Abstract ED05-03: The development of tractable mouse models to study therapeutic response Free

ED05-03

Many human cancers fail to respond to chemotherapy, and cancers that initially respond frequently acquire drug resistance and relapse. While chemoresistance has been observed since the earliest chemotherapeutic application, relatively little is known about the genetic determinants of drug response. Thus, chemotherapy is commonly administered without regard to the specific constellation of genetic alterations present in a given tumor. This current clinical reality is problematic for a number of reasons. First, patients are frequently given chemotherapies that have little or no chance of success. Second, potential tumor vulnerabilities conferred by specific genetic lesions are rarely considered prior to therapeutic administration, so the “right therapy” is generally not matched with the “right tumor”. Third, combination therapies are currently assembled by random trial and error, rather than through a genuine understanding of the basis for drug synergy in a given tumor. Finally, potentially effective drugs frequently fail in clinical trials due to an inability to genetically define small subsets of tumors in which these drugs have significant efficacy. Thus, new approaches to define patient populations most likely to benefit from a particular drug and to identify potentially effective drug combinations are urgently needed. Our lab combines emerging RNA interference technologies with tractable mammalian cancer models to identify genes that influence the action of conventional and molecularly targeted therapies. Specifically, we have performed highly parallel in vivo genetic screens to identify short hairpin RNAs (shRNAs) capable of enhancing or reducing the sensitivity of cancer cells to select anticancer agents, with the objective of finding potential biomarkers that may be used for patient selection, pathways required for drug action, and strategies for effective combination therapy. Importantly, these screens are carried out in vivo, in mammalian systems that more closely approximate the pharmacokinetic, pharmocodynamic, microenvironmental and immunological setting encountered in the treatment of human cancers. It is our expectation that these approaches will provide powerful preclinical test systems that can be used to identify therapies that circumvent traditional drug resistance mechanisms or test novel ‘targeted’ therapeutics.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):ED05-03.