BCCMA: Translational research to improve the care of advanced bladder cancer

膀胱癌是男性第四大常见癌症，也是第七大致死性癌症。 退伍军人。几乎所有的癌症死亡都是由晚期膀胱癌(ABC)引起的 这项合作研究的重点。患有ABC的患者通常接受 包括化疗、免疫治疗和靶向治疗，如果是局部晚期 膀胱癌，根治性膀胱切除术。药物治疗充其量也就是适度有效。目标是 这一协作应用的目的是通过改造来改善ABC的治疗结果 所有四种疗法都来自三个在基础科学方面有专业知识的互补研究团队， 翻译研究、内科肿瘤学和泌尿科。我们假设预后和 通过优化ABC的所有治疗方式，可以提高ABC患者的生活质量 具有互补专业知识的研究团队。 BLRD协作功评奖的具体目标：三个高度融合 研究项目旨在优化三种医疗疗法，随后可以进一步 改进ABC的外科治疗：项目1是使用无毒的口服化合物来克服 化疗耐药和通过细胞毒-自噬提高化疗效果；项目2 正在开发针对口腔癌的四功能局部免疫治疗平台，以增强 癌症免疫治疗，消除相关的免疫介导性毒性 诊断潜力；项目3是针对我们新发现的ARID1A-PI3K途径和 开发新的、更有效的针对ABC的靶向治疗。 表观遗传修饰基因在近90%的ABC中发生突变，20%的ABC发生截断 导致染色质AT富相互作用结构域1A(ARID1A)失活的突变 修改器。在VA RDA赠款的资助下，我们之前证明了ARID1A有缺陷(Def) BLCa依赖于PI3K信号，通过上调一个相对未知的调节因子 PI3K亚基PIK3R3与MAPK信号的下调。我们发现：1)ARID1Adef 细胞对EZH2抑制剂敏感是由于对PI3K信号的依赖，并上调了 内源性PI3K抑制蛋白PIK3IP1，2)PIK3IP1的上调是必要的，并且 足以使ARID1Adef细胞死亡，以及3)PIK3R3上调是必要的， 足以激活PI3K/AKT通路，促进肿瘤生长。我们利用这些数据 支持该PI作为研究EZH2抑制剂的联合调查者的II期临床试验 转移性膀胱癌ARID1A突变患者的维持性治疗 肿瘤。这些数据强调了这一提议的中心假设，即ARID1A是有缺陷的 膀胱癌在转录上重新连接，以暴露可能是 利用个性化治疗改善退伍军人和膀胱患者的预后 癌症。我们将从三个方面检验这一假设： 目的1：阐明PI3K/AKT通路的分子机制 ARID1Adef细胞的依赖性。 目的2：阐明PIK3IP1抑制PI3K的分子机制 发信号。 目的3：研究ARID1Adef膀胱癌对PI3K/AKT的敏感性 抑制剂和免疫疗法。

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/AKT pathway dependence in ARID1Adef cells. Aim 2: Elucidate the molecular mechanisms by which PIK3IP1 inhibits PI3K signaling. Aim 3: Investigate the sensitivity of ARID1Adef bladder cancer to PI3K/AKT inhibitors and immunotherapy.