Epigenetic regulators of subtype plasticity in bladder cancer

膀胱癌亚型可塑性的表观遗传调节因子

基本信息

批准号：
10579267
负责人：
John Robert Christin
金额：
$ 7.38万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10579267
关键词：
3-Dimensional ATAC-seq Ablation Adjuvant Adjuvant Chemotherapy American Biochemical Biological Models Biopsy Bladder Bladder Neoplasm Cancer Patient Categories Chemicals Chromatin Clustered Regularly Interspaced Short Palindromic Repeats DNA Sequence Alteration Data Analyses Development Disease Early identification Enzymes Epigenetic Process Etiology Excision Fresh Tissue Gene Silencing Genetic Human Human Characteristics Immunodeficient Mouse Immunotherapy In Vitro KDM1A gene Knock-out Malignant Neoplasms Malignant neoplasm of urinary bladder Maps Molecular Monitor Morbidity - disease rate Mutation Neoadjuvant Therapy Organoids Pathway interactions Patients Phase I Clinical Trials Phenotype Pre-Clinical Model Property Radical Cystectomy Resources Role Sampling Testing Transplantation Transurethral Resection Validation Work Xenograft procedure aggressive therapy anticancer research biobank chemotherapy epigenetic regulation experience gene repression high risk histone demethylase histone modification immune checkpoint blockade improved in vivo in vivo imaging inhibitor innovation intravesical male mortality muscle invasive bladder cancer new therapeutic target non-muscle invasive bladder cancer novel novel therapeutics patient derived xenograft model patient stratification pharmacologic pre-clinical progression risk risk stratification small hairpin RNA standard of care therapeutic target transcription factor translational impact tumor tumor progression

项目摘要

Project Summary/Abstract Bladder cancer can be subdivided into two categories: non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC). NMIBC is treated by transurethral resection followed by either intravesical immunotherapy or intravesical chemotherapy, which have a 10-year disease-specific survival of 75%. In contrast, standard of care for MIBC is radical cystectomy with either adjuvant or neoadjuvant chemotherapy, with much lower disease-specific survival. However, approximately 20% of patients with high- grade NMIBC will progress to MIBC, and ongoing studies have been unable to determine the molecular mechanisms of this NMIBC-MIBC transition. Based on recent data from analyses of patient-derived bladder tumor organoids, we propose that NMIBC that is prone to progress is epigenetically distinct from stable NMIBC and transitions to MIBC through a mechanism of lineage plasticity. Specifically, a subset of organoids established from luminal NMIBC tumors undergo a phenotypic switch in culture to a basal/squamous phenotype, which is more typical of MIBC. Preliminary studies analyzing chromatin accessibility indicate that these phenotypically plastic patient derived organoids (PDOs) are epigenetically distinct from phenotypically stable PDOs. Furthermore, a chemical screen targeting epigenetic regulators in the phenotypically plastic organoid lines has revealed a key pathway governing phenotypic plasticity. Based on the hypothesis that phenotypic plasticity and epigenetic regulators promote the transition of NMIBC to MIBC, this proposed project will pursue two specific aims: (1) Map the chromatin accessibility and the histone modification landscape of phenotypic plasticity in NMIBC and validate these findings in human patient samples, and (2) Test whether the epigenetic regulators identified in a chemical screen can modulate plasticity in bladder cancer and determine whether these regulators are potential novel therapeutic targets. Combined, these two aims should lead to improved prediction of which high-grade NMIBCs will progress to MIBC and new therapeutics for treatment of high-grade NMIBC.

项目概要/摘要膀胱癌可分为两类：非肌层浸润性膀胱癌（NMIBC）和肌层浸润性膀胱癌（MIBC）。 NMIBC 的治疗方法是经尿道切除术，然后进行膀胱内免疫治疗或膀胱内化疗，其疾病特异性生存期为 10 年 75%。相比之下，MIBC 的护理标准是根治性膀胱切除术加辅助或新辅助治疗化疗，疾病特异性生存率要低得多。然而，大约 20% 的患者患有高 NMIBC 将进展为 MIBC，正在进行的研究无法确定分子水平 NMIBC-MIBC 转变的机制。基于患者来源膀胱分析的最新数据肿瘤类器官，我们认为易于进展的 NMIBC 在表观遗传学上与稳定的 NMIBC 不同并通过谱系可塑性机制转变为 MIBC。具体来说，建立了类器官的子集从管腔 NMIBC 肿瘤在培养中经历表型转变为基底/鳞状表型，即更典型的是 MIBC。分析染色质可及性的初步研究表明，这些表型塑料患者衍生类器官 (PDO) 在表观遗传学上与表型稳定的 PDO 不同。此外，针对表型可塑类器官系中的表观遗传调节剂的化学筛选已经揭示了控制表型可塑性的关键途径。基于表型可塑性和表观遗传调节因子促进表型可塑性转变的假设从 NMIBC 到 MIBC，该拟议项目将追求两个具体目标：（1）绘制染色质可及性图谱和 NMIBC 中表型可塑性的组蛋白修饰景观并在人类患者中验证这些发现样品，以及（2）测试化学筛选中鉴定的表观遗传调节剂是否可以调节可塑性膀胱癌并确定这些调节因子是否是潜在的新治疗靶点。综合起来，这两个目标应该能够改进对哪些高级 NMIBC 将发展为 MIBC 以及新的 NMIBC 的预测。用于治疗高级别 NMIBC 的疗法。