Abstract PL01-01: Using synthetic lethality to find effective combination therapies for cancer.

Abstract

Abstract Cancer remains difficult to treat, even with the new generation of targeted cancer drugs. By far the most formidable obstacle is the rapid emergence of therapy resistance. Indeed, many of the new cancer drugs elicit powerful initial responses, leading to dramatic effects on "progression free survival," but far less long-term benefit is seen in terms of overall survival. Combination therapies can help fight therapy resistance, but with an arsenal of over 1000 cancer drugs in clinical development, the number of possible combinations seems nearly endless. In my laboratory we employ functional genetic screens to find powerful combinations of cancer drugs by exploiting the concept of "synthetic lethality." Using RNA interference-based genetic screens with collections of shRNAs that target druggable gene families, we search for genes whose inactivation is particularly synergistic with clinically-relevant cancer drugs. Such screens can identify drug combinations that are far more powerful than the sum of the two single agents. We aim to understand the molecular rationale for the observed synergy between two cancer drugs. Once we have insight into the molecular mechanism, we aim to bring such rationally-designed combinations to the cancer clinic as soon as possible through our clinical collaborations in our comprehensive cancer center. As a second approach, we use genome wide loss-of-function genetic screens in cancer cells that are sensitive to the drug-of-interest to search for genes whose down-regulation confers resistance to the drug-of-interest. Such genetic screens can identify novel mechanisms of drug resistance. This in turn may suggest strategies that help prevent drug resistance. Examples of genetic screens that help to optimize the treatment of cancer will be presented. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL01-01. Citation Format: René Bernards. Using synthetic lethality to find effective combination therapies for cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PL01-01.