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：
10377351
负责人：
John Robert Christin
金额：
$ 6.98万
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/10377351
关键词：
3-Dimensional ATAC-seq Adjuvant American Archives Biochemical Genetics 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 Transcription Human Human Characteristics Immunodeficient Mouse Immunotherapy In Vitro KDM1A gene Knock-out Lead Malignant Neoplasms Malignant neoplasm of urinary bladder Maps Molecular Monitor Morbidity - disease rate Mutation Neoadjuvant Therapy Organoids Pathway interactions Patients Pharmacology Phase I Clinical Trials Phenotype Pre-Clinical Model Property Radical Cystectomy Resources Risk Role Sampling Testing Transplantation Transurethral Resection Validation Work Xenograft procedure aggressive therapy anticancer research base biobank chemotherapy epigenetic regulation experience 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 pre-clinical 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.

项目摘要/摘要膀胱癌可分为两类：非肌肉浸润性膀胱癌（NMIBC）和肌肉浸润性膀胱癌（MIBC）。 NMIBC通过经尿道切除术，然后是静脉内免疫疗法或静脉内化学疗法，其具有10年特异性生存率 75％。相比之下，MIBC的护理标准是与佐剂或新辅助的根治性膀胱切除术化学疗法，疾病特异性生存率较低。但是，大约20％的高 NMIBC级将发展为MIBC，并且正在进行的研究无法确定分子这种NMIBC-MIBC过渡的机制。基于来自患者来源膀胱分析的最新数据肿瘤类器官，我们认为容易进步的NMIBC表观遗传与稳定的NMIBC不同并通过谱系可塑性机制过渡到MIBC。具体而言，建立的一部分器官从腔内NMIBC肿瘤在培养中经历表型转换到基础/鳞状表型， MIBC更典型。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的类器官（PDOS）在表观遗传上与表型稳定的PDO不同。此外，一个靶向表型构型塑料器官线中的表观遗传调节剂的化学筛选具有揭示了一个控制表型可塑性的关键途径。基于以下假设：表型可塑性和表观遗传调节剂促进了 NMIBC到MIBC，该提议的项目将追求两个具体的目的：（1）映射染色质的可及性和 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和（2）测试化学筛网中鉴定的表观遗传调节剂是否可以调节可塑性在膀胱癌中，确定这些调节剂是否是潜在的新型治疗靶标。合并这两个目标应改善高级NMIBC将发展为MIBC和新的预测用于治疗高级NMIBC的治疗剂。