Method of using histone deacetylase inhibitors and monitoring biomarkers in combination therapy

Patent metadata

Field	Value
Publication number	US-9408816-B2
Application number	US-95298507-A
Country	US
Kind code	B2
Filing date	Dec 7, 2007
Priority date	Dec 26, 2006
Publication date	Aug 9, 2016
Grant date	Aug 9, 2016

Abstract

Provided herein are methods for using at least one histone deacetylase inhibitor to decrease cellular DNA repair activity, methods for monitoring the decrease of cellular DNA repair activity using at least one biomarker, methods of treating cancer by using at least one histone deacetylase inhibitor to decrease cellular DNA repair activity in combination therapy, methods of combination therapy where at least one histone deacetylase inhibitor interferes with a DNA repairing mechanism involving RAD51, methods for predicting a induction time period between a first administration of at least one histone deacetylase inhibitor and a second administration of at least one other therapeutic treatment, and pharmaceutical compositions for combination therapy.

First claim

What is claimed is:

1. A method of inhibiting or relieving a cancer associated with a defect in non-homologous end joining of DNA in an individual in need thereof, comprising: (a) identifying the cancer as containing a defect in non-homologous end joining of DNA, wherein the defect comprises a defect in a gene selected from the group consisting of: Ku70, Ku80, Ku86, Ku, PRKDC, LIG4, XRCC4, DCLRE1C, and XLF; and (b) administering to the individual: (i) a therapeutically effective amount of 3-((dimethylamino)methyl)-N-(2-(4-(hydroxycarbamoyl)phenoxy)ethyl)benzofuran-2-carboxamide, or a pharmaceutically acceptable salt thereof; and (ii) a treatment capable of damaging cellular DNA.

2. The method of claim 1 , wherein the cancer is selected from a breast cancer, colon cancer, colorectal carcinomas, non-small cell lung cancer, small-cell lung cancer, liver cancer, ovarian cancer, prostate cancer, uterine cervix cancer, urinary bladder cancer, gastric carcinomas, gastrointestinal stromal tumors, pancreas cancer, germ cell tumors, mast cell tumors, neuroblastoma, mastocytosis, testicular cancers, glioblastomas, astrocytomas, lymphomas, melanoma, myelomas, acute myelocytic leukemia (AML), acute lymphocytic leukemia (ALL), myelodysplastic syndrome, chronic myelogenous leukemia, Burkitt's lymphoma, chronic myelogenous leukemia, and B-cell lymphoma.

3. The method of claim 1 , wherein the therapeutically effective amount of 3-((dimethylamino)methyl)-N-(2-(4-(hydroxycarbamoyl)phenoxy)ethyl)benzofuran-2-carboxamide is from about 0.2 mg to about 2000 mg.

4. The method of claim 1 , wherein the treatment capable of damaging cellular DNA is selected from: radiotherapy, an anticancer agent, or any combination thereof.

5. The method of claim 1 , wherein the treatment capable of damaging cellular DNA is radiotherapy.

6. The method of claim 1 , wherein the treatment capable of damaging cellular DNA is selected from: a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, a nitrogen mustard, a nitroso urea, an angiogenesis inhibitor, an inhibitor of a cell proliferation and survival signaling pathway, an apoptosis inducing agent, an agents that interferes with a cell cycle checkpoints, a biphosphate, or any combination thereof.

7. A method of inhibiting or relieving a cancer in which RAD51 is overexpressed in an individual in need thereof, comprising: (a) identifying the cancer as overexpressing RAD51; and (b) administering to the individual: (i) a therapeutically effective amount of 3-((dimethylamino)methyl)-N-(2-(4-(hydroxycarbamoyl)phenoxy)ethyl)benzofuran-2-carboxamide, or a pharmaceutically acceptable salt thereof; and (ii) a treatment capable of damaging cellular DNA.

Assignees

• Adimoolam Shanthi
• Buggy Joseph J
• Magda Darren
• Miller Richard
• Pharmacyclics Llc

Inventors

• Adimoolam Shanthi
• Buggy Joseph J
• Magda Darren
• Miller Richard

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K31/164 Primary

  of a carboxylic acid with an aminoalcohol, e.g. ceramides · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title