Project Summary/Abstract The long-term goal of this study is to develop a highly effective non-toxic regimen by a combination of natural products green tea (GT) and quercetin (Q) to enhance the therapeutic effect of docetaxel (Doc) in treatment of metastatic and castration-resistant prostate cancer (mCRPC) in African-American (AA) patients. The risk of advanced prostate cancer including mCRPC in AA men is 2.5 fold greater vs. Caucasians, and the increased risk can not be eliminated by corrections for factors that may affect the access to health care. This emphasizes the importance of improving the clinical treatment of prostate cancer in order to reduce the disparity in prostate cancer mortality. Doc is a standard treatment for mCRPC. However, severe dose limiting toxicities along with chemoresistance limit the clinical success of Doc. The resistance to Doc is associated with upregulation of anti-apoptotic signaling and overexpression of transport proteins including MRP. Previously we found that Q can synergistically enhance the anti-cancer effect of GT in prostate tumor cells by increasing bioavailability of non-methylated GT polyphenols, increasing pro-apoptotic signaling and decreasing MRP1 expression. Therefore, GT and Q may be ideal candidates to be combined with Doc to sensitize tumor cells to Doc. Our in vitro studies demonstrated that combining GT and Q with Doc synergistically enhanced the anti-proliferative effect in CRPC cell lines. The combined effect of GT/Q/Doc was further confirmed in our animal studies, where GT and Q enhanced the potency of Doc 2-fold in inhibition of PC-3 xenograft tumor growth, with no increased toxicity. The objective of the proposed phase I/II trial is to assess the efficacy and safety of GT and Q in combination with Doc for mCRPC in AA patients. Specific aim 1 will evaluate the safety and efficacy of GT and Q in combination with Doc in AA patients with enzalutamide- or abiraterone- resistant mCRPC. Aim 1a will determine the recommended phase II dose (RP2D) of GT and Q with Doc/prednisone. A phase I-II trial with the EffTox design will be carried out to test three dose levels with 8 cohort of patients (n=3 per cohort). The selection of optimal doses for successive patient cohorts will be based on both efficacy and toxicity. Aim 1b will assess the efficacy of GT and Q with Doc/prednisone compared to Doc/prednisone. An extended phase II study will be conducted with the enrollment of additional patients on RP2D and a control group, with 30 patients for each group. Specific aim 2 will validate the effect of GT+Q in reversing the resistance to Doc in prostate cancer mouse models. Two different mouse models will be utilized, including a xenograft model of Doc-resistant PC-3 tumors and a prostate-specific PTEN knockout mouse model with a Doc-resistant tumor phenotype. The proposed study will set the stage for phase III clinical trials of this highly promising and urgently needed regimen to enhance the treatment of m...