Combinatory small molecule drug targeting of prosurvival pathways in preclinical models of prostate cancer

Our laboratory has been studying the interaction between several prosurvival pathways in prostate cancer (PCa), which includes the androgen receptor (AR) signaling and unfolded protein response (UPR) pathways. In this regard, we previously found that targeting the IRE1 signaling, one of the canonical UPR pathways, either genetically or pharmacologically, consistently inhibited in vitro and in vivo growth of PCa cell lines modeling both castration-naïve and -resistant stages. Moreover, combination of the IRE1 inhibitor MKC8866 with clinically-used agents resulted in strong additive effects in vitro. These agents include second generation antiandrogens abiraterone acetate and enzalutamide; chemotherapeutic agents docetaxel, cabazitaxel and paclitaxel; PARP inhibitor olaparib; and proteasome inhibitor bortezomib. In this application, we therefore would like to evaluate the combinatory efficacy of these drugs in preclinical settings in vivo. By subcutaneously engrafting different PCa cells into the flanks of nude mice and routinely applying the drugs, we will determine if combining MKC8866 with these clinical agents would have additive or synergistic effects on tumor growth.