Epigenetic Regulation of Immune Evasion in Bladder Cancer

膀胱癌免疫逃避的表观遗传调控

基本信息

批准号：
10620119
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
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-10-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10620119
关键词：
Accounting Aftercare Antigen Presentation Award Bladder Bladder Neoplasm Blocking Antibodies CD3 Antigens CD8B1 gene Cancer Etiology Cancer Model Cancer Therapy Evaluation Program Carcinogens Carcinoma Cause of Death Cells Chromatin Chromatin Remodeling Factor Clinical Clinical Trials Clinical Trials Network Complex Data Detection Early Therapeutic-Clinical Trials Network Enhancers Enzymes Epigenetic Process Equilibrium Eragrostis Exposure to Frequencies Funding Genes Genetic Transcription Genomics Goals Histones Human Immune Immune Evasion Immune response Immune system Immunotherapy Impairment In Vitro Infiltration Interdisciplinary Study Investigation Investigational Therapies Link Lymphocyte Malignant Neoplasms Malignant neoplasm of urinary bladder Mediating Molecular Mus Mutation Nature Organoids Outcome PD-1 inhibitors Pathologic Pathway interactions Patients Phase I/II Clinical Trial Phase I/II Trial Polycomb Precision therapeutics Production Property Recurrence Regulation Regulatory T-Lymphocyte Repression Repressor Proteins Research Resistance Risk Reduction Role Site Smoking Solid Neoplasm Somatic Mutation T-Cell Activation T-Lymphocyte Trans-Activators Transcriptional Regulation Transitional Cell Carcinoma Translating Urothelium Veterans Work anti-PD1 therapy anti-tumor immune response bench-to-bedside translation cancer cell cancer survival checkpoint therapy chemokine chemotherapy epigenetic regulation epigenetic therapy histone demethylase immune activation immune cell infiltrate immune checkpoint improved inhibitor innovation loss of function mutation lymph nodes men mouse model novel therapeutic intervention novel therapeutics pembrolizumab recruit refractory cancer response stem-like cell therapy resistant treatment strategy tumor tumor microenvironment

项目摘要

Bladder cancer is the fourth most common cancer in men and a significant burden for Veterans and the VHA due to the high frequency of recurrence and progression linked to smoking and exposure to deployment-related carcinogens. Less than 45% of patients with Stage IV bladder cancer survive more than a year in the VA suggesting the aggressive nature of metastatic urothelial tumors identified among Veterans. The primary cause of death from bladder cancer is resistance to therapy as these invasive carcinomas acquire cellular plasticity and stem cell-like properties from long-term changes in epigenetic regulators. In our first VA Merit Award, we first genomically validated a carcinogen-induced bladder cancer model that replicated smoking induced bladder cancer and shared the somatic alterations found in locally advanced bladder cancers. To re-establish an epigenetic balance, we then identified a significant decrease in carcinogen-induced bladder cancers in mice treated with an enzymatic EZH2-inhibitor. While bladder tumors decreased in size after treatment, we found a significant increase in the CD3+ T cell immune infiltrate associated with tumor regression. These results were rapidly translated into an NCI-sponsored clinical trial for patients with metastatic bladder cancer (ETCTN#10183). In this Phase I/II clinical trial, we are currently treating patients with an EZH2-inhibitor (tazemetostat) and a PD1 inhibitor (pembrolizumab). The PI of this application is the co-PI of the trial and despite clinical response there remains much to be investigated about the immunotherapy in bladder cancer and how a histone modifying complex (polycomb repressor complex 2, and EZH2) is involved in immune evasion. The long-term goal of our research is to investigate the molecular and epigenetic pathways associated with immune evasion of bladder cancer. By understanding these mechanisms, we may develop rational and novel therapeutics for Veterans with bladder cancer that combine precision targets and immunotherapy. Given this preliminary data, our central hypothesis is that EZH2 drives immune evasion by three distinct mechanisms that will be focus of this VA Merit proposal. In Aim 1 we will determine how EZH2 regulates antigen presentation by MHCI and MHCII to evade immune detection. In Aim 2, we evaluate how inhibition of EZH2 leads to recruitment of T cells to tumor microenvironment and in Aim 3 will focus on the action of EZH2 in Tregulatory cells that suppress an immune response. Through a multi-disciplinary collaboration we have demonstrated feasibility with our approach with rapid translation from bench to bedside. Successful completion of the studies described in this proposal will provide an innovative approach to both investigate the mechanisms involved in the evasion of the immune system of bladder cancer and potentially identify a novel therapeutic approach to treat bladder cancer.

膀胱癌是男性第四大癌症，对退伍军人和VHA负担很大由于与吸烟相关的复发和进展的频率很高，并与部署有关致癌物。 IV期膀胱癌患者中只有不到45％的人在VA中生存了一年以上表明在退伍军人中确定的转移性尿路上皮肿瘤的侵略性。主要原因膀胱癌死亡是对治疗的抗药性，因为这些侵入性癌获得了细胞可塑性和从表观遗传调节剂长期变化的干细胞样性质。在我们的第一个VA功绩奖中，我们首先基因组验证了致癌诱导的膀胱癌模型，该模型复制了吸烟引起的膀胱癌症并分享了局部晚期膀胱癌中发现的体细胞改变。重新建立表观遗传平衡，我们随后确定了致癌物诱导的小鼠膀胱癌的显着降低用酶EZH2抑制剂处理。虽然治疗后膀胱肿瘤的大小减少，但我们发现与肿瘤消退相关的CD3+ T细胞免疫浸润的显着增加。这些结果是迅速转化为用于转移性膀胱癌患者的NCI赞助的临床试验（ETCTN＃10183）。在此I/II临床试验中，我们目前正在治疗EZH2抑制剂（TazeMetostat）和PD1患者抑制剂（pembrolizumab）。该应用程序的PI是试验的co-Pi，尽管那里有临床反应关于膀胱癌的免疫疗法以及组蛋白如何修饰仍然有很多研究复合物（Polycomb抑制剂复合物2和EZH2）参与免疫逃避。我们的长期目标研究是研究与膀胱免疫逃避相关的分子和表观遗传途径癌症。通过了解这些机制，我们可能会为退伍军人开发出理性和新颖的治疗学结合精度靶标和免疫疗法的膀胱癌。鉴于此初步数据，我们的中央假设是EZH2通过三种不同的机制来驱动免疫逃避，这将是该VA优点的重点提议。在AIM 1中，我们将确定EZH2如何调节MHCI和MHCII的抗原表现免疫检测。在AIM 2中，我们评估了EZH2的抑制如何导致T细胞募集到肿瘤微环境和在AIM 3中将集中于EZH2在抑制免疫的Tregulation细胞中的作用回复。通过多学科合作，我们通过我们的方法证明了可行性从长凳到床边的快速翻译。成功完成本提案中描述的研究将提供一种创新的方法来研究逃避免疫的机制膀胱癌系统，并有可能识别一种治疗膀胱癌的新型治疗方法。

项目成果

期刊论文数量（33）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Editorial Comment.

编辑评论。

DOI：
10.1097/ju.0000000000001640.01
发表时间：
2021
期刊：
The Journal of urology
影响因子：
0
作者：
Bauer,ScottR;Huang,Alison
通讯作者：
Huang,Alison

Limited Upstaging in Luminal Subtype Tumors: Ready for Clinical Practice?

管腔亚型肿瘤的有限升级：准备好临床实践了吗？

DOI：
10.1016/j.eururo.2019.05.025
发表时间：
2019
期刊：
European urology
影响因子：
23.4
作者：
Meeks,JoshuaJ;McConkey,DavidJ
通讯作者：
McConkey,DavidJ

Expression-based subtypes define pathologic response to neoadjuvant immune-checkpoint inhibitors in muscle-invasive bladder cancer.

DOI：
10.1038/s41467-023-37568-9
发表时间：
2023-04-27
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Robertson, A. Gordon;Meghani, Khyati;Cooley, Lauren Folgosa;McLaughlin, Kimberly A.;Fall, Leigh Ann;Yu, Yanni;Castro, Mauro A. A.;Groeneveld, Clarice S.;de Reynies, Aurelien;Nazarov, Vadim I.;Tsvetkov, Vasily O.;Choy, Bonnie;Raggi, Daniele;Marandino, Laura;Montorsi, Francesco;Powles, Thomas;Necchi, Andrea;Meeks, Joshua J.
通讯作者：
Meeks, Joshua J.

High-Risk of Adverse Pathologic Features in Patients With Clinical T1 High-Grade Bladder Cancer Undergoing Radical Cystectomy.

接受根治性膀胱切除术的临床 T1 高级别膀胱癌患者出现不良病理特征的高风险。