ABSTRACT Prostate cancer (PCa) is the most frequently diagnosed cancer in American men and the 2nd leading cause of male cancer-related deaths in the U.S. Indolent localized PCa is curable, but metastatic PCa is fatal. Progression to metastatic disease is characterized by reactivation of androgen signaling including androgen receptor (AR) function. This knowledge led to anti-androgen pathway therapy which is a mainstay for treatment of progressive PCa. Unfortunately, patients eventually become resistant to anti-androgen therapy and the benefit of subsequent taxane-based chemotherapy is limited to only extending patient survival for up to a year. An urgent need for identification of novel actionable targets remains. The long-term goal of this project is to develop better treatment strategies and rational drug therapies for precision medicine in advanced PCa. Our previous studies demonstrated ABI1 as a bona fide PCa tumor suppressor gene. ABI1 downregulation promotes epithelial mesenchymal transition (EMT) downstream from activation of the non-canonical WNT- FYN-STAT3 pathway. Our published and preliminary data indicate that ABI1 downregulation, in conjunction with loss of PTEN, is associated with high grade and metastatic PCa in a significant subset of human PCa. Because ABI1 expression is downregulated following androgen deprivation therapy, we hypothesize that anti- AR treatment leads to activation of the WNT-FYN-STAT3 pathway. Moreover, taxane therapies might promote activation of the WNT pathway and potentially cause cross-pathway effects with anti-AR treatment. Our objective is to develop a more comprehensive understanding of the contribution of ABI1 and PTEN on tumor sensitivity to the current treatment regimen of androgen receptor (AR)-targeting agents for both castrate- sensitive (CSPC) and resistant (CRPC) PCa, as well as druggability of the ABI1/PTEN pathway itself. Our central hypothesis is that ABI1-deficient tumors have a low sensitivity to anti-AR agents. In addition, we propose that ABI1-deficient tumors are sensitive to STAT3 pathway inhibitors. We propose that ABI1 is a candidate marker of tumor sensitivity for current treatments of PCa. Using the novel Abi1/Pten null mouse and organoid prostate models, we will assess drug sensitivity and characterize the tumor response in search for treatment resistance targets. We aim to: 1) Determine sensitivity of Abi1/Pten null tumors to AR inhibition (using enzalutamide) or taxane chemotherapy (using cabazitaxel) before and after androgen deprivation; 2) determine sensitivity of Abi1/Pten null tumors to STAT3 inhibition and synergy with AR inhibition (enzalutamide) or taxane (cabazitaxel) chemotherapy. Tumor gene expression patterns will be analyzed by RNA-Seq. Identified drug response-pathways will be studied using organoid and xenograft models of human metastatic PCa lacking ABI1 and PTEN genes. The expected outcome is a better understanding of ABI1 and PTEN involvement in tumor sensitivit...