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: 10647629
• 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/10647629
• 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; 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; Epithelium; 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; Invaded; Invasive Lesion; KDM1A gene; Kava; Knowledge; 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; Play; Precision therapeutics; Predictive Value; Prevention; Prevention trial; Primary 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 driven; biomarker identification; biomarker signature; bladder cancer prevention; bladder carcinoma in situ; cancer cell; cancer initiation; cancer risk; cancer stem cell; cancer subtypes; carcinogenesis; comparison control; 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 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.

项目总结摘要 在这里，一组协作的功绩审查应用程序(CMA)旨在提高精确度 膀胱癌(BCA)的治疗，尤其是早期尿路上皮AS的起始 吸烟和部署相关致癌物响应的动态上皮变化模型。 恶性肿瘤是退伍军人的第二大常见死因，BCA是第四大死因 退伍军人事务部最常见的癌症。在肿瘤类型中，70%的BCA局限于 膀胱(T1期、Ta期和CIS期)，其余部分为肌肉浸润性或转移性。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的组合来治疗 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，目前还没有方法在早期和早期识别高危患者 更能治愈的阶段。拟议的CMA旨在解决这些限制，并显著扰乱 通过解剖遗传和疾病来预防、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：CMA1旨在确定 独联体的遗传和免疫抑制前景，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PPAR如何 直接上皮分化可能是CIS的调节因子。CMA3将研究表观遗传学基础 尿路上皮细胞分化的机制以及LSD1抑制剂甲硫氨酸作为化学预防药物的作用 恢复尿路上皮的表观遗传失衡。最后，CMA4将发展人工智能 增强的膀胱镜成像技术或BCA检测和风险分层的算法。 这些CMA彼此之间存在内在联系，也与所有贡献者存在外在联系 在退伍军人事务部研发的支持下，优秀奖专注于BCA，以最大限度地发挥协同效应，确保成功。 理由：超过80%的退伍军人报告有烟草吸烟史，90%的退伍军人患有 BCA自我报告的吸烟者。与肺癌、前列腺癌或结直肠癌不同的是，没有筛查方案 推荐给有BCA风险的退伍军人。没有关于制服的初级保健建议 评估尿液中的血液，并且没有尿检有很高的阴性预测值，可以 更换膀胱镜检查。几乎所有的BCA患者都会在某个时间出现尿血，但有 通常延迟数月至数年进行评估，导致肿瘤进展，原因是缺乏 转诊至泌尿外科进行评估。一旦确诊，尿路上皮通常很难跟进。 而高达20%的浸润性肿瘤将进展为更高阶段的癌症。早期侵袭性疾病的治疗 膀胱癌依赖于卡介苗免疫疗法，但卡介苗经常无法获得， 维护未得到充分利用，30%的BCG对BCG反应迟钝。因此，三大 提高BCA患者存活率的挑战是：1)早期发现高危肿瘤2) 确定进展为更高阶段的癌症和3)对卡介苗免疫疗法的治疗抵抗。 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 在遗传、表观遗传和分子水平上，可能会被治疗并导致更难治的癌症。 根据我们的初步研究以及在诊断和治疗方面的差距，我们假设 尿路上皮细胞可以受到上皮分化状态的影响，并驱动其向更稳定的方向发展 状态(如果在早期时间点检测到)。

项目成果

The Potent Anti-Tumor Effects of Rhodiola Drinking Are Associated with the Inhibition of the mTOR Pathway and Modification of Tumor Metabolism in the UPII-Mutant Ha-Ras Model.

• DOI: 10.3390/cancers15123086
• 发表时间: 2023-06-07
• 期刊: Cancers
• 影响因子: 5.2

Chemoprevention of Urothelial Cell Carcinoma Tumorigenesis by Dietary Flavokawain A in UPII-Mutant Ha-ras Transgenic Mice.

• DOI: 10.3390/pharmaceutics14030496
• 发表时间: 2022-02-24
• 期刊: Pharmaceutics
• 影响因子: 5.4
• 作者: Liu Z;Song L;Xie J;Simoneau AR;Uchio E;Zi X
• 通讯作者: Zi X

Dysfunction of the aging female mouse urethra is associated with striated muscle loss and increased fibrosis: an initial report.

衰老雌性小鼠尿道功能障碍与横纹肌丧失和纤维化增加有关：初步报告。

• 发表时间: 2023
• 期刊: American journal of clinical and experimental urology
• 影响因子: 1.2
• 作者: Sadeghi,Zhina;Wu,YiXi;Vu,Amberly;Song,Liankun;Phan,William;Kim,Jeffery;Keast,JanetR;Balis,Ulysses;DeLancey,John;Villalta,SArmando;Zi,Xiaolin
• 通讯作者: Zi,Xiaolin

Kava root extracts hinder prostate cancer development and tumorigenesis by involvement of dual inhibition of MAO-A and LSD1.

• DOI: 10.20517/jtgg.2021.22
• 发表时间: 2021
• 期刊: Journal of translational genetics and genomics
• 作者: Li X;Song L;Xu S;Tippin M;Meng S;Xie J;Uchio E;Zi X
• 通讯作者: Zi X