Method of treating cancers using beta-lapachone or analogs or derivatives thereof

Abstract

Cancers and/or malignancies can be treated by administration of a cell cycle checkpoint activator, which is preferably β-lapachone, or a derivative or analog thereof, combined with an oncogenic kinase modulator, preferably imatinib. This combination of the cell cycle checkpoint activator with the oncogenic kinase modulator results in an unexpectedly greater than additive (i.e., synergistic) apoptosis in cancer cells. The invention includes methods of treating cancers by administering the combination of the cell cycle checkpoint activator and the oncogenic kinase modulator, pharmaceutical compositions comprising the combination of drugs used in these methods, as well as pharmaceutical kits.

1 . A method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of β-lapachone, or a derivative or analog thereof, and an oncogenic kinase modulator, such that the cancer is treated. 
     
     
         2 . The method of  claim 1 , wherein the oncogenic kinase modulator is a tyrosine kinase modulator. 
     
     
         3 . The method of  claim 3 , wherein the tyrosine kinase modulator is an epidermal growth factor receptor signal transduction pathway modulator or a Bcr-Abl signal transduction pathway modulator. 
     
     
         4 . The method of  claim 3 , wherein the Bcr-Abl signal transduction pathway modulator is imatinib. 
     
     
         5 . The method of  claim 1 , wherein the cancer is selected from the group consisting of multiple myeloma, chronic myelogenous leukemia, pancreatic cancer, non-small cell lung cancer, lung cancer, breast cancer, colon cancer, ovarian cancer, prostate cancer, malignant melanoma, non-melanoma skin cancers, hematologic tumors, hematologic tumors, hematologic malignancies, childhood leukemia, childhood lymphomas, multiple myeloma, Hodgkin's disease, lymphomas of lymphocytic origin, lymphomas of cutaneous origin, acute leukemia, chronic leukemia, acute lymphoblastic leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, plasma cell neoplasm, lymphoid neoplasm and cancers associated with AIDS. 
     
     
         6 . The method of  claim 1 , wherein the β-lapachone, or a derivative or analog thereof, and the oncogenic kinase modulator are administered intravenously, orally or intraperitoneally. 
     
     
         7 . The method of  claim 1 , wherein the oncogenic kinase modulator is administered orally. 
     
     
         8 . The method of  claim 1 , wherein the β-lapachone, or a derivative or analog thereof is administered intravenously. 
     
     
         9 . The method of  claim 1 , wherein the oncogenic kinase modulator is administered simultaneously with, preceding administration of, or following administration of the β-lapachone, or a derivative or analog thereof. 
     
     
         10 . The method of  claim 9 , wherein the oncogenic kinase modulator is administered following administration of the β-lapachone, or a derivative or analog thereof. 
     
     
         11 . The method of  claim 10 , wherein the oncogenic kinase modulator is administered within 24 hours after the β-lapachone, or a derivative or analog thereof is administered. 
     
     
         12 . The method of  claim 1 , wherein the therapeutically effective amount of the β-lapachone, or a derivative or analog thereof, is contained in a first vial, and the oncogenic kinase modulator is contained in a second vial, the contents of the first and second vials being administered to the patient simultaneously or sequentially. 
     
     
         13 . The method of  claim 1 , wherein the oncogenic kinase modulator is administered at a dosage from about 10 mg/day to about 2000 mg/day. 
     
     
         14 . The method of  claim 1 , wherein the β-lapachone, or a derivative or analog thereof is administered at a dosage from about 100 to 500,000 μg per kilogram body weight of recipient per day. 
     
     
         15 . The method of  claim 1 , wherein the β-lapachone, or a derivative or analog thereof is administered at a dosage from about 2 mg/m 2  to 5000 mg/m 2  per day. 
     
     
         16 . The method of  claim 1 , wherein the β-lapachone, or a derivative or analog thereof, further comprises a pharmaceutically acceptable carrier. 
     
     
         17 . The method of  claim 16 , wherein the pharmaceutically acceptable carrier is a water solubilizing carrier molecule selected from the group consisting of Poloxamer, Povidone K17, Povidone K12, Tween 80, ethanol, Cremophor/ethanol, polyethylene glycol (PEG) 400, propylene glycol, Trappsol, alpha-cyclodextrin or analogs thereof, beta-cyclodextrin or analogs thereof, and gamma-cyclodextrin or analogs thereof. 
     
     
         18 . The method of  claim 1 , wherein the subject is human. 
     
     
         19 . A kit for the treatment of a malignancy in a subject comprising separate vials containing β-lapachone or a derivative, or analog thereof and an oncogenic kinase modulator, with instructions for administering β-lapachone first. 
     
     
         20 . The kit of  claim 19 , wherein the oncogenic kinase modulator is imatinib.