Abstract 4165: Myc vs. Akt therapy in RapidCap, a GEM model for metastatic prostate cancer

Abstract

Abstract We describe our efforts to determine the effect of MYC and PI3K inhibition in a genetically engineered mouse model of naïve and castration-resistant metastatic prostate cancer. Metastasis is a major driver of mortality and morbidity in prostate cancer, the most common cancer type in men and the second leading cause of cancer-related deaths in the western world. To recapitulate the metastatic process in genetically engineered mice, we have developed the RapidCaP system, which uses prostate-directed viral infection to trigger focal loss of Pten and Trp53. Using luminescence and fluorescence, the RapidCaP system allows us to track disease progression in real-time and isolate metastases in distant tissues. This system provides a powerful platform for the identification and validation of candidate driver genes and for the efficient testing of novel therapeutics. Using this system, we have recently identified Myc as a critical, spontaneously activated driver in Pten-negative metastatic prostate cancer. Preliminary trials indicate that the Myc-suppressing Brd4 inhibitor JQ1 is ineffective towards primary disease, but induces metastatic regression. This specificity correlates with a switch from AKT-driven primary disease to MYC-driven metastatic disease. Our current efforts seek to determine how, when and why targeting of Myc using JQ1 and the PI 3-Kinase pathway using NVP-BKM120 can be best used to treat naïve and castration-resistant metastatic prostate cancer. In addition, we are examining changes to the transcriptome and epigenetic alterations that characterize Pten-negative metastatic prostate cancer, with the goal of understanding the mechanisms of progression toward a metastatic state and establishing new therapeutic targets. Citation Format: Carlos E. Stahlhut, Alexandra J. Ambrico, Kaitlin E. Watrud, Hyejin Cho, Lily Wang, Jun Qi, Lewis C. Cantley, James Bradner, Lloyd Trotman. Myc vs. Akt therapy in RapidCap, a GEM model for metastatic prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4165.