-phenyl-octanediamide (suberoylanilide hydroxamic acid, SAHA), pyroxamide, CBHA, trichostatin A (TSA), trichostatin C, salicylihydroxamic acid (SBHA), azelaic bihydroxamic acid (ABHA), azelaic- l-hydroxamate-9-analide (AAHA), 6-(3-chlorophenylureido) carpoic hydroxamic acid (3Cl- UCHA), oxamflatin, A-161906, scriptaid, PXD-101, LAQ-824, CHAP, MW2796, LBH589 or MW2996, or derivatives of any of these compounds
  • the HDAC inhibitor is selected from, by way of non-limiting example, hydroxamic acids, suberoylanilidine hydroxamic acid, TSA, TSC, m- carboxycinnamic acid bishydroxamide (CBHA), pyrozamide, salicylbishyudoxamic acid, suberoyl bishydroxamic acid (SBHA), azelaic bishydroxamic acid (ABHA), Azelaic- l-hydroxamate-9-anilide (AAHA), Oxamflatin, Scriptaid, CHAP, MW2996, MW2976, butanoic acid, valproic acid, 4-phenylbutanoic acid, N-acetyldinaline, CI-994 trapoxins, depeudecin, depsipeptide, FK 228, FR225497, Apicidin cyclic tetrapeptide, Apicidin Ia, Apici
  • 4-phenylbutyrate (4-PBA), phenylbutyrate (PB) propionate, butyaramide, isobutyramide, phylacetate, 3-bromopropionate, tributyrin, valproic acid, Valproate, Pivanex, Savicol, Baceca and LBH589, or derivatives of any of these compounds.
  • 4-phenylbutyrate (4-PBA), phenylbutyrate (PB) propionate, butyaramide, isobutyramide, phylacetate, 3-bromopropionate, tributyrin, valproic acid, Valproate, Pivanex, Savicol, Baceca and LBH589, or derivatives of any of these compounds.
  • the HDAC inhibitor may be used in a method of treating cancer containing cancer stem cells that combines or uses the HDAC with a second agent that comprises administering an additional cancer therapy to a patient.
  • the additional cancer therapy is, by way of non-limiting example, surgery, radiation therapy or at least one chemotherapeutic agent.
  • the present invention provides for compositions and methods for treating a patient suffering from cancer by administering a therapeutically effective amount of a first agent and a therapeutically effective amount of a second agent, wherein the first agent is an HDAC inhibitor.
  • the methods described herein are cancer stem cell targeted therapy.
  • the present invention provides for compositions and methods for inhibiting the proliferation of cancer cells by contacting cancer stem cells with an effective amount of a first agent and an effective amount of a second agent, wherein the first agent is an HDAC inhibitor.
  • the present invention provides for compositions and methods for inducing terminal differentiation in cancer stem cells by contacting the cancer stem cells with an effective amount of a first agent and an effective amount of a second agent, wherein the first agent is an HDAC inhibitor.
  • the process of inducing terminal differentiation involves a process of forced cell maturation, which causes the cancer stem cells to progressively lose their ability to proliferate for long periods of time.
  • the methods described herein include methods of inhibiting clonogenic cancer growth by contacting cancer stem cells of the cancer with an effective amount of a first agent and an effective amount of a second agent, wherein the first agent is an HDAC inhibitor.
  • the method of inhibiting clonogenic cancer cell growth includes methods of reducing the clonogenic cell growth by at least 50%. In other embodiments, clonogenic cancer cell growth is reduced by at least 60%, 70%, 75%, 80%, 85%, 90%, 95% or 99%. In certain embodiments, the level of clonogenic cancer cell growth inhibition is determined based on a comparison of treated cancer stem cells to untreated cancer stem cells. In other embodiments, the level of clonogenic cancer growth inhibition is determined based on overall clonogenic cancer growth.
  • the first agent is a Class I selective HDAC inhibitor.
  • the HDAC inhibitor inhibits at least one of HDAC-I, HDAC-2, HDAC-3, HDAC-8, or HDAC-11.
  • the first agent inhibits HDAC-I.
  • the first agent inhibits HDAC-2.
  • the first agent inhibits HDAC-3.
  • the first agent inhibits HDAC-11.
  • the first agent inhibits HDAC-I, HDAC-2, HDAC-3 and HDAC-11.
  • the Class I selective HDAC inhibitor is, , by way of non-limiting example, MGCD-0103 (N-(2-amino-phenyl)-4-[(4-pyridin-3-yl- pyrimidin-2-ylamino)-methyl]-benzamide) and derivatives of MGCD-0103, MS-275 (N-(2-aminophenyl)-4- (N-(pyridin-3-ylmethoxycarbonyl)aminomethyl) benzamide and derivatives of MS-275 (see, e.g., U.S. Patent No.
  • the HDAC inhibitor is MS-275.
  • the HDAC inhibitor is a non-selective HDAC inhibitor.
  • the non-selective HDAC inhibitor is, by way of non-limiting example, N'- hydroxy-N-phenyl-octanediamide (suberoylanilide hydroxamic acid, SAHA), pyroxamide, CBHA, trichostatin A (TSA), trichostatin C, salicylihydroxamic acid (SBHA), azelaic bihydroxamic acid (ABHA), azelaic-l-hydroxamate-9-analide (AAHA), 6-(3-chlorophenylureido) carpoic hydroxamic acid (3C1-UCHA), oxamflatin, A- 161906, scriptaid, PXD-101, LAQ-824, CHAP, MW2796, LBH589 or MW2996, or a derivative of any of the foregoing.
  • SAHA suberoylanilide hydroxamic acid
  • TSA trichostatin A
  • TSA trichost
  • the HDAC inhibitor is SAHA.
  • the HDAC inhibitor is selected from, by way of non-limiting example, hydroxamic acids, suberoylanilidine hydroxamic acid, TSA, TSC, m-carboxycinnamic acid bishydroxamide (CBHA), pyrozamide, salicylbishyudoxamic acid, suberoyl bishydroxamic acid (SBHA), azelaic bishydroxamic acid (ABHA), Azelaic- l-hydroxamate-9-anilide (AAHA), Oxamflatin, Scriptaid, CHAP, MW2996, MW2976, butanoic acid, valproic acid, 4-phenylbutanoic acid, N-acetyldinaline, CI-994 trapoxins, depeudecin, depsipeptide, FK 228, FR225497, Apicidin cyclic tetrapeptide
  • the first agent is an HDAC inhibitor and the second agent is a cytokine.
  • the second agent is a growth factor.
  • the cytokine is a lineage-specific growth factor.
  • the cytokine is selected from, by way of non-limiting example, an interleukin, a chemokine and a growth factor. In specific embodiments, the cytokine is an interleukin. In some embodiments, the cytokine is a growth factor. In various embodiments, the cytokine or interleukin is selected from, by way of non-limiting example, IL-2, IL-4, IL-6 and IL-7. In certain embodiments, the cytokine or growth factor is selected from, by way of non-limiting example, GM- CSF (granulocyte monocyte colony stimulating factor) and G-CSF (granulocyte colony stimulating factor). In specific embodiments, the first agent is MS-275 and the second agent is IL-6.
  • the first agent is MS-275 and the second agent is GM-CSF. In still other embodiments, the first agent is MS-275 and the second agent is G-CSF. In yet other embodiments, the first agent is MS-275 and the second agent is IL-7. In other embodiments, the first agent is MS-275 and the second agent is IL-2. In still other embodiments, the first agent is MS-275 and the second agent is IL-4.
  • a method of treating cancer with a first agent and a second agent further comprises administering an additional cancer therapy to a patient.
  • the additional cancer therapy is, by way of non -limiting example, surgery, radiation therapy or at least one chemotherapeutic agent.
  • the present invention provides for compositions and methods for inhibiting the proliferation of cancer cells by contacting cancer stem cells with an effective amount of a first agent, an effective amount of a second agent, and an effective amount of an additional chemotherapeutic agent. In some embodiments, the present invention provides for compositions and methods for inducing terminal differentiation in cancer stem cells by contacting the cancer stem cells with an effective amount of a first agent, an effective amount of a second agent, and an effective amount of an additional chemotherapeutic agent.
  • the at least one chemotherapeutic agent includes, by way of non-limiting example, one or more of adriamycin, gemcitabine, mitomycin, oxaliplatin, fluorouracil, leucovorin, cytarabine, etoposide, capecitabine, temozolomide, doxorubicin, paclitaxel, docetaxel, bevacizumab and trastuzumab.
  • the additional chemotherapeutic agent includes, by way of non-limiting example, bexarotene and 5- azacytidine.
  • the cancer is multiple myeloma, the first agent is MS-275 and the second agent is IL-6. In certain embodiments, the cancer is multiple myeloma, the first agent is MS-275, the second agent is IL-6 and the additional chemotherapeutic agent is bexarotene. In some embodiments, the cancer is multiple myeloma, the first agent is MS-275, the second agent is IL-6 and the additional chemotherapeutic agent is 5-azacytidine. In various embodiments, the cancer is multiple myeloma, the first agent is MS-275, and the second agent is GM-CSF.
  • the cancer is acute myeloid leukemia/myelodysplastic syndrome
  • the first agent is MS-275 and the second agent is GM-CSF.
  • the cancer is acute myeloid leukemia/myelodysplastic syndrome
  • the first agent is MS-275
  • the second agent is G-CSF
  • the additional chemotherapeutic agent is 5-azacytidine.
  • the cancer is acute myeloid leukemia/myelodysplastic syndrome
  • the first agent is MS-275
  • the second agent is G-CSF
  • the additional chemotherapeutic agent is 5-azacytidine.
  • the cancer is acute myeloid leukemia/myelodysplastic syndrome
  • the first agent is MS-275
  • the second agent is G-CSF
  • the additional chemotherapeutic agent is 5-azacytidine.
  • the acute lymphoid leukemia, the first agent is MS-275 and the second agent is GM-CSF. In some embodiments, the acute lymphoid leukemia, the first agent is MS-275 and the second agent is IL-7.
  • the cancer is non-Hodgkin's lymphoma
  • the first agent is MS-275 and the second agent is GM-CSF.
  • the non-Hodgkin's lymphoma, the first agent is MS-275 and the second agent is IL-2.
  • the non-Hodgkin's lymphoma, the first agent is MS-275 and the second agent is IL-4.
  • the cancer is Hodgkin's disease (Hodgkin's lymphoma)
  • the first agent is MS- 275
  • the second agent is IL-6.
  • Figure 1 illustrates the phenotypic differentiation of cancer stem cells by an HDAC inhibitor, a cytokine/growth factor and a combination thereof.
  • the human multiple myeloma cell lines RPMI 8226 and NCI-H929 were treated for 72 hours with SNDX-275, interleukin-6 and a combination thereof. Results are expressed as the mean fluorescence plus or minus standard error of the mean for each group compared to the untreated control cells.
  • Figure 2 illustrates the inhibition of cancer stem cells by an HDAC inhibitor, a cytokine/growth factor and a combination thereof.
  • the human multiple myeloma cell lines RPMI8226, U266 and NCI-H929 were treated for 72 hours with SNDX-275, interleukin-6 and a combination thereof. Results are expressed as the mean plus or minus standard error of the mean for each group compared to untreated control cells.
  • the pharmaceutical compositions are for the treatment of disorders in a mammal.
  • the mammal is a human.
  • the human is an adult human.
  • the adult human is more than about 12 years old, more than about 16 years old or more than about 18 years old.
  • the first agent is administered to a patient first and the second agent is administered at a later time or date. In other embodiments, the first and second agents are administered simultaneously. In still another embodiment, the first and second agents are administered simultaneously and the second agent is administered again, in the absence of the first agent, at a later time or date. In yet another embodiment, the first agent is administered, in the absence of the second agent, and the second agent is administered together with the first agent at a later time or date. In some embodiments, the first agent is administered as a first pharmaceutical composition and the second agent is administered as a second pharmaceutical composition. In other embodiments, the first and second agents are co-administered in a single pharmaceutical composition.
  • disclosure of administration of any agent (e.g., a first, second, or any additional agent) to a patient or individual is includes the disclosure of contacting a cancer stem cell with the agent specified.
  • contacting a cancer stem cell with one or more agent as disclosed herein includes administering the agent or agents to a patient or individual, whereby contact with the cancer stem cell occurs in vivo.
  • contacting a cancer stem cell with one or more agent as disclosed herein includes directly contacting the agent or agents to the cancer stem cells in vitro.
  • the amount of first agent administered is a therapeutically effective amount.
  • the therapeutically effective amount of the first agents is about 0.01 to about 1,000 mg/m 2 .
  • the therapeutically effective amount of the first agent is from about 0.1 to about 500 mg/m 2 .
  • the therapeutically effective amount of the first agent is, independently, from about 0.5 to about 100 mg/m 2 .
  • therapeutically effective amounts are about 0.5 to about 15 mg/m 2 .
  • therapeutically effective amounts are about 2 to about 8 mg/m 2 .
  • the therapeutically effective amount of MS-275 is, by way of non-limiting example, about 1, 2, 4, 6 or 8 mg/m . In other embodiments wherein the first agent is MGCD-0103, therapeutically effective amounts are about 5 to about 100 mg/m . In certain embodiments wherein the first agent is MGCD-0103, therapeutically effective amounts are about 10 to about 80 mg/m 2 . In other embodiments wherein the first agent is MGCD-0103, therapeutically effective amounts are about 12 to about 60 mg/m 2 . In still other embodiments wherein the first agent is MGCD-0103, therapeutically effective amounts are about 12.5 to about 36 mg/m . In specific embodiments wherein the first agent is MGCD-0103, the therapeutically effective amount of MGCD-0103 is, by way of non-limiting example, about 5, 10, 12.5, 20, 27, 36, 40, 60, 75 or 80 mg/m 2 .
  • the first agent is administered in a regimen that is therapeutically effective.
  • the first agent is administered, by way of non-limiting example, twice daily, once daily, five times a week, four times a week, three times a week, twice a week, once weekly, once every two weeks or once every 6 weeks.
  • the amount of the second agent administered is a therapeutically effective amount.
  • the therapeutically effective amount of the second agents is about 0.01 to about 1,000 mg/m 2 .
  • the therapeutically effective amount of the first agent is from about 0.1 to about 500 mg/m 2 .
  • the therapeutically effective amount of the second agent is about 0.2 to about 100 mg/m .
  • the therapeutically effective amount of the second agent is between about 1 pg/kg/day and about 100 mg/kg/day.
  • the therapeutically effective amount of the second agent is between about 250 pg/kg/day and about 100 ⁇ g/kg/day.
  • the therapeutically effective amount of the second agent is between about 1 ⁇ g/kg/day and about 5 ⁇ g/kg/day.
  • the second agent is IL-6 and the therapeutically effective amount of the IL-6 is between about 250 pg/kg/day and about 100 ⁇ g/kg/day. In some embodiments, the therapeutically effective amount of IL-6 is between about 1 ⁇ g/kg/day and about 5 ⁇ g/kg/day
  • the second agent is administered in a regimen that is therapeutically effective.
  • the second agent is administered, by way of non-limiting example, twice daily, once daily, five times a week, four times a week, three times a week, twice a week, once weekly, once every two weeks or once every 6 weeks.
  • the second agent is delivered twice weekly.
  • the first agent is administered for a period of time prior to administration of the second agent. In certain embodiments, the first agent is administered for 1 day, 2 days, 3 days, 1 week, 2 weeks, 1 month, 6 weeks or 2 months prior to administration of the second agent.
  • the cancer described herein is, by way of non -limiting example, brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, colorectal cancer, leukemia, myeloid leukemia, acute myeloid leukemia (AML), glioblastoma, follicular lymphona, pre-B acute leukemia, chronic lymphocytic B-leukemia, mesothelioma or small cell lung cancer.
  • Additional cancers to be treated with the methods and compositions described herein include hematologic and non -hematologic cancers.
  • Hematologic cancer includes multiple myeloma, leukemias, and lymphomas, acute leukemia, acute lymphocytic leukemia (ALL) and acute nonlymphocytic leukemia (ANLL), chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML).
  • Lymphoma further includes Hodgkin's lymphoma and non-Hodgkin's lymphoma, cutaneous t-cell lymphoma (CTCL), pediatric acute leukemia, pediatric acute myeloid leukemia, pediatric acute lymphoid leukemia, and mantle cell lymphoma (MCL).
  • CTCL cutaneous t-cell lymphoma
  • MCL mantle cell lymphoma
  • Non-hematologic cancer includes brain cancer, cancers of the head and neck, lung cancer, breast cancer, cancers of the reproductive system, cancers of the gastro-intestinal system, pancreatic cancer, and cancers of the urinary system, cancer of the upper digestive tract or colorectal cancer, bladder cancer or renal cell carcinoma, and prostate cancer.
  • the cancers described herein include cancers that are epithelial malignancies (having epithelial origin), and cancers (tumors) that express EGFR.
  • cancers that are epithelial malignancies (having epithelial origin)
  • cancers tumors
  • premalignant or precancerous cancers/tumors having epithelial origin include actinic keratoses, arsenic keratoses, xeroderma pigmentosum, Bowen's disease, leukoplakias, metaplasias, dysplasias and papillomas of mucous membranes, e.g.
  • precancerous changes of the bronchial mucous membrane such as metaplasias and dysplasias (especially frequent in heavy smokers and people who work with asbestos and/or uranium), dysplasias and leukoplakias of the cervix uteri, vulval dystrophy, precancerous changes of the bladder, e.g. metaplasias and dysplasias, papillomas of the bladder as well as polyps of the intestinal tract.
  • Non-limiting examples of semi-malignant or malignant cancers/tumors of the epithelial origin are breast cancer, skin cancer (e.g., basal cell carcinomas), bladder cancer (e.g., superficial bladder carcinomas), colon cancer, gastro-intestinal (GI) cancer, prostate cancer, uterine cancer, cervical cancer, ovarian cancer, esophageal cancer, stomach cancer, laryngeal cancer and lung cancer.
  • Additional cancers of the present invention include: cancers of oral cavity and pharynx, cancers of the respiratory system, cancers of bones and joints, cancers of soft tissue, skin cancers, cancers of the genital system, cancers of the eye and orbit, cancers of the nervous system, cancers of the lymphatic system, and cancers of the endocrine system.
  • cancers further include cancer of the tongue, mouth, pharynx, or other oral cavity; esophageal cancer, stomach cancer, or cancer of the small intestine; colon cancer or rectal, anal, or anorectal cancer; cancer of the liver, intrahepatic bile duct, gallbladder, pancreas, or other biliary or digestive organs; laryngeal, bronchial, and other cancers of the respiratory organs; heart cancer, melanoma, metastatic melanoma, basal cell carcinoma, squamous cell carcinoma, other non-epithelial skin cancer; uterine or cervical cancer; uterine corpus cancer; ovarian, vulvar, vaginal, or other female genital cancer; prostate, testicular, penile or other male genital cancer; urinary bladder cancer; cancer of the kidney; renal, pelvic, or urethral cancer or other cancer of the genito-urinary organs; thyroid cancer or other endocrine cancer; chronic lymph
  • cancers which are included herein include: adenocarcinoma, angiosarcoma, astrocytoma, acoustic neuroma, anaplastic astrocytoma, basal cell carcinoma, blastoglioma, chondrosarcoma, choriocarcinoma, chordoma, craniopharyngioma, cutaneous melanoma, cystadenocarcinoma, endotheliosarcoma, embryonal carcinoma, ependymoma, Ewing's tumor, epithelial carcinoma, fibrosarcoma, gastric cancer, genitourinary tract cancers, glioblastoma multiforme, hemangioblastoma, hepatocellular carcinoma, hepatoma, Kaposi's sarcoma, large cell carcinoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, lymphangioendothelios
  • Cancers of epithelial origin can also be identified by similar histology.
  • Common histological markers for epithelial cancers are mucin 16 (CA125), mucin 1, transmembrane (MUCl), mesothelin, WAP four-disulfide core demain 2 (HE4), kallikrein 6, kallikrein 10, matrix metallopreinase 2, prostasin, osteopontin, tetranectin, and inhibin.
  • Additional histological markers include prostate-specific antigen (PSA), MUC6, IEN, and aneuploidy.
  • histological markers for epithelial cancers include E- cadherin, EZH2, Nectin-4, Her-2, p53, Ki-67, ErbB3, ZEBl and/or SIPl expression.
  • the cancer is a hematological cancer.
  • Non-limiting examples of hematological cancers include lymphoma (including, but not limited to, Hodgkin's lymphoma, diffuse large b- cell lymphoma (DLBCL) also know as immunoblastic lymphoma, aggressive lymphomas also known as intermediate and high grade lymphomas, indolent lymphomas also known as low grade lymphomas, mantle cell lymphoma, follicular lymphoma), leukemia, acute promyelocytic leukemia, acute myeloideleukaemia, chronic myeloide leukaemia, chronic lymphatic leukaemia, Hodgkin's disease, multiple myeloma, myelodysplasia, myeloproliferative disease, and refractory anemia.
  • lymphoma including, but not limited to, Hodgkin's lymphoma, diffuse large b- cell lymphoma (DLBCL) also know as immunoblastic lymphoma, aggressive lymphomas also known as intermediate and high
  • Hematological cancers can also be identified by similar histology.
  • Common histological markers for hematological cancers are tumor-antigens, M34, antibodies, cancer antigens, CA15-3, carcinoembryonic antigen, CA125, cytokeratins, hMAM, MAGE, pancytokeratins, and HLA Class I or Class II antigens such as HLA-DR and HLA-D, MB, MT, MTe, Te, and SB.
  • histological markers for B-cell malignancies include CD5, CD6, CDlO, CD19, CD20, CD21, CD22, CD23, CD24, CD25, CD26, CD28, CD30, CD32, CD35, CD37, CD38, CD39, CD40, CD43, CD45RO, CD45RA, CD45RB, CD49B, CD49C, CD49D, CD50, CD52, CD57, CD62L, CD69, CD70, CD72, CD73, CD74, CD75, CD77, CD79 ⁇ , ⁇ , CD80, CD83, CDW84, CD86, CD89, CD97, CD98, CDl 19, CDW121B, CD122, CD124, CD125, CD126, CD127, CD130, CD132, CD135, CDW137, CD171, CD179A, CD179B, CD180, CD183, CDW197, CD200, CDW210, CD213A1 and CD213A2.
  • histological markers for T-cell malignancies include CD4, CD8, CD5, CD2, CD25, CD26, CD28, CD27, CD30, CD37, CD38, CD45RO, CD45RA, CD45RB, CD49A, CD49E, CD49F, CD50, CD52, CD56, CD57, CD62L, CD69, CD70, CD73, CD89, CD90, CD94, CD96, CD97, CD98, CDlOl, CD107A, CD107B, CD109, CD121A, CD122, CD124, CDW128, CD132, CD134, CDW137, CD148, CD152, CD153, CD154, CD160, CD161, CD165, CD166, CD171, CD178, CDW197, CDW210, CD212, CDW217, CD223, CD226, CD231, CD245 and CD247.
  • the cancer is a neuroendocrine cancer.
  • neuroendocrine cancers include lung and pancreatic cancers as well as neuroendocrine tumors of the digestive system. More specifically, these types of cancer may be called gastrinoma, insulinoma, glucagonoma, vasoactive intestinal peptideoma (VIPoma), PPoma, somatostatinoma, CRHoma, calcitoninoma, GHRHoma, ACTHoma, and GRFoma.
  • VIPoma vasoactive intestinal peptideoma
  • PPoma vasoactive intestinal peptideoma
  • somatostatinoma CRHoma
  • calcitoninoma GHRHoma
  • ACTHoma ACTHoma
  • GRFoma GRFoma
  • neuroendocrine cancers include medullary carcinoma of the thyroid, Merkel cell cancer, small-cell lung cancer (SCLC), large-cell neuroendocrine carcinoma of the lung, neuroendocrine carcinoma of the cervix, Multiple Endocrine Neoplasia type 1 (MEN-I or MENl), Multiple Endocrine Neoplasia type 2 (MEN-2 or MEN2), neurofibromatosis type 1 , tuberous sclerosis, von Hippel-Lindau (VHL) disease, neuroblastoma, pheochromocytoma (phaeochromocytoma), paraganglioma, neuroendocrine tumor of the anterior pituitary, and Carney's complex.
  • MEN-I or MENl Multiple Endocrine Neoplasia type 2
  • VHL von Hippel-Lindau
  • Neuroendocrine cancers can also be identified by similar histology.
  • Common histological markers for neuroendocrine cancers are hormone markers, chromogranin A (CgA), urine 5 -hydroxy indole acetic acid (5-HIAA) (grade C), neuron-specific enolase (NSE, gamma-gamma dimer), synaptophysin (P38), N- terminally truncated variant of heat shock protein 70 (Hsp 70), CDX-2, neuroendocrine secretory protein-55, and blood serotonin.
  • the first and second agents of the present invention are each used individually or in combination.
  • the first agent is administered or used either alone or as a pharmaceutical composition.
  • the second agent is administered either alone or as a pharmaceutical composition.
  • the pharmaceutical compositions are prepared by admixing at least one active ingredient together with one or more carriers, excipients, buffers, adjuvants, stabilizers, or other materials well known to those skilled in the art and optionally other therapeutic agents.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any known methods. All formulations and pharmaceutical compositions, as well as any methods of using such pharmaceutical compositions, disclosed herein are contemplated and considered to be within the scope of the disclosure provided herein.
  • Administration of the agents and pharmaceutical compositions described herein can be effected by any method that enables delivery of the agents to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical, intrapulmonary, rectal administration, by implant, by a vascular stent impregnated with the agent, and other suitable methods.
  • agents and pharmaceutical compositions described herein can be administered locally to the area in need of treatment.
  • Administration is achieved by, by way of non-limiting example, local infusion during surgery, topical application e.g., cream, ointment, injection, catheter, or implant, said implant made, e.g., out of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
  • topical application e.g., cream, ointment, injection, catheter, or implant
  • said implant made, e.g., out of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
  • the administration can also be by direct injection at the site (or former site) of a tumor or neoplastic or pre-neoplastic tissue.
  • compositions included herein are those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intramedullary, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intratracheal, subcuticular, intraarticular, subarachnoid, and intrastemal), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual, intranasal, intraocular, and vaginal) administration.
  • parenteral including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intramedullary, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intratracheal, subcuticular, intraarticular, subarachnoid, and intrastemal
  • intraperitoneal including transmucosal, transdermal, rectal and topical (including dermal, buccal
  • the pharmaceutical compositions described herein are conveniently formulated in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association an agent ("active ingredient”) or combination of agents ("active ingredients”) with the carrier which constitutes one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • formulations suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient or ingredients; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient or ingredients are presented as a bolus, electuary or paste.
  • formulations suitable for oral administration include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • tablets are made by compression or molding, optionally with one or more accessory ingredients.
  • compressed tablets are prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), inert diluents, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) or lubricating, surface active or dispersing agents.
  • molded tablets are made by molding in a suitable machine a mixture of the powdered active ingredient or ingredients moistened with an inert liquid diluent. The tablets are optionally coated or scored.
  • tablets are formulated so as to provide slow or controlled release of the active ingredient therein. Tablets are optionally provided with an enteric coating, to provide release in parts of the gut other than the stomach. All formulations for oral administration should be in dosages suitable for such administration.
  • the push-fit capsules contain the active ingredient or ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • soft capsules contain the active ingredient or ingredients dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers are optionally added.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used, which optionally contains gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs, pigments or other color agents are optionally to the tablets or Dragee coatings for identification (e.g., as a pharmaceutical composition comprising the first agent, the second agent or a combination of first and second agents) or to characterize different doses.
  • compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • formulations for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an optional preservative.
  • formulations take forms including, by way of non-limiting example, suspensions, solutions or emulsions in oily or aqueous vehicles, and optionally contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the formulations are presented in unit- dose or multi-dose containers, for example sealed ampoules and vials.
  • the formulations are stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • Extemporaneous injection solutions and suspensions are prepared, by way of non -limiting example, from sterile powders, granules and tablets of the kind previously described.
  • Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active agents which may contain antioxidants, buffers, biocide, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which optionally include suspending agents and thickening agents.
  • suitable isotonic vehicles for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes or other microparticulate systems may be used to target the agent to blood components or one or more organs.
  • fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes or other microparticulate systems may be used to target the agent to blood components or one or more organs.
  • the concentration of the active ingredient or ingredients in the solution varies depending on intended usage.
  • the invention further provides pharmaceutical compositions and methods of making said pharmaceutical composition.
  • the pharmaceutical compositions comprise an effective amount of the first and second agents.
  • a first pharmaceutical composition comprises the first agent and a second pharmaceutical composition comprises the second agent.
  • the pharmaceutical composition may comprise admixing at least one active ingredient with one or more carriers, excipients, buffers, adjuvants, stabilizers, or other materials well known to those skilled in the art and optionally other therapeutic agents.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any known methods.
  • Non-limiting examples of excipients that are used in conjunction with the present invention include water, saline, dextrose, glycerol or ethanol.
  • the injectable compositions optionally comprise minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.
  • Example of pharmaceutically acceptable carriers that are optionally used include, but are not limited to aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.
  • compositions are formulated as a depot preparation.
  • long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the agents or combinations described herein are formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions described herein are formulated for buccal or sublingual administration
  • the pharmaceutical compositions described herein takes the form of tablets, lozenges, pastilles, or gels formulated in conventional manner.
  • Such compositions optionally flavored agents such as sucrose and acacia or tragacanth.
  • compositions are formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
  • compositions are administered topically.
  • Topical administration includes non-systemic administration.
  • the active ingredient or ingredients are applied externally to the epidermis or the buccal cavity and the instillation of such a agent into the ear, eye and nose, such that the agent does not significantly enter the blood stream.
  • the pharmaceutical compositions described herein are delivered systemically, which includes oral, intravenous, intraperitoneal and intramuscular administration.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, suspensions, powders, solutions, spray, aerosol, oil, and drops suitable for administration to the eye, ear or nose.
  • a formulation comprises a patch or a dressing such as a bandage or adhesive plaster impregnated with the active ingredient or ingredients and optionally one or more excipients or diluents.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient or ingredients in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient or ingredients are dissolved or suspended in a suitable carrier, including an aqueous solvent.
  • Formulations for administration by inhalation are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
  • Pressurized packs optionally comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit is determined by providing a valve to deliver a metered amount.
  • formulations take the form of a dry powder composition, for example a powder mix of the agent and a suitable powder base such as lactose or starch.
  • the powder composition is presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • the agents and compositions described herein may include other agents or components conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the agents or pharmaceutical compositions described herein are delivered in a vesicle, e.g., a liposome.
  • the agents and pharmaceutical compositions described herein are delivered in a controlled release system.
  • a pump is used.
  • a controlled release system is placed in proximity of the therapeutic target.
  • the pharmaceutical compositions described are formulated into a formulation suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use are prepared according to any method known to the art for the manufacture of pharmaceutical compositions.
  • pharmaceutical compositions described herein optionally contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents.
  • Tablets contain the active ingredient or ingredients in admixture with one or more non-toxic pharmaceutically acceptable excipient which is suitable for the manufacture of tablets.
  • Excipients include, by way of non-limiting example, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granulating and disintegrating agents (e.g., microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid), binding agents (e.g., starch, gelatin, polyvinyl-pyrrolidone or acacia), and lubricating agents (e.g., magnesium stearate, stearic acid or talc).
  • the tablets are optionally coated or un-coated.
  • Coating of a tablet is accomplished by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a water soluble taste masking material such as hydroxypropylmethyl-cellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, or cellulose acetate butyrate may be employed as appropriate.
  • formulations for oral use are in the form of hard gelatin capsules wherein the active ingredient or ingredients are mixed with an inert solid diluent.
  • Suitable inert solid diluents include, by way of non-limiting example, calcium carbonate, calcium phosphate or kaolin.
  • formulations for oral use are in the form of soft gelatin capsules wherein the active ingredient or ingredients are mixed with water soluble carrier.
  • Water soluble carriers include, by way of non-limiting example, polyethyleneglycol or an oil medium (e.g., peanut oil, liquid paraffin, or olive oil).
  • Aqueous suspensions contain the active material in admixture with one or more excipient suitable for the manufacture of aqueous suspensions.
  • Suitable excipients include, by way of non -limiting example, suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia), dispersing or wetting agents (e.g., a naturally- occurring phosphatide such as lecithin, condensation products of an alkylene oxide with fatty acids such as polyoxyethylene stearate, condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethylene-oxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate).
  • suspending agents e.g., sodium carboxymethylcellulose,
  • the aqueous suspensions optionally contain one or more preservatives (e.g., ethyl, or n- propyl p-hydroxybenzoate), one or more coloring agents, one or more flavoring agents, and one or more sweetening agents (e.g., sucrose, saccharin or aspartame).
  • preservatives e.g., ethyl, or n- propyl p-hydroxybenzoate
  • coloring agents e.g., ethyl, or n- propyl p-hydroxybenzoate
  • flavoring agents e.g., a coloring agents, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents (e.g., sucrose, saccharin or aspartame).
  • sweetening agents e.g., sucrose, saccharin or aspartame
  • oily suspensions are formulated by suspending the active ingredient in, by way of non-limiting example, a vegetable oil (e.g., arachis oil, olive oil, sesame oil or coconut oil), or in mineral oil (e.g., liquid paraffin).
  • the oily suspensions optionally contain a thickening agent (e.g., beeswax, hard paraffin or cetyl alcohol).
  • Sweetening agents such as those set forth above, and flavoring agents are optionally added to provide a palatable oral preparation.
  • Preservatives and/or anti-oxidants e.g., butylated hydroxyanisol or alpha-tocopherol are optionally added as well.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional optional excipients include, by way of non-limiting example, sweetening, flavoring, coloring agents and anti-oxidants. Anti-oxidants include ascorbic acid. [00112] In certain embodiments, pharmaceutical compositions are formulated as oil-in-water emulsions.
  • the oily phase is selected from, by way of non-limiting example, vegetable oil (e.g., olive oil or arachis oil), a mineral oil (e.g., liquid paraffin) or mixtures thereof.
  • Suitable emulsifying agents include naturally-occurring phosphatides (e.g., soy bean lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensation products of the said partial esters with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate).
  • the emulsions optionally contain sweetening agents, flavoring agents, preservatives and antioxidants.
  • Syrups and elixirs are optionally formulated with sweetening agents (e.g., glycerol, propylene glycol, sorbitol or sucrose). Such formulations also optionally contain one or more demulcent, one or more preservative, one or more flavoring agent, one or more coloring agent and/or one or more antioxidant.
  • sweetening agents e.g., glycerol, propylene glycol, sorbitol or sucrose
  • Such formulations also optionally contain one or more demulcent, one or more preservative, one or more flavoring agent, one or more coloring agent and/or one or more antioxidant.
  • pharmaceutical compositions are in the form of a sterile injectable aqueous solution. Acceptable vehicles and solvents that are employed are, by way of non-limiting example, water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation is a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then introduced into a water and glycerol mixture and processed to form a microemulsion.
  • the injectable solutions or microemulsions may be introduced into a patient's blood-stream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant active ingredient or ingredients. In order to maintain such a constant concentration, a continuous intravenous delivery device is utilized in some embodiments.
  • the pharmaceutical compositions is in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration.
  • This suspension is formulated according to the known art using suitable dispersing, wetting agents and/or suspending agents, all of which are discussed herein.
  • the sterile injectable preparation is a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3 -butane diol.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions are administered in the form of suppositories for rectal administration of the drug.
  • these pharmaceutical compositions are prepared by mixing the active ingredient or ingredients with a suitable non -irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non -irritating excipient include, by way of non -limiting example, cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • the pharmaceutical compositions described herein are formulated for topical use, creams, ointments, jellies, solutions or suspensions, etc., containing an agent or a pharmaceutical composition described herein is used.
  • topical application include mouth washes and gargles.
  • pharmaceutical compositions are administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. Tansdermal delivery system, include continuous administration of the active ingredient or ingredients.
  • the pharmaceutical compositions described herein are formulated as a form suitable for oral administration, as a tablet, as a capsule, as a cachet, as a pill, as a lozenge, as a powder or as a granule.
  • the pharmaceutical compositions are formulated as sustained release formulations, solutions, liquids, suspensions, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment, cream, lotions, sprays, foams, gel or paste, or for rectal or vaginal administration as a suppository or pessary.
  • the pharmaceutical compositions are formulated in unit dosage forms suitable for single administration of precise dosages.
  • the pharmaceutical composition includes a conventional pharmaceutical carrier or excipient and an agent as described herein as an active ingredient.
  • other medicinal or pharmaceutical agents, carriers, adjuvants, etc. are included.
  • Exemplary parenteral administration forms include solutions or suspensions of active agents in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms are optionally buffered.
  • Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents.
  • the pharmaceutical compositions optionally contain additional ingredients such as flavorings, binders, excipients and the like.
  • additional ingredients such as flavorings, binders, excipients and the like.
  • tablets containing various excipients, such as citric acid are employed together with various disintegrants.
  • Disintegrants include, by way of non-limiting example, starch or other cellulosic material, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are optionally used.
  • compositions and/or formulations described herein include lactose or milk sugar and high molecular weight polyethylene glycols.
  • active ingredient or ingredients are optionally combined with various sweetening or flavoring agents, coloring agents or dyes and, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
  • the first and second agents described herein are administered with one or more additional therapeutic agent.
  • either or both of the first and second agents described herein can be in a fixed combination with an additional therapeutic agent or a non-fixed combination with an additional therapeutic agent.
  • an additional therapeutic agent is combined with the first agent.
  • an additional therapeutic agent is combined with the second agent.
  • the additional therapeutic agent is administered separately from either the first or second agents.
  • the therapeutic agent is formulated with both the first and second agents in a single formulation.
  • the first agent is formulated into a first pharmaceutical composition that further comprises an additional therapeutic agent and the second agent is formulated into a second pharmaceutical composition that also contains an additional therapeutic agent.
  • the first agent is formulated into a first pharmaceutical composition that does not comprise an additional therapeutic agent and the second agent is formulated into a second pharmaceutical composition that does contain an additional therapeutic agent.
  • the first agent is formulated into a first pharmaceutical composition that further comprises an additional therapeutic agent and the second agent is formulated into a second pharmaceutical composition that does not contain an additional therapeutic agent.
  • the different pharmaceutical compositions are distinguished by color (e.g., by using different coloring agents in each of the pharmaceutical compositions utilized). Provided below are various embodiments of additional therapeutic agents that are combined with the first and second agents described hereinabove.
  • any reference to an additional therapeutic agent refers to one or more additional therapeutic agents.
  • a method of treating cancer with a first agent, a second agent, and an additional therapeutic agent.
  • a method of treating cancer disorder with a first agent, a second agent, a first additional therapeutic agent, and a second additional therapeutic agent.
  • the present invention provides for compositions and methods for inhibiting the proliferation of cancer cells by contacting cancer stem cells with a first agent, a second agent, and an additional therapeutic agent.
  • the present invention provides for compositions and methods for inhibiting the proliferation of cancer cells by contacting cancer stem cells with a first agent, a second agent, a first additional therapeutic agent, and a second additional therapeutic agent. In some embodiments, the present invention provides for compositions and methods for inducing terminal differentiation in cancer stem cells by contacting the cancer stem cells with a first agent, a second agent, and an additional therapeutic agent. In some embodiments, the present invention provides for compositions and methods for inducing terminal differentiation in cancer stem cells by contacting the cancer stem cells with a first agent, a second agent, a first additional therapeutic agent, and a second additional therapeutic agent. In certain embodiments, the additional therapeutic agent(s) is used in a (therapeutically) effective amount.
  • the additional therapeutic agent is an anti-hypertensive agent.
  • the additional therapeutic agent is an agent that enhances the efficacy of either or both of the first and second agents.
  • the additional therapeutic agent is another therapeutic agent (including a therapeutic regimen, therapy or treatment) that also has a therapeutic benefit.
  • the additional therapeutic agent provides an additive benefit.
  • the additional therapeutic agent provides a synergistic benefit with either one or both of the first and second agents.
  • therapies include, but are not limited to, administration of other therapeutic agents, radiation therapy or both.
  • the agents described herein need not be administered in the same pharmaceutical composition as any additional therapeutic agents.
  • the first agent, second agent and any additional therapeutic agent are administered by different routes.
  • one or more of the first agent, second agent and any additional therapeutic agent is administered by the same route.
  • each of the first agent, second agent and any additional therapeutic agent are administered by the same route.
  • one or more of the agents is administered orally, while one or more of the other agents are administered intravenously.
  • the dosage, modes of administration and times of administration of one or more of the agents is modified after administration is begun.
  • the first agent, second agent, and where applicable additional therapeutic agents are administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol).
  • the first agent, second agent, and where applicable additional therapeutic agent are administered sequentially.
  • certain agents are administered concurrently while others are administered sequentially.
  • the manner in which the agents are delivered depends on the nature of the disease, the condition of the patient, and/or the choice of additional therapeutic agent and/or therapy (e.g., radiation) to be administered.
  • these administration methods include the administration of one or all of the agents in a pharmaceutical composition as described herein.
  • the first agent, second agent and the additional therapeutic agent need not be administered simultaneously or essentially simultaneously. Indeed, in some embodiments, the initial order of administration of the agents or pharmaceutical compositions thereof is not important. Thus, in certain embodiments, the first and second agent or pharmaceutical compositions thereof are administered prior to the administration of the additional therapeutic agent. In another embodiment, the additional therapeutic agent is administered prior to the first and second agents. In still another embodiment, the first agent is administered first, the additional therapeutic agent is administered second, and the second agent is administered third. In various embodiments, a treatment protocol repeats the sequence of steps described or combines them. In certain embodiments, the treatment protocol is repeated until treatment is complete. In further embodiments, as treatment proceeds a treatment protocol is modified according to the individual patient's needs.
  • Indications of the patient's needs include, but are not limited to, relief of disease-related symptoms, inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Tumor size is measured by standard methods, including radiological studies (e.g., CAT or MRI scan).
  • additional therapeutic agents are found in the pharmacotherapeutic classifications listed below. These lists are illustrative only and are not to be construed as limiting.
  • the additional therapeutic agent is administered in any acceptable manner including, by way of non-limiting example, oral, intravenous, intraocular, subcutaneous, dermal, and inhaled topical.
  • additional therapeutic agents include chemotherapeutic agents.
  • chemotherapeutic agents are anticancer agents, alkylating agents, cytotoxic agents, antimetabolic agents, hormonal agents, plant-derived agents, and biologic agents.
  • the chemotherapeutic agent is a retinoid (e.g., a selective RXR agonist) or a methyltransferase inhibitor.
  • Selective RXR agonists include, by way of non-limiting example, docosahexanoic acid (DHA), phytanic acid, methoprene acid, LG100268 (LG268), LG100324, LGD1057, SRl 1203, SRl 1217, SRl 1234, SRl 1236, SRl 1246, AGN194204, 3-methyl TTNEB, and bexarotene.
  • the selective RXR agonist is bexarotene.
  • Methyltransferase inhibitors include, by way of non-limiting example, 5-azacytidine, 5-aza-2'-deoxycytidine (decitabine), l-beta-D-arabinofuranosyl-5-aza-cytosine, dihydro-5-aza-cytidine and MG98.
  • the methyltransferase inhibitor is 5-azacytidine.
  • Anti-tumor substances are selected from, by way of non-limiting example, mitotic inhibitors (e.g., vinblastine), alkylating agents (e.g., c ⁇ -platin, carboplatin and cyclophosphamide), anti-metabolites (5- fluorouracil, cytosine arabinside and hydroxyurea), one of the anti-metabolites disclosed in European Patent Application No.
  • mitotic inhibitors e.g., vinblastine
  • alkylating agents e.g., c ⁇ -platin, carboplatin and cyclophosphamide
  • anti-metabolites 5- fluorouracil, cytosine arabinside and hydroxyurea
  • antibiotics e.g, adriamycin and bleomycin
  • enzymes e.g., interferon
  • anti-hormones e.g., anti- estrogens such as NolvadexTM (
  • Alkylating agents include, by way of non-limiting example, bischloroethylamines (nitrogen mustards, e.g. chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, uracil mustard), aziridines (e.g. thiotepa), alkyl alkone sulfonates (e.g. busulfan), nitrosoureas (e.g. carmustine, lomustine, streptozocin), nonclassic alkylating agents (altretamine, dacarbazine, and procarbazine), platinum compounds (carboplastin and cisplatin).
  • nitrogen mustards e.g. chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, uracil mustard
  • aziridines e.g. thiotepa
  • Cytotoxic agents include, by way of non-limiting example, anthracyclines (e.g. doxorubicin, daunorubicin, epirubicin, idarubicin and anthracenedione), mitomycin C, bleomycin, dactinomycin, plicatomycin.
  • anthracyclines e.g. doxorubicin, daunorubicin, epirubicin, idarubicin and anthracenedione
  • mitomycin C e.g. doxorubicin, daunorubicin, epirubicin, idarubicin and anthracenedione
  • mitomycin C e.g. doxorubicin, daunorubicin, epirubicin, idarubicin and anthracenedione
  • mitomycin C e.g. doxorubicin, daunorubicin, epirubicin, idarubicin and anthracenedi
  • Antimetabolic agents include, by way of non-limiting example, fluorouracil (5-FU), floxuridine (5-FUdR), methotrexate, leucovorin, hydroxyurea, thioguanine (6-TG), mercaptopurine (6-MP), cytarabine, pentostatin, fludarabine phosphate, cladribine (2-CDA), asparaginase, and gemcitabine.
  • Hormonal agents are a group of drug that regulate the growth and development of their target organs.
  • Hormonal agents include sex steroids and their derivatives and analogs thereof, such as estrogens, androgens, and progestins.
  • Hormonal agents include, by way of non -limiting example, synthetic estrogens (e.g. diethylstibestrol), antiestrogens (e.g.
  • tamoxifen toremifene, fluoxymesterol and raloxifene
  • antiandrogens bicalutamide, nilutamide, flutamide
  • aromatase inhibitors e.g., aminoglutethimide, anastrozole and tetrazole
  • ketoconazole goserelin acetate, leuprolide, megestrol acetate and mifepristone.
  • Plant-derived agents include, by way of non-limiting example, vinca alkaloids (e.g., vincristine, vinblastine, vindesine, vinzolidine and vinorelbine), podophyllotoxins (e.g., etoposide (VP- 16) and teniposide (VM-26)), taxanes (e.g., paclitaxel and docetaxel).
  • vinca alkaloids e.g., vincristine, vinblastine, vindesine, vinzolidine and vinorelbine
  • podophyllotoxins e.g., etoposide (VP- 16) and teniposide (VM-26)
  • taxanes e.g., paclitaxel and docetaxel.
  • biological agents refers to a group of biomolecules that elicit cancer/tumor regression when used alone or in combination with chemotherapy and/or radiotherapy.
  • Biologic agents include, by way of non-limiting example, immuno-modulating proteins such as cytokines, monoclonal antibodies against tumor antigens, tumor suppressor genes, and cancer vaccines.
  • the additional therapeutic agent is selected from, by way of non-limiting example, aromatase inhibitors, antiestrogen, anti-androgen, corticosteroids, gonadorelin agonists, topoisomerase land 2 inhibitors, microtubule active agents, alkylating agents, nitrosoureas, antineoplastic antimetabolites, platinum containing compounds, lipid or protein kinase targeting agents, IMiDs, protein or lipid phosphatase targeting agents, anti-angiogenic agents, Akt inhibitors, IGF-I inhibitors, FGF3 modulators, mTOR inhibitors, Smac mimetics, other HDAC inhibitors, agents that induce cell differentiation, bradykinin 1 receptor antagonists, angiotensin II antagonists, cyclooxygenase inhibitors, heparanase inhibitors, lymphokine inhibitors, cytokine inhibitors, IKK inhibitors,
  • additional therapeutic agents include interleukins.
  • Specific interleukins include, by way of non-limiting example, interleukin 2 (IL-2), interleukin 4 (IL-4), and interleukin 12 (IL- 12).
  • Interferons include more than 23 related subtypes with overlapping activities, all of the IFN subtypes within the scope of the present invention. IFN has demonstrated activity against many solid and hematologic malignancies, the later appearing to be particularly sensitive.
  • cytokines included within the scope of the additional therapeutic agent are cytokines that exert profound effects on hematopoiesis and immune functions.
  • examples of such cytokines include, by way of non-limiting example, erythropoietin, granulocyte-CSF (filgrastin), and granulocyte, macrophage-CSF (sargramostim).
  • the cytokine is a lineage-specific growth factor.
  • immuno-modulating agents include, by way of non-limiting example, bacillus Calmette- Guerin, levamisole, and octreotide, a long-acting octapeptide that mimics the effects of the naturally occurring hormone somatostatin.
  • Monoclonal antibodies against tumor antigens are antibodies elicited against antigens expressed by tumors, including tumor-specific antigens.
  • Monoclonal antibodies of the present invention include, by way of non-limiting example, HERCEPTIN.RTM and RITUXAN.RTM.
  • tumor suppressor genes are genes that function to inhibit the cell growth and division cycles, thus preventing the development of neoplasia.
  • Tumor suppressor genes include, by way of non- limiting example, DPC-4, NF-I, NF-2, RB, p53, WTl, BRCAl and BRCA2.
  • TAA tumor-associated antigens
  • GM2 gangliosides
  • PSA prostate specific antigen
  • AFP alpha-fetoprotein
  • CEA carcinoembryonic antigen
  • breast, lung, gastric, and pancreas cancer s melanoma associated antigens
  • melanoma associated antigens MART-I, gp 100, MAGE 1,3 tyrosinase
  • papillomavirus E6 and E7 fragments whole cells or portions/lysates of antologous tumor cells and allogeneic tumor cells.
  • the additional therapeutic agent is a proteasome inhibitor.
  • Proteasome inhibitors include, by way of non-limiting example, bortezomib (Velcade, PS-341), PR-171, NPI-0052 (salinosporamide A), MG- 132, omuralide, lactacystin and NEOSHlOl.
  • the first and second agents are administered concurrently or sequentially (in either order) and the proteasome inhibitor is administered after both the first and second agents have been administered.
  • the proteasome inhibitor is bortezomib.
  • an adjuvant is used in the combination to augment the immune response to TAAs.
  • adjuvants include, by way of non-limiting example, bacillus Calmette-Guerin (BCG), endotoxin lipopolysaccharides, keyhole limpet hemocyanin (GKLH), interleukin-2 (IL-2), granulocyte- macrophage colony-stimulating factor (GM-CSF) and Cytoxan.
  • the additional therapeutic agent is, by way of non- limiting example, betamethasone dipropionate (augmented and nonaugmented), betamethasone valerate, clobetasol propionate, prednisone, methyl prednisolone, diflorasone diacetate, halobetasol propionate, amcinonide, dexamethasone, dexosimethasone, fluocinolone acetononide, fluocinonide, halocinonide, clocortalone pivalate, dexosimetasone, flurandrenalide, salicylates, ibuprofen, ketoprofen, etodolac, diclofenac, meclofenamate sodium, naproxen, piroxicam, celecoxib, cyclobenzaprine, baclofen, cyclobenzaprine/lidocaine, baclofen/cyclobenz
  • the treatments and uses described herein carry with them side effects that include, for example, nausea, vomiting, immunosuppression and susceptibility to infections, anemia and pain. Therefore, in certain embodiments, the additional therapeutic agent is any agent that abrogates treats, reduces the incidence of or prevents such side effects.
  • additional therapeutic agents include, by way of non-limiting example, anti-emetic agents, immuno-restorative agents, antibiotic agents, anemia treatment agents, and analgesic agents for treatment of pain and inflammation.
  • anti-emetic agents are defined as drugs effective for treatment of nausea and emesis (vomiting).
  • Anti-emetic agents include, by way of non-limiting example, 5-HT 3 seratonin receptor antagonists.
  • 5-HT 3 antagonists include, by way of non -limiting example, dolasetron (Anzemet®), granisetron (Kytril®), ondansetron (Zofran®), palonosetron and tropisetron.
  • anti-emetic agents include, by way of non-limiting example, dopamine receptor antagonists (e.g., chlorpromazine, domperidone, droperidol, haloperidol, metaclopramide, promethazine, and prochlorperazine), antihistamines (e.g., cyclizine, diphenhydramine, dimenhydrinate, meclizine, promethazine, and hydroxyzine), lorazepram, scopolamine, dexamethasone, emetrol®, propofol, and trimethobenzamide.
  • dopamine receptor antagonists e.g., chlorpromazine, domperidone, droperidol, haloperidol, metaclopramide, promethazine, and prochlorperazine
  • antihistamines e.g., cyclizine, diphenhydramine, dimenhydrinate, meclizine, promethazine, and hydroxyzine
  • immuno-restorative agents are defined as drugs that counter the immuno-suppressive effects of cancer therapies.
  • Immuno-restorative agents include, by way of non -limiting example, synthetic analogs of the hormone, granulocyte colony stimulating factor (G-CSF), filgrastim (Neupogen®), PEG- filgrastim (Neulasta®) and lenograstim.
  • antibiotic agents include drugs that have anti-bacterial, anti-fungal, and anti-parasite properties.
  • Antibiotics include, by way of non-limiting example, amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, loracarbef, ertapenem, cilastatin, meropenem, cefadroxil, cefazolin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, teicoplanin, vancomycin, azithromycin, clarithromycin, dirithromycin, erthromycin, roxi
  • anemia treatment agents are drugs directed toward treatment of low red blood cell and platelet production.
  • Anemia treatment agents include, by way of non -limiting example, recombinant erythropoietin (EPOGEN®, Dynopro®) and Darbepoetin alfa (Aranesp®).
  • the additional therapeutic agent is selected from, by way of non-limiting example, corticosteroids, non-steroidal anti-inflammatories, muscle relaxants, anesthetics, expectorants, antidepressants, anticonvulsants, antihypertensives, opioids, topical cannabinoids, and capsaicin.
  • corticosteroids non-steroidal anti-inflammatories
  • muscle relaxants anesthetics, expectorants, antidepressants, anticonvulsants, antihypertensives, opioids, topical cannabinoids, and capsaicin.
  • any reference to the administration of a first agent, a second agent, an additional therapeutic agent, or any combination thereof includes the administration of a pharmaceutical composition comprising the agent or agents disclosed as being administered.
  • kits for the treatment of disorders such as the ones described herein.
  • kits comprise a first and second agent or pharmaceutical compositions thereof in a container and, optionally, instructions teaching the use of the kit according to the various methods and approaches described herein.
  • kits optionally include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, disease state for which the composition is to be administered, or other information useful to the health care provider.
  • kits described herein can be provided, marketed and/or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits are, in some embodiments, marketed directly to the consumer.
  • the packaging material further comprises a container for housing the composition and optionally a label affixed to the container.
  • the kit optionally comprises additional components, such as, by way of non-limiting example, syringes for administration of the composition.
  • the kit described herein contains a therapeutically effect amount of first agent and a therapeutically effective amount of a second agent, wherein the first and second agents are as described herein.
  • the present invention provides for a kit comprising a pharmaceutical composition, wherein the pharmaceutical composition contains either one of or both of the first and second agents.
  • the kit comprises at least one first pharmaceutical composition and at least one second pharmaceutical composition.
  • the first pharmaceutical composition contains a therapeutically effective amount of the first agent and the second pharmaceutical composition contains a therapeutically effective amount of the second agent.
  • the first pharmaceutical composition does not contain a therapeutically effective amount of the second agent.
  • the second pharmaceutical composition does not contain a therapeutically effective amount of the first agent.
  • the first pharmaceutical composition contains a therapeutically effective amount of the first agent and a therapeutically effective amount of the second agent.
  • the second pharmaceutical composition contains a therapeutically effective amount of the second agent and a therapeutically effective amount of the first agent.
  • the kit further contains a third pharmaceutical composition that contains therapeutically effective amounts of the first and second agents.
  • the kit comprises (1) a first pharmaceutical composition that contains a therapeutically effective amount of a first agent and a therapeutically effective amount of the second agent, and (2) a second pharmaceutical composition that contains a therapeutically effective amount of the second agent and does not contain a therapeutically effective amount of the first agent.
  • the kit comprises (1) a first pharmaceutical composition that contains a therapeutically effective amount of a first agent and does not contain a therapeutically effective amount of the second agent, and (2) a second pharmaceutical composition that contains a therapeutically effective amount of the second agent and a therapeutically effective amount of the first agent.
  • the kit comprises a first pharmaceutical composition that is visibly different from a second pharmaceutical composition.
  • the visible differences may be for example shape, size, color, state (e.g. liquid/solid), physical markings (e.g. letters, numbers) and the like.
  • the kit comprises a first pharmaceutical composition that is a first color and a second pharmaceutical composition that is a second color.
  • the first and second colors are different, the different colors of the first and second pharmaceutical compositions is used, e.g., to distinguish between the first and second pharmaceutical compositions.
  • the third pharmaceutical composition is a third color.
  • the packaging material further comprises a container for housing the pharmaceutical composition
  • the kit comprises a first pharmaceutical composition that is in a different physical location within the kit from a second pharmaceutical composition.
  • the different physical locations containing the first and second pharmaceutical compositions comprise separately sealed individual compartments.
  • the kit comprises a first pharmaceutical composition that is in a first separately sealed individual compartment and a second pharmaceutical composition that is in a second separately sealed individual compartment.
  • the first and second compartments are separate, the different locations of the first and second pharmaceutical compositions are used, e.g., to distinguish between the first and second pharmaceutical compositions.
  • the third pharmaceutical composition is in a third physical location within the kit.
  • agents are understood to refer to either the first and second agent or the first, second and additional therapeutic agent.
  • the methods used to detect, analyze, isolate and quantify undifferentiated cells, including circulating cancer stem cells involve at least two of the following steps:
  • the methods described herein use at least three of these steps, while in other embodiments the methods use at least four of these steps. In certain embodiments, the methods described herein use all of these steps.
  • the isolation and/or enrichment steps are repeated more than once before the expression level of ALDH is determined.
  • the isloation and/or enrichment steps can be repeated using the same or different techniques two times, three times, four times, five times, etc., depending on the cell-type being isolated.
  • the present invention provides for a method of selecting a cancer patient who is predicted to benefit from the therapeutic administration of an HDAC inhibitor and a cytokine/growth factor comprising the steps of:
  • the patient is predicted to benefit from therapeutic administration of an HDAC inhibitor and a cytokine/growth factor when the isolated cells are ALDH + .
  • these cells have a high level of Aldehyde Dehydrogenase (ALDH high), e.g., relative to the level of ALHD in corresponding normal cells, such as in normal stem cells (e.g., normal hematological stem cells).
  • ALDH high Aldehyde Dehydrogenase
  • "High” includes differences of at least about 50%, 2 fold, 5 fold, 10 fold, or any statistically significant difference.
  • ALDH high includes both high ALDH protein or activity levels.
  • patients are predicted to benefit from therapeutic administration of an
  • HDAC inhibitor and a cytokine/growth factor based on the identification of isolated cells having the markers described herein for cancer stem cells.
  • the isolated predetermined cells are CD138 " , while in other embodiments the isolated predetermined cells are CD20 + . In certain embodiments of such methods, the isolated predetermined cells are CD19 + , while in other embodiments the isolated predetermined cells are
  • the isolated predetermined cells are Hoerchst " , while in other embodiments the isolated predetermined cells are ALDH + . In certain embodiments of such methods, the isolated predetermined cells are CD 15 " , while in other embodiments the isolated predetermined cells are
  • the isolated predetermined cells are CD34.
  • the cancer is a B cell malignancy, while in other embodiments the cancer is multiple myeloma. In certain embodiments of such methods, the cancer is
  • the cancer is non-Hodgkin's lymphoma. In certain embodiments of such methods, the cancer is not multiple myeloma. In certain embodiments of such methods, the cancer is not Hodgkin's disease, while in other embodiments the cancer is not non-Hodgkin's lymphoma.
  • the cancer is Hodgkin's Lymphoma (HL) and the isolated predetermined cells are CD1387CD19 + ; CD1387CD20 + ; CD1387CD27 + ; CD1387CD15 " , and/or CD138 "
  • the cancer is Hodgkin's Lymphoma and the isolated cells are CD 19+,
  • the cancer is Multiple Myeloma and the isolated predetermined cells are CD1387CD27 + ; CD1387CD19 + , and/or CD1387CD20 + .
  • the cancer is Multiple Myeloma and the isolated cells are CD 138-, CD27+, CD 19+ and/or CD20+.
  • the cancer is leukemia and the isolated predetermined cells are CD1387CD34 + and/or CD1387CD38 " . In some embodiments, the cancer is leukemia and the isolated cells are CD34+ and CD38-.
  • the cancer is Non Hodgkin's Lymphoma and the isolated cells are CD 1387CD 19+ and/or CD1387CD20+. In certain embodiments of such methods, the cancer is Non
  • Hodgkin's Lymphoma and the isolated cells are CD19+ and/or CD20+.
  • the sample is from the patient's blood, while certain embodiments the sample is from the patient's bone marrow.
  • a high expression level of ALDH in the isolated population predicts a therapeutic benefit for the administration of a chemotherapeutic, while in other embodiments of such methods, a high expression level of ALDH in the isolated population predicts no therapeutic benefit for the administration of a chemotherapeutic.
  • a low expression level of ALDH in the isolated population predicts a therapeutic benefit for the administration of a chemotherapeutic, while in other embodiments of such methods, a low expression level of ALDH in the isolated population predicts no therapeutic benefit for the administration of a chemotherapeutic.
  • use of the term "cytokine/growth factor" includes the use of a cytokine, the use of a growth factor, or a combination thereof.
  • Example 1 Evaluation of Therapeutic Effect of SNDX-275 and IL-6 on Multiple Myeloma
  • HDAC inhibitor e.g., SNDX-275
  • cytokine/growth factor e.g., IL-6
  • Phase I Patients receive subcutaneous IL-6 daily beginning day 15 of cycle 1 with oral SNDX-275 on days 1, 8 and 15. Treatment repeats every 28 days in the absence of unacceptable toxicity. In cycles 2 and higher, IL-6 will be given daily beginning day 1 of the cycle.
  • Test dose ranges are initially determined via the established individual dose ranges for SNDX-275 and IL-6.
  • a standard dosage for IL-6 is from 0.25 micrograms/kg/day to 100 microgams/kg/day.
  • An established dosage for SNDX-275 includes 2-8 mg/m 2 once weekly times 2-3 doses every 28 days.
  • the anticipated starting dose of SNDX-275 is 4 mg/m2 days 1, 8 and 15 every 28 days.
  • the anticipated starting dose of IL-6 is 2.5 mcg/kg/day beginning day 15 cycle 1.
  • Additional dosages are determined based on the standard dose for both SNDX-275 and IL-6.
  • the MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
  • Dose limiting toxicities are determined according to the definitions and standards set by the National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) Version 3.0 (March 9, 2006).
  • Phase II Patients receive IL-6 as in phase I at the MTD determined in phase I and SNDX-275 as in phase I. Treatment repeats every 6 weeks for 2-6 courses in the absence of disease progression or unacceptable toxicity. After completion of 2 courses of study therapy, patients who achieve a complete or partial response may receive an additional 4 courses. Patients who maintain stable disease for more than 2 months after completion of 6 courses of study therapy may receive an additional 6 courses at the time of disease progression, provided they meet original eligibility criteria.
  • Bone marrow and pheripheral blood will be obtained at baseline, prior to the initiation of IL-6, after 1, 2, and 6 months of combined SNDX-275 and IL-6 therapy and at 6 months after completion of combination therapy or at the time taken off study (if possible).
  • Cancer stem cells will be analyzed by phenotype and in a defined clonogenic assay system to measure the number of cancer stem cells and changes in response to therapy.
  • Pharmacokinetic parameters are calculated by model independent methods on a Digital Equipment Corporation VAX 8600 computer system using the latest version of the BIOAVL software. The following pharmacokinetics parameters are determined: peak serum concentration (C m3x ); time to peak serum concentration (I 013x ); area under the concentration-time curve (AUC) from time zero to the last blood sampling time (AUCo- 72 ) calculated with the use of the linear trapezoidal rule; and terminal elimination half-life (Xm), computed from the elimination rate constant.
  • the elimination rate constant is estimated by linear regression of consecutive data points in the terminal linear region of the log-linear concentration-time plot.
  • the mean, standard deviation (SD), and coefficient of variation (CV) of the pharmacokinetic parameters are calculated for each treatment.
  • the ratio of the parameter means preserved formulation/non-preserved formulation) is calculated.
  • Partial response is defined by the presence of all of the following: >50% reduction in the level of paraprotein, maintained for a minimum of 6 weeks; a reduction of urin M protein excretion by >90% or to ⁇ 200 mg, maintained for a minimum of 6 weeks; >50% reduction in the size of soft tissue plasmacytomas; no increase in the size and number of lytic bone lesions.
  • Minimal response is defined as the floowing: 25-49% reduction in the level of serum monoclonal paraprotein maintained for a minimum of 6 weeks; 50-89% reduction in 24 hour urinary light chain excretion, which still exceeds 200 mg/24 hr maintained for a minimum of 6 weeks; 25-49% reduction in the size of soft tissue plasmacytomas; no increase in the size and number of lytic bone lesions.
  • Example 3 Evaluation of Therapeutic Effect of SNDX-275, IL-6 and Bexarotene on Multiple Myeloma
  • Example 2 Evaluation of Therapeutic Effect of SNDX-275, IL-6 and Bexarotene on Multiple Myeloma
  • Example 6 Evaluation of Therapeutic Effect of SNDX-275 and GM-CSF on Acute myeloid leukemia/myelodysplastic syndromes
  • Example 7 Treatment with SNDX-275 and GM-CSF
  • Treatments include the use of chemotherapy, hematopoietic growth factors, and biologic therapy such as monoclonal antibodies. This duration of time appears adequate for wash out due to the relatively short-acting nature of most anti-leukemia agents. Patients must have recovered from all toxicities (to grade 0 or 1) associated with previous treatment. All subjects are evaluated for safety and all blood collections for pharmacokinetic analysis are collected as scheduled. All studies are performed with institutional ethics committee approval and patient consent.
  • Phase I Patients receive subcutaneous GM-CSF daily and oral SNDX-275 on days 1, 8 , 15 and 22. Treatment repeats every 42 days in the absence of unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of GM-CSF and SNDX-275 until the maximum tolerated dose (MTD) for the combination of GM-CSF and SNDX-275 is determined. Test dose ranges are initially determined via the established individual dose ranges for SNDX-275 and GM-CSF. A standard dosage for GM-CSF is from 10 - 400 mcg/m 2 . This trial will use a dose of 125 mgm/m2 daily.
  • MTD maximum tolerated dose
  • An established dosage for SNDX-275 includes 2-8 mg/m 2 This trial will use a dose of 4 mg/m2 weekly times 4 every 42 days. Additional dosages, both decreasing and increasing in amount as well a frequency, are determined based on the standard dose for both SNDX-275 and GM-CSF.
  • the MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Dose limiting toxicities are determined according to the definitions and standards set by the National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) Version 3.0 (August 9, 2006).
  • Phase II Patients receive GM-CSF as in phase I at the MTD determined in phase I and SNDX-275 as in phase I. Treatment repeats every 6 weeks for 2-6 courses in the absence of disease progression or unacceptable toxicity. After completion of 2 courses of study therapy, patients who achieve a complete or partial response may receive an additional 4 courses. Patients who maintain stable disease for more than 2 months after completion of 6 courses of study therapy may receive an additional 6 courses at the time of disease progression, provided they meet original eligibility criteria.
  • Bone marrow and pheripheral blood will be obtained at baseline, prior to the initiation of GM-CSF, after 1, 2, and 6 months of combined SNDX-275 and GM-CSF therapy and at 6 months after completion of combination therapy or at the time taken off study (if possible).
  • Cancer stem cells will be analyzed by phenotype and in a defined clonogenic assay system to measure the number of cancer stem cells and changes in response to therapy.
  • Bone marrow will be analyzed at baseline, prior to the initiation of GM-CSF and after 6 months of combination therapy (or at time taken off study) by flow cytometry for evidence of cell cycle inhibition, apoptosis and induction of expression of markers indicative of maturation of the cancer stem cells.
  • Pharmacokinetics Patients undergo plasma/serum sample collection for pharmacokinetic evaluation before beginning treatment and at days 1, 2, 3, 4, 5, 6, 7, 8, 14 and 28.
  • Pharmacokinetic parameters are calculated by model independent methods on a Digital Equipment Corporation VAX 8600 computer system using the latest version of the BIOAVL software. The following pharmacokinetics parameters are determined: peak serum concentration (C m3x ); time to peak serum concentration (I 013x ); area under the concentration-time curve (AUC) from time zero to the last blood sampling time (AUCo- 72 ) calculated with the use of the linear trapezoidal rule; and terminal elimination half-life (tm), computed from the elimination rate constant.
  • C m3x peak serum concentration
  • I 013x time to peak serum concentration
  • AUC area under the concentration-time curve
  • AUCo- 72 area under the concentration-time curve
  • tm terminal elimination half-life
  • the elimination rate constant is estimated by linear regression of consecutive data points in the terminal linear region of the log-linear concentration-time plot.
  • the mean, standard deviation (SD), and coefficient of variation (CV) of the pharmacokinetic parameters are calculated for each treatment.
  • the ratio of the parameter means is calculated.
  • Traditional response criteria rely on the measurement of paraprotein that is produced by the mature plasma cells that comprise the bulk of the tumor and lack replicative potentia. It is possible that paraprotein levels and plasma cell numbers will initially rise. As plasma cells senesce, the level of protein and number of plasma cells would subsequently fall. As such, traditional response criteria will be measured monthly. An assessment of response using these criteria will be made after 2 months of combination therapy and at completion of therapy.
  • Example 8 Evaluation of Therapeutic Effect of SNDX-275 and G-CSF on Acute myeloid leukemia/myelodysplastic syndromes
  • Example 9 Evaluation of Therapeutic Effect of SNDX-275, GM-CSF and 5-azacytidine on Acute myeloid leukemia/myelodysplastic syndromes
  • Example 10 Evaluation of Therapeutic Effect of SNDX-275, G-CSF and 5-azacytidine on acute myeloid leukemia/myelodysplastic syndromes
  • Example 11 Evaluation of Therapeutic Effect of SNDX-275 and IL-7 on acute lymphoid leukemia [00199] In a manner analogous to Example 7, the therapeutic effectiveness of SNDX-275 and IL-7 on acute lymphoid leukemia is evaluated.
  • Example 12 Evaluation of Therapeutic Effect of SNDX-275 and GM-CSF and on acute lymphoid leukemia
  • Example 13 Evaluation of Therapeutic Effect of SNDX-275 and IL-2 on non-Hodgkin's lymphoma
  • SNDX-275 and IL-7 Evaluation of Therapeutic Effect of SNDX-275 and IL-2 on non-Hodgkin's lymphoma
  • Example 14 Evaluation of Therapeutic Effect of SNDX-275 and GM-CSF on non-Hodgkin's lymphoma
  • Example 15 Evaluation of Therapeutic Effect of SNDX-275 and IL-4 on non-Hodgkin's lymphoma
  • Example 7 Evaluation of Therapeutic Effect of SNDX-275 and IL-4 on non-Hodgkin's lymphoma
  • Example 16 Evaluation of Therapeutic Effect of SNDX-275 and IL-6 on Hodgkin's lymphoma [00204] In a manner analogous to Example 7, the therapeutic effectiveness of SNDX-275 and IL-6 on non- Hodgkin's lymphoma is evaluated.
  • Example 17 Parenteral Composition
  • An i.v. solution is prepared in a sterile isotonic solution of water for injection and sodium chloride (-300 mOsm) at pH 11.2 with a buffer capacity of 0.006 mol/l/pH unit.
  • Theprotocol for preparation of 100 ml of a 5 mg/ml a first and/or second agent for i.v. infusion is as follows: add 25 ml of NaOH (0.25 N) to 0.5 g of a first and/or second agent and stir until dissolved without heating. Add 25 ml of water for injection and 0.55 g of NaCl and stir until dissolved. Add 0. IN HCl slowly until the pH of the solution is 11.2. The volume is adjusted to 100 ml. The pH is checked and maintained between 11.0 and 11.2. The solution is subsequently sterilized by filtration through a cellulose acetate (0.22 ⁇ m) filter before administration.
  • Example 18 Oral Composition
  • a pharmaceutical composition for oral delivery is prepared by mixing 100 mg of a first and/or second agent with 750 mg of a starch. The mixture is incorporated into an oral dosage unit, such as a hard geletin capsule or coated tablet, which is suitable for oral administration.

Abstract

L'invention concerne des agents pharmaceutiques, des compositions pharmaceutiques, des méthodes de traitement, des régimes de traitement et des trousses pour le traitement du cancer.
PCT/US2007/084836 2007-11-15 2007-11-15 Combinaisons d'inhibiteurs de hdac et de cytokines/facteurs de croissance WO2009064300A1 (fr)

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US20120094927A1 (en) * 2010-09-13 2012-04-19 Stam Ronald Therapy for mll-rearranged leukemia
WO2012159085A3 (fr) * 2011-05-19 2013-06-13 Glax L.L.C. Compositions et méthodes de traitement et de prévention du cancer par ciblage et inhibition de cellules souches cancéreuses
WO2017180519A1 (fr) 2016-04-10 2017-10-19 George State University Research Foundation, Inc. Méthodes pour traiter le cancer et inhiber le rejet de greffe

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WO2005018578A2 (fr) * 2003-08-26 2005-03-03 Aton Pharma, Inc. Procédé pour traiter le cancer au moyen d'inhibiteurs d'hdac
US20070197473A1 (en) * 2005-11-04 2007-08-23 Frankel Stanley R Methods of using SAHA and Bortezomib for treating cancer
US20070197568A1 (en) * 2005-11-04 2007-08-23 Paul Bunn Methods of using SAHA and Erlotinib for treating cancer

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US20030161830A1 (en) * 2001-06-14 2003-08-28 Jackson Donald G. Novel human histone deacetylases
WO2005018578A2 (fr) * 2003-08-26 2005-03-03 Aton Pharma, Inc. Procédé pour traiter le cancer au moyen d'inhibiteurs d'hdac
US20070197473A1 (en) * 2005-11-04 2007-08-23 Frankel Stanley R Methods of using SAHA and Bortezomib for treating cancer
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US20120094927A1 (en) * 2010-09-13 2012-04-19 Stam Ronald Therapy for mll-rearranged leukemia
US8859502B2 (en) * 2010-09-13 2014-10-14 Celgene Corporation Therapy for MLL-rearranged leukemia
WO2012159085A3 (fr) * 2011-05-19 2013-06-13 Glax L.L.C. Compositions et méthodes de traitement et de prévention du cancer par ciblage et inhibition de cellules souches cancéreuses
WO2017180519A1 (fr) 2016-04-10 2017-10-19 George State University Research Foundation, Inc. Méthodes pour traiter le cancer et inhiber le rejet de greffe
US11026972B2 (en) 2016-04-10 2021-06-08 Georgia State University Research Foundation, Inc. Methods for generating macrophages with enhanced cancer phagocytosis
EP3995139A1 (fr) * 2016-04-10 2022-05-11 Georgia State University Research Foundation, Inc. Composition pour utilisation dans le traitement du cancer

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