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

基本信息

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
项目类别：
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

项目摘要

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，也是男性第七大致命癌症退伍军人。几乎所有癌症死亡都是由晚期膀胱癌（aBC）引起的，这是本次合作研究的重点。 aBC 患者通常会接受药物治疗包括化疗、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。药物治疗至多是中等有效的。目标该合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均来自三个具有基础科学专业知识的互补研究团队，转化研究、医学肿瘤学和泌尿学。我们假设预测和 aBC 患者的生活质量可以通过优化所有治疗方式来提高具有互补专业知识的研究团队。 BLRD协作优异奖的具体目标：三个高度集成研究项目旨在优化三种医学疗法，随后可以进一步改善 aBC 的手术治疗：项目#1 是使用无毒口服化合物来克服通过细胞毒自噬增强化疗耐药性并增强化疗疗效；项目#2 开发口腔癌特异性四功能局部免疫治疗平台以增强癌症免疫疗法，除其治疗效果外，还消除了相关的免疫介导的毒性诊断潜力；项目 #3 是针对我们新发现的 ARID1A-PI3K 通路开发针对 aBC 的新型更有效的靶向疗法。近 90% 的 aBC 中表观遗传修饰基因发生突变，其中 20% 存在截短导致 AT 丰富相互作用域 1A (ARID1A)（一种染色质）失活的突变修饰符。在 VA RDA 拨款的资助下，我们之前表明 ARID1A 缺陷 (def) BLCa 通过上调相对未表征的调节因子来依赖 PI3K 信号传导 PI3K 亚基 PIK3R3 和 MAPK 信号传导下调。我们证明：1) ARID1Adef 由于依赖 PI3K 信号传导和上调，细胞对 EZH2 抑制剂敏感内源性 PI3K 抑制蛋白 PIK3IP1，2) PIK3IP1 的上调是必要的，并且足以导致 ARID1Adef 细胞死亡，并且 3) PIK3R3 上调是必要的并且足以激活 PI3K/AKT 通路并促进肿瘤生长。我们使用这些数据来支持与该 PI 作为共同研究者研究 EZH2 抑制剂的 II 期临床试验他泽美司他作为 ARID1A 突变转移性膀胱癌患者的维持治疗肿瘤。这些数据强调了该提案的中心假设，即 ARID1A 缺陷膀胱癌的转录重新连接暴露出药理脆弱性，这些脆弱性可以通过利用个性化疗法来改善退伍军人和膀胱患者的治疗结果癌症。我们将在三个目标中检验这一假设：目标1：阐明PI3K/AKT通路的分子机制 ARID1Adef 细胞的依赖性。目标2：阐明PIK3IP1抑制PI3K的分子机制发信号。目标 3：研究 ARID1Adef 膀胱癌对 PI3K/AKT 的敏感性抑制剂和免疫疗法。