Targeting the IRE1α pathway in a metastatic castration resistant prostate cancer xenograft model

Our laboratory is studying proteins that are implicated in the progression of prostate cancer (PCa) and have previously identified a number of signaling pathways and family of proteins that are involved in this regard. One of these is the IRE1 signaling, one of the canonical endoplasmic reticulum (ER) stress pathways. Combining both in vitro and in vivo methods, our previous work has shown that IRE1 signaling is essential for PCa growth, while targeting this pathway with a small molecule inhibitor, toyocamycin, retards tumor growth in preclinical model. This has led us to assess the effect of another specific IRE1 inhibitor, MKC8866. We have tested this drug in both AR-responsive and castration-resistant PCa (CRPC) cell models, and obtained exciting and consistent inhibition of cell growth in vitro and in vivo. In this application, we will further evaluate the effect of this drug in a metastatic CRPC cell model, C42B. By subcutaneously engrafting C42B cells into the flanks of nude mice and routinely applying the drug, we will determine if MKC8866 affects tumor growth in vivo as what we have observed before.