TREATMENT OF CANCER

• US 20140206757A1
• Filed: 09/04/2012
• Published: 07/24/2014
• Est. Priority Date: 09/01/2011
• Status: Active Grant

• Current Assignee: Brigham and Women's Hospital Incorporated
• Original Assignee: Brigham and Women's Hospital Incorporated
• Inventors: Shi, Yujiang Geno, Lian, Christine Guo
• Granted Patent: US 9,289,415 B2
• Time in Patent Office: Days
• US Class Current: 514/44.R
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/22 of acyclic acids, e.g. pravastatin
• CPC Class Codes: A61K 31/351 not condensed with another ring
• CPC Class Codes: A61K 31/366 having six-membered rings, e.g. delta-lactones
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61N 5/10 X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy A61N5/01 takes precedence
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 2600/154 Methylation markers
• CPC Class Codes: G01N 2333/90245 acting on paired donors with incorporation of molecular oxygen (1.14)
• CPC Class Codes: G01N 33/5011 for testing antineoplastic activity

Abstract

This disclosure provides agents, compositions and methods of treating cancer by inhibiting histone lysine specific demethylase 1 (LSD1) and/or and a histone lysine specific demethylase 2 (LSD2). Agents and compositions comprise statins and/or inhibitors of LSD1/2.

Claims

1. A method for treating cancer in a subject comprising administering to a subject in need thereof a therapeutically effective amount of an epigenetic modulating adjuvant agent in conjunction with at least one chemotherapy, wherein the epigenetic modulating adjuvant agent promotes chemo-protection and reducing chemo-resistance.

37. The methods of claim 1, wherein the epigenetic modulating adjuvant agent is an inhibitor of a histone demethylase.

38. The methods of claim 37, wherein the histone demethylase is histone lysine specific demethylase 1 (LSD1) and/or and a histone lysine specific demethylase 2 (LSD2).

39. The methods of claim 38, wherein the inhibitor is a statin.

40. The methods of claim 1, wherein the at least one chemotherapy is an alkylating chemotherapeutic drug.

2-32. -32. (canceled)

33. A method for treating chemotherapy resistant cancer in a subject, the method comprising:

a. determining whether chemotherapy resistant cancer cell population of the subject are susceptible to an epigenetic modulating agent; and

if so

b. administering to the subject a therapeutically effective amount of the epigenetic modulating agents, wherein the agent treats chemotherapy resistant cancer in the subject by inducing apoptosis of the chemotherapy resistant cancer cells, and wherein the apoptosis induced is at least 10% compared to cancer cells of the subject in the absence of the epigenetic modulating agent.

34. The method of claim 33, wherein the susceptibility to an epigenetic modulating agent is determined comprising:

i. providing a population of cancer cells derived from a subject;

ii. contacting the cells with at least one epigenetic modulating adjuvant agent; and

iii. measuring the methylation on H3K4Me2-containing DNA sequences, wherein an increase in methylation on H3K4Me2-containing DNA sequences indicate that the cancer cell population is susceptible to the at least one epigenetic modulating adjuvant agent.

35. A method for enhancing the drug efficacy of at least one cancer chemotherapy in a subject comprising administering to the subject in need thereof a therapeutically effective amount of at least one an epigenetic modulating adjuvant agent in conjunction with the at least one chemotherapy to promote chemo-protection and reducing the development of chemo-resistance cancer cells in the subject.

36. A method for assessing the susceptible of a cancer cell population to at least one epigenetic modulating adjuvant agent comprising providing a population of cancer cells derived from a subject, contacting the cells with at least one epigenetic modulating adjuvant agent, and measuring the methylation on H3K4Me2-containing DNA sequences, wherein an increase in methylation on H3K4Me2-containing DNA sequences indicate that the cancer cell population is susceptible to the at least one epigenetic modulating adjuvant agent.

41. A method for treating cancer in a subject comprising administering to a subject in need thereof a therapeutically effective amount of an inhibitor of a histone lysine specific demethylase 1 (LSD1) and/or and a histone lysine specific demethylase 2 (LSD2).

42. The method of claim 41, wherein cancer cells of the subject has been determined to be susceptible to apoptosis induced by the inhibitor of LSD 1 and/or LSD2.

43. The method of claim 42, wherein the apoptosis induced is at least 10% compared to cancer cells of the subject in the absence of the inhibitor of LSD1 and/or LSD2.

44. The method of claim 42, wherein the susceptibility to apoptosis induced by the inhibitor of LSD 1 and/or LSD2 is determined by:

a. providing a population of cancer cells derived from a subject;

b. contacting the cells with at least one epigenetic modulating adjuvant agent; and

c. measuring the methylation on H3K4Me2-containing DNA sequences, wherein an increase in methylation on H3K4Me2-containing DNA sequences indicate that the cancer cell population is susceptible to the at least one epigenetic modulating adjuvant agent

45. The method of claim 41, wherein the inhibitor of LSD1 and/or LSD2 is a statin.

46. The method of claim 45, wherein the statin is selected from the group consisting of fluvastatin, lovastatin, simvastatin, mevastatin, pravastatin, atorvastatin, and rosuvastatin.

47. The method of claim 41, wherein the inhibitor of LSD1 and/or LSD2 is a monoamine oxidase inhibitor.

48. The method of claim 47, wherein the monoamine oxidase inhibitor is tranylcypromine, derivatives or analogues thereof.

49. The method of claim 41, wherein the inhibitor of LSD1 and/or LSD2 is administered by a route selected from the group consisting of:

intravenous, intramuscular, subcutaneous, intradermal, topical, intraperitoneal, intrathecal, intrapleural, intrauterine, rectal, vaginal, intrasynovial, intraocular/periocular, intratumor, and parenteral administration.

50. The method of claim 41, wherein the inhibitor of LSD1 and/or LSD2 is administered in conjunction with at least one additional cancer therapy to achieve a combination cancer therapy.

51. The method of claim 50, wherein the at least one additional cancer therapy is selected from the group consisting of radiation therapy, chemotherapy, immunotherapy and gene therapy.