Tumor Suppressor Signaling Approaches for the Treatment of Metastatic Prostate Cancer

Genomic alterations that occur in tumors may cause sensitivities and weaknesses that can be exploited for therapeutic benefit. Mutations in the PTEN and p53 tumor suppressor genes are highly prevalent in advanced disease and represent potentially important targets for the treatment of metastatic, lethal prostate cancer. Parsons and team are studying the biology and therapeutic effects of targeting p53 and PTEN mutations in advanced prostate cancer. Loss of PTEN promotes tumor cell progression by unleashing the tumor-promoting PI3K pathway. The team will study the role of PTEN-loss in prostate cancer by measuring the activity of PTEN and the PI3K pathway in normal prostate, primary prostate cancer, and metastatic prostate cancer samples from patients. The effects of PTEN-loss on the metabolism and proliferative abilities of prostate cells will be investigated. The team will then explore whether inhibitors of PI3K, mTOR, or RAC are able to restore normal metabolism in cells that have lost PTEN. Mutations in p53 can lead to altered functions that promote tumor growth instead of tumor suppression. The team will identify mutations in p53 that promote prostate tumor progression and investigate the underlying mechanisms. ETS gene fusions commonly co-occur with PTEN-loss in advanced prostate cancer. In order to understand the biology and impact of these genetic events, the team will investigate the effects of ETS fusions combined with PTEN-loss on prostate cancer cell growth, gene expression, metabolism, metastatic activities, and sensitivity to androgen receptor (AR) targeted therapy. In addition, the activity of several novel therapeutic compounds that have indicated promise in the treatment of p53 and PTEN-deficient prostate cancer will be tested alone and in combinations in preclinical tumor models. These include inhibitors of tankyrase, PI3K, BRD4, EZH2, AR, glutaminase and enzymes involved in de novo pyrimidine synthesis. If successful, this project will result in identification of novel therapeutic strategies for the treatment of patients with p53 and/or PTEN-deficient prostate tumors. What this means for patients: Genomic alterations that occur in tumors may cause sensitivities and weaknesses that can be exploited for therapeutic benefit. This team will develop new precision medicine treatment strategies for prostate tumors harboring mutations in the tumor suppressor genes p53 and PTEN.