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

BCCMA：改善晚期膀胱癌护理的转化研究

• 批准号: 10588500
• 负责人: James E Ferguson
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588500
• 关键词: ARID Domain; Autophagocytosis; Award; Basic Science; Binding; Biological; Biological Assay; Biology; Cancer Biology; Cancer Patient; Candidate Disease Gene; Caring; Cause of Death; Cell Death; Cells; Chemoresistance; Chromatin Remodeling Factor; Co-Immunoprecipitations; Collaborations; Complex; Correlative Study; Cytotoxic Chemotherapy; Data; Dependence; Diagnostic; Down-Regulation; EZH2 gene; Epigenetic Process; Exposure to; Funding; Genes; Genetic Transcription; Goals; Grant; Human; Immune; Immunocompetent; Immunotherapy; In Vitro; Investigation; MAP Kinase Gene; Maintenance Therapy; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Medical; Medical Oncology; Modality; Modeling; Molecular; Mutate; Mutation; Operative Surgical Procedures; Oral; PI3K/AKT; PIK3CG gene; PIK3R3 gene; Pathway interactions; Patients; Phase II Clinical Trials; Phenotype; Process; Prognosis; Proteins; Quality of life; Radical Cystectomy; Research; Research Personnel; Research Project Grants; Role; Sampling; Signal Transduction; Testing; Therapeutic; Toxic effect; Translational Research; Treatment outcome; Ubiquitination; Up-Regulation; Urology; Veterans; Western Blotting; cancer immunotherapy; chemotherapy; design; efficacy testing; experimental study; improved; improved outcome; in vivo; inhibitor; male; malignant mouth neoplasm; multicatalytic endopeptidase complex; mutant; novel; personalized medicine; pharmacologic; synergism; targeted treatment; theranostics; tumor; tumor growth

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.

膀胱癌（BLCa）是男性第四大常见癌症，第七大致命癌症。 老兵几乎所有的癌症死亡都是由晚期膀胱癌（aBC）引起的， 这是这次合作研究的重点。aBC患者通常接受药物治疗， 包括化疗、免疫治疗和靶向治疗，如果局部晚期 膀胱癌根治性膀胱炎药物治疗最多是中等有效的。目标 这种合作应用的目的是通过改造来改善aBC的治疗效果。 所有四种疗法都来自三个互补的研究团队，他们都具有基础科学方面的专业知识， 转化研究、医学肿瘤学和泌尿学。我们假设预后和 aBC患者的生活质量可以通过优化所有治疗方式来改善， 具有互补专业知识的研究团队。 BLRD协作优异评审奖的具体目标：三个高度集成的 研究项目旨在优化三种医学疗法， 改善aBC外科治疗：项目#1是使用无毒口服化合物来克服 通过细胞毒性自噬增强化疗的疗效;项目#2 目的是开发口腔癌特异性四功能局部免疫治疗诊断平台， 癌症免疫治疗，消除相关的免疫介导的毒性，除了其 诊断潜力;项目#3是针对我们新发现的ARID 1A-PI 3 K通路， 开发新的更有效的aBC靶向治疗。 表观遗传修饰基因在几乎90%的aBC中发生突变，20%的aBC具有截短性。 导致AT丰富的交互作用结构域1A（ARID 1A）失活的突变， 修饰语在VA RDA赠款的资助下，我们先前表明ARID 1A缺陷（def） BLCa依赖于PI 3 K信号转导，通过上调相对未表征的调节性信号转导途径。 PI 3 K亚基PIK 3R 3和MAPK信号转导的下调。我们发现：1）ARID 1Adef 细胞对EZH 2抑制剂敏感，这是由于依赖于PI 3 K信号传导， 内源性PI 3 K抑制蛋白PIK 3 IP 1，2）PIK 3 IP 1的上调是必需的， 足以使ARID 1Adef细胞死亡，3）PIK 3R 3上调是必需的， 足以激活PI 3 K/AKT通路并增加肿瘤生长。我们利用这些数据 支持II期临床试验，该PI作为研究EZH 2抑制剂的合作研究者 Tazemetostat作为ARID 1A突变转移性膀胱癌患者的维持治疗 肿瘤的这些数据强调了这一提议的中心假设，即ARID 1A缺乏 膀胱癌是转录重新布线，以暴露药理学的弱点， 利用个性化疗法改善退伍军人和膀胱癌患者的预后 癌我们将在三个目标中检验这一假设： 目的1：阐明PI 3 K/AKT信号通路的分子机制 ARID 1Adef细胞的依赖性。 目的2：阐明PIK 3 IP 1抑制PI 3 K的分子机制 信号 目的3：研究ARID 1Adef膀胱癌对PI 3 K/AKT的敏感性 抑制剂和免疫疗法。