BCCMA: Basic and Translational Mechanisms of Cancer Initiation of the Urothelium in Veterans Exposed to Carcinogens: Defining the Molecular and Spatial Features of Carcinoma in situ of the Bladder

BCCMA：暴露于致癌物的退伍军人尿路上皮癌症发生的基本和转化机制：定义膀胱原位癌的分子和空间特征

• 批准号: 10513321
• 负责人: Joshua James Meeks
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10513321
• 关键词: Address; Artificial Intelligence; Award; Bacillus Calmette-Guerin Therapy; Biological Warfare; Bladder; Blood; Cancer Detection; Carcinogens; Carcinoma in Situ; Cause of Death; Cell Cycle; Cell Proliferation; Cells; Chemical Warfare; Chemicals; Colorectal Cancer; CpG Islands; Cystoscopy; DNA Methylation; Data; Detection; Diagnosis; Diagnostic; Early Diagnosis; Early treatment; Eligibility Determination; Enhancers; Ensure; Epigenetic Process; Epithelium; Evaluation; Exposure to; Foundations; Frequencies; Functional disorder; Gene Expression; Gene Mutation; Genetic; Genetic Processes; Genetic Transcription; Genomics; Goals; Hazardous Chemicals; Human; Imaging technology; Immune; Immune Evasion; Immunologics; Immunosuppression; Immunotherapy; Indolent; Induced Mutation; Invaded; Invasive Lesion; KDM1A gene; Knowledge; Laboratories; Lesion; Link; Lymphocyte; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Malignant neoplasm of urinary bladder; Measures; Medical center; Methods; Modeling; Molecular; Morbidity - disease rate; Muscle; Mutation; Neoplasm Metastasis; Occupational; Occupational Exposure; Operative Surgical Procedures; PPAR gamma; Pathologic; Pathway interactions; Patient Self-Report; Patients; Precision therapeutics; Predictive Value; Predisposition; Prevention; Primary Care; Proliferating; RB1 gene; RNA; Reagent; Recommendation; Recording of previous events; Recurrence; Regulatory Pathway; Reporting; Resources; Risk; Role; S phase; Scientist; Screening procedure; Second Primary Neoplasms; Site; Smoker; Smoking; Somatic Mutation; T-Lymphocyte; Testing; Therapeutic; Time; Tobacco smoke; Tobacco smoking behavior; Transcriptional Regulation; Urine; Urologic Surgical Procedures; Urothelium; Veterans; artificial intelligence algorithm; base; bladder cancer prevention; bladder carcinoma in situ; cancer initiation; cancer invasiveness; cancer risk; combat; digital; effective therapy; epigenetic therapy; exhaust; exhaustion; exome sequencing; high risk; image guided; imaging biomarker; immune activation; immune cell infiltrate; immunoregulation; improved; inhibitor; molecular marker; molecular targeted therapies; neoantigens; new therapeutic target; novel diagnostics; novel therapeutics; personalized management; prevent; promoter; research and development; response; risk stratification; screening guidelines; small molecule inhibitor; success; synergism; targeted sequencing; therapy resistant; transcriptome; treatment response; tumor; tumor progression; tumor-immune system interactions; urinary

PROJECT SUMMARY ABSTRACT Herein, a group of collaborative merit review applications (CMA) aim to advance the precision management of bladder cancer (BCa), especially focused on the early stage initiation of urothelium as a model of dynamic epithelial changes in response to smoking and deployment-related carcinogens. Malignancies are the second most common cause of death among Veterans and BCa is the fourth most common cancer in the VA. Among tumor types, 70% of BCa is confined to the superficial part of the bladder (Stages T1, Ta, and CIS), with the remainder invasive of the muscle or metastatic. If BCas are identified at an earlier stage, nearly all of these tumors are treatable with a combination of surgery and intracavitary therapy. Yet, there are currently no validated or recommended screening procedures to identify asymptomatic BCas and there are no methods to identify at-risk patients at an earlier and more curable stage. The proposed CMAs aim to address these limitations and to significantly disrupt BCa prevention, detection, risk stratification and precision treatment by dissecting the genetic and molecular foundations of early stage BCa. The projects include the following: CMA1 aims to determine the genetic and immune-suppressive landscape of CIS to identify new therapeutics and immunotherapies. CMA2 investigates the plasticity of the urothelium to determine how PPARg can direct epithelial differentiation as a possible modulator of CIS. CMA3 will examine the epigenetic basis of urothelial differentiation and the role of LSD1-inhibitor, Methysticin, as a chemopreventative agent to restore the epigenetic imbalance of the urothelium. Finally, CMA4 will develop artificial intelligence algorithms for enhanced cystoscopy imaging technologies or BCa detection and risk stratification. These CMAs are linked both intrinsically among each other and extrinsically with all contributors already supported by VA R&D with Merit Awards focused on BCa to maximize synergy and ensure success. Rationale: More than 80% of Veterans report a history of tobacco smoking with 90% of Veterans with BCa self-reported smokers. Unlike lung, prostate or colorectal cancer, there are no screening protocols recommended for Veterans at risk for BCa. There is no primary care recommendation for uniform evaluation of blood in the urine, and no urinary tests have a high negative predictive value that can replace cystoscopy. Almost all patients with BCa develop blood in the urine at some time, but there is often delays in pursuing an evaluation by months to years that lead to tumor progression due to lack of referrals to urologic surgery for evaluation. Once diagnosed, the urothelium is often challenging to follow and up 20% of invasive tumors will progress to higher stage cancer. Treatment for early stage invasive bladder cancer is dependent on BCG immunotherapy, but BCG is frequently unavailable and underutilized for maintenance and 30% of BCas become BCG unresponsive. Therefore, the three major challenges for improving survival for patients with BCa are 1) early detection of high-risk tumors 2) identification of progression to higher stage cancer and 3) treatment resistance to BCG immunotherapy. Our preliminary data suggest that the urothelium has plasticity in early stage BCa that, if understood at the genetic, epigenetic and molecular level, could be treated and driven to a more indolent cancer. Based on our preliminary studies and the gaps in diagnosis and treatment we hypothesize that the urothelium can be influenced by the state of epithelial differentiation and driven towards a more stable state if detected at early time point.

项目概要摘要 在此，一组协作绩效审查应用程序（CMA）旨在提高精度 膀胱癌（BCa）的治疗，特别关注尿路上皮的早期启动 响应吸烟和部署相关致癌物的动态上皮变化模型。 恶性肿瘤是退伍军人第二大常见死因，BCA 是第四大常见死因 退伍军人管理局最常见的癌症。在肿瘤类型中，70%的BCa局限于肿瘤浅表部分。 膀胱（T1、Ta 和 CIS 阶段），其余部分侵入肌肉或转移。如果 BCas 在早期发现，几乎所有这些肿瘤都可以通过手术组合来治疗 和腔内治疗。然而，目前还没有经过验证或推荐的筛查程序 识别无症状的 BCas，并且没有方法可以更早和更早地识别高危患者 更可治愈的阶段。拟议的 CMA 旨在解决这些限制并显着扰乱 通过剖析遗传和基因来预防、检测、风险分层和精准治疗 早期 BCa 的分子基础。这些项目包括以下内容： CMA1 旨在确定 CIS 的遗传和免疫抑制景观，以确定新的治疗方法和 免疫疗法。 CMA2 研究尿路上皮的可塑性以确定 PPARg 如何发挥作用 直接上皮分化作为 CIS 的可能调节剂。 CMA3将检查表观遗传基础 尿路上皮分化的作用以及 LSD1 抑制剂 Methysticin 作为化学预防剂的作用 恢复尿路上皮的表观遗传失衡。最后，CMA4将开发人工智能 用于增强膀胱镜检查成像技术或 BCa 检测和风险分层的算法。 这些 CMA 之间既存在内在联系，又与所有贡献者存在外在联系 由 VA R&D 提供支持，并颁发专注于 BCa 的优异奖，以最大限度地发挥协同作用并确保成功。 理由：超过 80% 的退伍军人有吸烟史，其中 90% 的退伍军人有吸烟史 BCA 自我报告的吸烟者。与肺癌、前列腺癌或结直肠癌不同，没有筛查方案 建议有 BCa 风险的退伍军人使用。没有关于制服的初级保健建议 评估尿液中的血液，并且没有尿液测试具有较高的阴性预测值，可以 替代膀胱镜检查。几乎所有 BCa 患者都会在某个时候出现尿中带血，但也有 由于缺乏评估，通常会延迟数月至数年进行评估，从而导致肿瘤进展 转诊至泌尿外科进行评估。一旦确诊，尿路上皮通常很难追踪 高达 20% 的侵袭性肿瘤将进展为更高阶段的癌症。早期侵入性治疗 膀胱癌依赖于 BCG 免疫治疗，但 BCG 经常无法获得，并且 未充分利用维护，30% 的 BCas 变得 BCG 无响应。因此，三大 提高 BCa 患者生存率的挑战是 1) 早期发现高风险肿瘤 2) 识别进展至较高阶段的癌症，以及 3) 对 BCG 免疫疗法的治疗耐药性。 我们的初步数据表明尿路上皮在 BCa 早期具有可塑性，如果在 遗传、表观遗传和分子水平上的癌症可以得到治疗并导致更惰性的癌症。 根据我们的初步研究以及诊断和治疗方面的差距，我们假设 尿路上皮可能会受到上皮分化状态的影响，并被驱动向更稳定的方向发展。 说明是否在早期时间点检测到。