CMA-Basic and Translational Mechanisms of Cancer Initiation of the Urothelium in Veterans Exposed to Carcinogens: Interception of tobacco smoking-related bladder cancer by an epigenetic approach

CMA-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：通过表观遗传学方法拦截与吸烟相关的膀胱癌

• 批准号: 10260302
• 负责人: Xiaolin Zi
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10260302
• 关键词: 4-biphenylamine; Address; Antitumor Response; Artificial Intelligence; Award; Bacillus Calmette-Guerin Therapy; Binding; Biological Warfare; Bladder; Blood; Cancer Biology; Cancer Burden; Cancer Detection; Cancer Patient; Carcinogens; Carcinoma in Situ; Cause of Death; Cell Lineage; Cells; Chemicals; Chemopreventive Agent; Colorectal Cancer; Control Groups; Cystoscopy; Cytokeratin-8 Staining Method; Data; Detection; Development; Diagnosis; Disease; E2F transcription factors; EZH2 gene; Early Diagnosis; Early treatment; Eligibility Determination; Ensure; Epigenetic Process; Epithelial; Evaluation; Exposure to; Foundations; Future; GATA3 gene; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Genomics; Goals; Growth; Hazardous Chemicals; Histones; Human; Imaging technology; Immune; Immunotherapy; Indolent; Intercept; KDM1A gene; Kava; Knowledge; Lead; Legal patent; Lesion; Link; Lysine; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Malignant neoplasm of urinary bladder; Mediating; Medical center; Methods; Methylation; Mixed-Lineage Leukemia; Modeling; Molecular; Molecular Profiling; Mus; Muscle; Mutate; Neoplasm Metastasis; Nitrosamines; Normal Cell; Occupational Exposure; Operative Surgical Procedures; Organoids; PPAR gamma; Pathway interactions; Patient Self-Report; Patients; Peroxisome Proliferator-Activated Receptors; Play; Precision therapeutics; Predictive Value; Prevention; Prevention trial; Primary Health Care; Reagent; Recommendation; Recording of previous events; Recurrence; Reporting; Resources; Risk; Role; Scientist; Screening procedure; Second Primary Neoplasms; Smoker; Smoking; TP53 gene; Testing; Therapeutic; Time; Tobacco; Tobacco smoke; Tobacco smoking behavior; Tobacco-Associated Carcinogen; Transcriptional Regulation; Treatment Efficacy; Tumor Suppressor Proteins; Urine; Urologic Surgical Procedures; Urothelium; Veterans; Xenograft procedure; artificial intelligence algorithm; base; biomarker signature; biomarker-driven; bladder cancer prevention; bladder carcinoma in situ; cancer cell; cancer initiation; cancer risk; cancer stem cell; cancer subtypes; carcinogenesis; differential expression; effective therapy; epigenetic therapy; exome sequencing; high risk; image guided; imaging biomarker; improved; in vivo; inhibitor; methyl group; molecular marker; molecular subtypes; muscle invasive bladder cancer; new therapeutic target; non-smoker; novel; novel diagnostics; novel strategies; novel therapeutics; overexpression; patient derived xenograft model; patient response; personalized management; predicting response; predictive marker; predictive signature; prevent; research and development; response; risk stratification; screening guidelines; success; synergism; therapy resistant; tobacco exposure; transcriptome sequencing; treatment response; treatment trial; tumor; tumor progression; tumorigenic; 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 PPAR 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.

项目摘要 在此，一组协作的价值审查应用程序（CMA）旨在提高精度 膀胱癌（BCa）的管理，特别是关注尿路上皮癌的早期启动 一种对吸烟和部署相关致癌物作出反应的动态上皮变化模型。 癌症是退伍军人中第二大常见的死亡原因，BCa是第四大 最常见的癌症。在肿瘤类型中，70%的BCa局限于浅表部分， 膀胱（T1、Ta和CIS期），其余为肌肉浸润或转移。如果BCas 在早期阶段被发现，几乎所有这些肿瘤都可以通过手术联合治疗， 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，没有方法在早期识别高危患者， 更容易治愈的阶段。拟议的CMA旨在解决这些限制，并显著破坏 BCa的预防、检测、风险分层和精确治疗， 早期BCa的分子基础。这些项目包括：CMA 1旨在确定 CIS的遗传和免疫抑制景观，以确定新的治疗方法， 免疫疗法CMA 2研究了尿道的可塑性，以确定PPAR γ如何能够 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 以及LSD 1抑制剂Methysticin作为一种化学预防剂， 恢复泌尿系统的表观遗传失衡最后，CMA4将开发人工智能 用于增强膀胱镜成像技术或BCa检测和风险分层的算法。 这些CMA之间既有内在的联系，又与所有贡献者有外在的联系。 在VA研发的支持下，重点关注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%的退伍军人报告有吸烟史，90%的退伍军人 BCA自我报告的吸烟者。与肺癌、前列腺癌或结直肠癌不同， 推荐给有BCa风险的退伍军人。没有初级保健建议的统一 尿液中的血液评估，并且没有尿液测试具有很高的阴性预测值，可以 取代膀胱镜检查。几乎所有BCa患者都会在某个时候出现尿液带血，但也有 通常延迟数月至数年进行评估，由于缺乏足够的药物， 转诊至泌尿外科进行评估。一旦确诊，尿路感染往往是具有挑战性的后续 并且高达20%的侵袭性肿瘤会发展为更高阶段的癌症。早期侵入性的治疗 膀胱癌依赖于BCG免疫疗法，但BCG经常不可用， 未充分用于维护，30%的BCAs变得BCG无反应。因此，三大 提高BCa患者生存率的挑战是1）早期发现高危肿瘤2） 鉴定向更高阶段癌症的进展和3）对BCG免疫疗法的治疗抗性。 我们的初步数据表明，在早期BCa阶段，尿托具有可塑性， 在遗传、表观遗传和分子水平上，可以被治疗并驱动为更惰性的癌症。 根据我们的初步研究和诊断和治疗的差距，我们假设， 尿路上皮可受上皮分化状态的影响， 如果在早期时间点检测到，则说明。