Predictors of chemoresistance in castration resistant prostate cancer

Abstract

Early markers of chemoresistance in metastatic castrate resistant prostate cancer (mCRPC) will allow cessation of ineffective therapy to avoid unnecessary toxicity and progression to alternative treatments. This thesis aimed to identify early markers of chemoresistance in mCRPC and investigate the role of macrophages in docetaxel resistance. Circulating free plasma mGSPT1 DNA was measured in men with mCRPC. Baseline mGSTP1 was associated with worse overall survival (OS) while a decrease in mGSTP1 after chemotherapy was associated with chemoresponse. In vitro, PC3 prostate cancer cells or their docetaxel-resistant subline (PC3Rx) were co-cultured with U937 monocytes, with and without docetaxel treatment. Cytokine production was higher in PC3Rx-U937 and was further enhanced by docetaxel exposure. Conditioned media from PC3Rx/U937 exposed to docetaxel conferred relative chemoresistance to PC3 cells. 28 circulating cytokines were measured before and after 1 cycle of docetaxel in men with metastatic CRPC. Changes in 7 circulating cytokines were associated with clinical benefit. The combination of changes in MIC1, IL-4 and IL-6 most strongly predicted PSA response. Higher baseline MIC1 predicted worse OS. In metastatic CRPC, mGSTP1 and MIC1/IL-4/IL-6 cytokine model, may be early markers of chemoresponse while baseline mGSTP1 and MIC1 are prognostic. In vitro studies suggest docetaxel resistance is partially mediated by interactions between docetaxel-resistant tumor cells and macrophages.