Myc Vs. Akt Therapy In Rapidcap, A Gem Model For Metastatic Prostate Cancer

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PAMetastasis 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 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. The system provides a powerful platform for identification and validation of candidate driver genes and for efficient testing of novel therapeutics. Using this approach, we have recently identified Myc as a critical, spontaneously activated driver in Pten-negative metastatic prostate cancer. In agreement, our previous trials indicated that the Myc-suppressing Brd4 inhibitor JQ1 is ineffective towards primary disease, but causes metastatic regression. Mechanistically, this specificity correlates with the switch from Akt-driven primary to Myc-driven metastatic disease.Intriguingly, however, advanced metastases in RapidCaP do not express the androgen receptor, in spite of being of epithelial origin as shown by the Nkx3.1 prostate marker. As a consequence, metastatic disease often shows little to no response to castration therapy and invariably results in lethal disease. Therefore, we will discuss how, when and why targeting of Myc using JQ1 and the PI 3-Kinase pathway using NVP-BKM120 are best used to treat naive or castration-resistant metastatic disease.Citation Format: Carlos E. Stahlhut, Kaitlin E. Watrud, Alexandra J. Ambrico, Hyejin Cho, Lily Wang, Jun Qi, Lewis C. Cantley, James Bradner, Lloyd C. Trotman. Myc vs. Akt therapy in RapidCap, a GEM model for metastatic prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2636. doi:10.1158/1538-7445.AM2015-2636