Combinatory small molecule drug targeting of prosurvival pathways in patient derived xenograft 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 for PCa, such as enzalutamide and cabazitaxel, resulted in strong synergistic effects in human PCa cell line xenograft models in mice. In this application, we would like to evaluate the singular efficacy of MKC8866 as well as that of combining MKC8866 with enzalutamide and cabazitaxel in patient derived xenograft (PDX) models of PCa, which will be another key step towards the clinical development of this drug. By subcutaneously engrafting different PDXs into the flanks of nude mice and routinely applying the drugs, we will determine the effect of MKC8866 alone, or in combination with these clinical agents, on the PDX tumor growth.