Bladder cancer (BLCa) is the 4th most common cancer and the 7th most deadly in male veterans. Almost all cancer deaths are caused by advanced bladder cancer (aBC) which is the focus of this collaborative study. Patients with aBC usually receive medical treatment which includes chemotherapy, immunotherapy and targeted therapy, and, in case of locally advanced bladder cancer, radical cystectomy. Medical treatment is at most moderately effective. The goal of this collaborative application is to improve the treatment outcomes of aBC through revamping all four therapies from three complementary research teams with expertise in basic science, translational research, medical oncology and urology. We hypothesize that the prognosis and patient quality of life in aBC can be improved through optimizing all therapeutic modalities from research teams with complementary expertise. Specific Aims of BLRD Collaborative Merit Review Award: Three highly integrated research projects are designed to optimize three medical therapies and subsequently can further improve surgical treatment for aBC: Project #1 is to use non-toxic oral compounds to overcome chemoresistance and enhance the efficacy of chemotherapy by cytotoxic-autophagy; Project #2 is to develop oral cancer-specific quadra-functional local immuno-theranostic platform to enhance cancer immunotherapy, eliminate the associated immune-mediated toxicity in addition to its diagnostic potential; Project #3 is to target our newly identified ARID1A-PI3K pathways and develop novel more effective targeted therapy for aBC. Epigenetic modifying genes are mutated in almost 90% of aBC, and 20% have truncating mutations that result in the inactivation of AT Rich Interactive Domain 1A (ARID1A), a chromatin modifier. With funding from a VA RDA grant, we previously showed that ARID1A deficient (def) BLCa is dependent on PI3K signaling via upregulation of a relatively uncharacterized regulatory PI3K subunit PIK3R3 and downregulation of MAPK signaling. We showed that: 1) ARID1Adef cells are sensitive to EZH2 inhibitors due to dependence on PI3K signaling, and upregulation of an endogenous PI3K inhibitory protein PIK3IP1, 2) upregulation of PIK3IP1 was necessary and sufficient for cell death in ARID1Adef cells, and 3) PIK3R3 upregulation was necessary and sufficient for PI3K/AKT pathway activation and increased tumor growth. We used these data to support a phase II clinical trial with this PI as co-investigator investigating the EZH2 inhibitor Tazemetostat as maintenance therapy in metastatic bladder cancer patients with ARID1A mutant tumors. These data underscore the central hypothesis of this proposal that ARID1A deficient bladder cancer is transcriptionally re-wired to expose pharmacologic vulnerabilities that can be exploited with personalized therapies to improve outcomes for veterans and patients with bladder cancer. We will test this hypothesis in three Aims: Aim 1: Elucidate the molecular mechanisms leading to PI3K/A...