Overcoming Resistance to Enzalutamide with first-in-field TGF-beta Inhibition

The TGF-beta signaling pathway and the androgen receptor axis crosstalk at multiple levels in the initiation and progression of prostate cancer. TGF-beta impairs prostate growth by inducing apoptosis through two membrane receptors, TRI and TRII in the early stages of tumorogenesis. TGF-beta however promotes tumor invasion in late stages of metastasis by inducing EMT. The process of epithelial-mesenchymal transition (EMT) via which epithelial cells loose cell polarity and has recently emerged as a significant contributor to prostate cancer progression to metastatic disease and therapeutic resistance. We have shown in a mouse model of prostate tumorigenesis that a super-activated TGF-beta signaling accelerates prostate tumor progression via selective effects on EMT induction and inflammation. Based on the knowledge that the emerging EMT landscape in prostate cancer is governed by interactive governing by TGF-beta signaling and androgen receptor (AR) signaling towards aggressive metastatic disease, this proposal (this Specific Aim ) will interrogate/determine the consequences of selective inhibition of TGF-beta signaling (by the TGF-beta receptor I inhibitor LY2157299) , as a single agent, or in combination with androgen/AR targeting on EMT and its reversion to MET (mesenchymal-epithelial-transition) . We propose that this cycling of EMT to MET is an effective targeted process by the combination treatment in order to overcome resistance to antiandrogens in advanced castration-resistant prostate cancer. Our studies will establish that disruption of the programming of EMT by the TGF-beta RI inhibitor sensitizes prostate cancer cells to antiandrogen treatment, lifting therapeutic resistance towards combating metastatic CRPC. This work is expected to lead to optimization of the clinical utility of the TGF-beta Receptor I inhibitor for the treatment of metastatic CRPC, by engaging actions dependent on AR and navigated by androgen axis.