Synthetic Lethal Gene for PTEN as a Therapeutic Target

: PTEN is the gene which is down-regulated in the majority of prostate cancer, and PTEN-Akt pathway is considered to play a critical role in radiation resistance. The overall goal of this project is to identify a specific gene that is essential for this important pathway in the hope that targeting such gene will sensitize PTEN-negative tumor stem cells to be radiation-sensitive. To accomplish this goal, we isolated cancer stem cells from prostate tumor cell lines and patient samples followed by preparing PTEN-deficient cells. We then screened genes that play critical roles in the PTEN pathway using a technique called the shRNA library screening, with or without radiation treatment of these cells. We have identified synthetic lethal genes, and we plan to examine the effect of such genes in an animal model to test our hypothesis. During the funding period, we have successfully accomplished Aim 1 and 2 and we identified five synthetic lethal genes. Testing the effect of knockout of these genes on radiation therapy in an in vivo model as planed in Aim 3 is currently in progress. We believe that targeting the synthetic lethal genes that we discovered will lead to the development of a novel therapeutic approach for radiation-resistant prostate cancer.