Preclinical Testing of Drug Combinations (HDAC, mTOR, CDK and MYC Inhibitors)

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

The goal of our preclinical studies for cancer treatment continue to be focused on preclinical evaluation of combination therapies that target both oncogenes (MYC, mTOR) and tumor suppressors (p16, MNDA). Rapamycin (mTOR inhibitor) and entinostat (HDAC, histone deactylase inhibitor) interact with two signal transduction pathways, mTOR and RB/p16 commonly altered in cancer. These drugs have been evaluated in over 100 tissue culture cell lines (Non-Hodgkin Lymphomas and the NCI-60 cell lines). Tumors that harbor mutations in MYC or FBXW7 do not respond to the drug combination. We identified a 37 gene signature that may be predictive of the cells that will respond to the treatment. We found that combinations of mTOR and HDAC inhibitors work synergistically to degrade MYC protein. Our work includes the development of new small molecule inhibitors to target DNA structures in the MYC gene. Our current goals are centered on testing drug combinations predicted to be synergistic by our analyses of single agent high throughput screens of more than 1900 compounds. Synergistic combinations are subjected to a secondary screen whereby MYC is down-regulated and p16 is upregulated. Combinations have been tested in head to head comparisons in immunocompetent animal models and HDAC inhibitors coupled to CDK inhibitors were the best performers in controlling tumor growth. We are currently investigating how bone marrow stromal cells contribute to drug resistance with this combinations.