Hdac1,2 inhibitors and methods of using the same

Abstract

Disclosed herein are methods for treating a cancer and a method for sensitizing a cancer to a chemotherapeutic agent. Each method administers an agent that selectively inhibits HDAC1 and HDAC2 to a subject in need thereof. Also disclosed herein are methods for determining if a cancer is sensitive to an agent that selectively inhibits HDAC1 and HDAC2 and methods for monitoring the efficacy of a treatment for a cancer that includes administration of an agent that selectively inhibits HDAC1 and HDAC2.

1 . A method of treating a cancer characterized by BCR-ABL expression or BBAP overexpression in a subject in need thereof, the method comprising administering to the subject an agent that selectively inhibits HDAC1 and HDAC2. 
     
     
         2 . The method of  claim 1 , wherein the cancer is a B cell malignancy. 
     
     
         3 . The method of  claim 2 , wherein the B cell malignancy is diffuse large B cell lymphoma or early Pre-B cell derived acute lymphoblastic leukemia (Pre-B-ALL). 
     
     
         4 . The method of  claim 3 , wherein the diffuse large B cell lymphoma contains a gain-of-function mutation in Enhancer of Zeste Homologue 2 (EZH2), a gain-of-function mutation in a histone H3K27 methyltransferase, or a loss-of-function mutation in a H3K27 demethylase. 
     
     
         5 . The method of  claim 3 , wherein the Pre-B-ALL contains a chromosomal translocation and wherein the chromosomal translocation is t(9;22). 
     
     
         6 . The method of  claim 1 , wherein the cancer is further characterized as being dependent upon on a double-stranded break repair pathway. 
     
     
         7 . The method of  claim 6 , wherein the double-stranded break repair pathway includes one or more of the group consisting of FEN1, EPC2, BAF180, and DNA Ligase I. 
     
     
         8 . The method of  claim 1 , wherein the cancer is further characterized by increased H3K27me3. 
     
     
         9 . The method of  claim 1 , further comprising determining if the cancer is characterized by BCR-ABL expression or BBAP overexpression,
 wherein determining comprises detecting a level of BCR-ABL, a level of BBAP, or a level of BCR-ABL and a level of BBAP in a sample obtained from the subject, and comparing the detected levels of BCR-ABL, BBAP, or BCR-ABL and BBAP to levels of BCR-ABL, BBAP, or BCR-ABL and BBAP in a control sample, wherein if the detected level of BCR-ABL is increased relative to the control level of BCR-ABL, the cancer is characterized by BCR-ABL expression, and wherein if the detected level of BBAP is increased relative to the control level of BBAP, the cancer is characterized by BBAP overexpression.   
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 1 , further comprising administering doxorubicin to the subject. 
     
     
         14 . A method of sensitizing a cancer characterized by BCR-ABL expression or BBAP overexpression to a chemotherapeutic agent in a subject in need thereof, the method comprising administering an agent that selectively inhibits HDAC1 and HDAC2 to the subject. 
     
     
         15 . The method of  claim 14 , wherein the cancer is a B cell malignancy. 
     
     
         16 . The method of  claim 15 , wherein the B cell malignancy is diffuse large B cell lymphoma or early Pre-B cell derived acute lymphoblastic leukemia (Pre-B-ALL). 
     
     
         17 . The method of  claim 16 , wherein the diffuse large B cell lymphoma contains a gain-of-function mutation in Enhancer of Zeste Homologue 2 (EZH2), a gain-of-function mutation in a histone H3K27 methyltransferase, or a loss-of-function mutation in a H3K27 demethylase. 
     
     
         18 . The method of  claim 16 , wherein the Pre-B-ALL contains a chromosomal translocation and wherein the chromosomal translocation is t(9;22). 
     
     
         19 . The method of  claim 14 , wherein the cancer is further characterized as being dependent upon on a double-stranded break repair pathway. 
     
     
         20 . The method of  claim 19 , wherein the double-stranded break repair pathway includes one or more of the group consisting of FEN1, EPC2, BAF180, and DNA Ligase I. 
     
     
         21 . The method of  claim 14 , wherein the cancer is further characterized by increased H3K27me3. 
     
     
         22 . The method of  claim 14 , further comprising determining if the cancer is characterized by BCR-ABL expression or BBAP overexpression,
 wherein determining comprises detecting a level of BCR-ABL, a level of BBAP, or a level of BCR-ABL and a level of BBAP in a sample obtained from the subject, and comparing the detected levels of BCR-ABL, BBAP, or BCR-ABL and BBAP to levels of BCR-ABL, BBAP, or BCR-ABL and BBAP in a control sample, wherein if the detected level of BCR-ABL is increased relative to the control level of BCR-ABL, the cancer is characterized by BCR-ABL expression, and wherein if the detected level of BBAP is increased relative to the control level of BBAP, the cancer is characterized by BBAP overexpression.   
     
     
         23 - 44 . (canceled)