Modeling bladder cancer pathogenesis and tumor evolution

膀胱癌发病机制和肿瘤进化建模

基本信息

批准号：
10475011
负责人：
Cory Abate-Shen
金额：
$ 168.46万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-11 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10475011
关键词：
ARID1A gene Abate Academic Medical Centers Achievement Affect Area Automobile Driving Basic Science Bioinformatics Biological Biological Process Biometry Bladder Bladder Tissue Cancer Model Cessation of life Cisplatin Clinical Clinical Research Clonal Evolution DNA Sequence Alteration Data Analyses Disease Disease Pathway Disease Progression Disease model Drug resistance Epigenetic Process Event Evolution Experimental Models Generations Genes Genetic Determinism Genetically Engineered Mouse Genomic Instability Genomics Health Heterogeneity Histologic Human Impairment Investigation Logistics Malignant Neoplasms Malignant neoplasm of urinary bladder Memorial Sloan-Kettering Cancer Center Metastatic to Methods Modeling Molecular Molecular Mechanisms of Action Mus Mutation New York City Oncogenes Organoids Pathogenesis Patients Pharmaceutical Preparations Records Reproducibility Research Research Personnel Resistance Role Technology Tissues Toxin United States Urothelium Xenograft Model anticancer research base biobank chemotherapy chromatin remodeling clinical investigation data hub data integration disease mechanisms study drug sensitivity epigenome experience genomic data genomic platform histone demethylase improved in vivo innovation insight member molecular pathology mouse model multidisciplinary muscle invasive bladder cancer novel novel therapeutic intervention patient derived xenograft model programs response single-cell RNA sequencing stem cell biology treatment response tumor tumor heterogeneity tumor progression

项目摘要

Project Summary/Abstract: This new Program Project will investigate the molecular mechanisms underlying the pathogenesis of bladder cancer. Our objectives are: (i) to study clonal evolution from non-muscle invasive to invasive to metastatic disease, and to elucidate molecular drivers for each stage of evolution; (ii) to study mechanisms of disease pathogenesis, with a major focus on the functional role of mutations that affect the epigenome; (iii) to elucidate mechanisms of disease response and resistance, with a major focus on understanding those that affect response to chemotherapy; and (iv) to generate novel human patient-derived and genetically-engineered mouse models (GEMMs) to study disease pathogenesis and to pursue co-clinical investigations. To achieve these objectives, we have assembled a highly accomplished multi-disciplinary team at Columbia University Medical Center (Cory Abate-Shen, Michael Shen, James McKiernan, Tian Zheng) and Memorial Sloan Kettering Cancer Center (David B. Solit, Hikmat Al-Ahmadie, Barry Taylor) with complementary expertise in genomic analyses (DBS, HA, BT), molecular investigations (CAS, MS, DBS), treatment response (CAS, MS, DBS, JM, BT), biostatistics and bioinformatics (TZ, BT), molecular pathology (HAA), generation of human and mouse cancer models (CAS, MS), co-clinical and clinical investigations (DBS, JM, CAS, JM, MS). We will pursue three interrelated Projects that are supported by three Cores. Project 1, led by David Solit, will seek to define the biologic functions of the histone demethylase, KDM6A, in bladder cancer pathogenesis, as well as the temporal occurrence of mutations in this gene during tumor progression. Project 2, led by Cory Abate-Shen, will analyze the functions of the chromatin remodeling gene, ARID1A, in muscle- invasive bladder cancer, focusing on its role in disease pathogenesis, its effect on treatment response and its molecular mechanisms of action. Project 3, led by Michael Shen, will investigate tumor evolution and drug response in human patient-derived bladder cancer organoids, focusing on genetic determinants of genomic instability, alterations of the epigenome, and the role of heterogeneity in drug sensitivity and resistance. The Molecular Pathology Core (Core A), led by Hikmat Al-Ahmadie, will maintain a biorepository of urothelial cancer tumors, including the tissues used for organoid generation, and will provide histopathological analyses for all three projects. The Bladder Cancer Models Core (Core B), led by Michael Shen will serve as a central hub for the generation and analysis of cancer models for all three projects, including human patient-derived organoid and xenograft models, and GEMMs. The Administrative Core (Core C), led by Cory Abate-Shen, will provide support for bioinformatic and biostatistical analyses and organizational support for Program Project investigators, and will coordinate with the Internal and External Advisory Boards. In summary, this Program Project is led by a highly collaborative team of investigators with diverse but complementary expertise who have substantial track records in cancer research, and are located in close proximity in New York City.

项目摘要/摘要：这个新程序项目将研究发病机理的分子机制膀胱癌。我们的目标是：（i）研究从非肌肉的侵入性到侵入性的克隆进化转移性疾病，并为每个进化阶段阐明分子驱动因素；（ii）研究机制疾病的发病机理，主要关注影响表观基因组突变的功能作用；（iii）至阐明疾病反应和抵抗的机制，重点是理解那些影响对化疗的反应；（iv）生成新型的人类患者衍生和遗传工程小鼠模型（GEMM）研究疾病发病机理并进行共同研究。实现这些目标，我们在哥伦比亚大学组建了一支高度成就的多学科团队医疗中心（Cory Abate-Shen，Michael Shen，James McKiernan，Tian Zheng）和Sloan纪念馆 Kettering Cancer Center（David B. Solit，Hikmat al-Ahmadie，Barry Taylor）具有补充专业知识基因组分析（DBS，HA，BT），分子研究（CAS，MS，DBS），治疗反应（CAS，MS，MS， DBS，JM，BT），生物统计学和生物信息学（TZ，BT），分子病理学（HAA），人类和人类的产生小鼠癌模型（CAS，MS），共同链接和临床研究（DBS，JM，CAS，JM，MS）。我们将追求三个相互关联的项目，这些项目得到了三个核心的支持。大卫领导的项目1 孤子将寻求定义组蛋白脱甲基酶KDM6A的生物学功能，在膀胱癌中发病机理以及该基因进展过程中突变的时间出现。项目 2由Cory Abate-Shen领导，将分析染色质重塑基因ARID1A的功能，在肌肉中侵入性膀胱癌，重点是其在疾病发病机理中的作用，对治疗反应的影响及其分子作用机理。由迈克尔·沉（Michael Shen）领导的项目3将研究肿瘤的演变和药物人类患者衍生的膀胱癌器官的反应，重点是基因组的遗传决定因素不稳定性，表观基因组的改变以及异质性在药物敏感性和抗性中的作用。这由Hikmat al-Ahmadie领导的分子病理学核心（核心A）将保持尿路上皮的生物位置癌症肿瘤，包括用于产生器官的组织，并将提供组织病理学分析对于所有三个项目。由迈克尔·沉（Michael Shen）领导的膀胱癌模型核心（Core B）将充当中央用于生成和分析所有三个项目的癌症模型的枢纽，包括人类患者衍生的器官和异种移植模型，以及宝石。由Cory Abate-Shen领导的行政核心（Core C）将为生物信息学和生物统计学分析和组织项目提供支持调查人员，并将与内部和外部咨询委员会协调。总之，这个程序项目由一个高度合作的调查员团队领导，具有多样化但互补的专业知识在癌症研究中拥有大量的记录，并且位于纽约市附近。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Urothelial Carcinoma: Divergent Differentiation and Morphologic Subtypes.

DOI：
10.1016/j.path.2022.07.003
发表时间：
2022-12
期刊：
Surgical pathology clinics
影响因子：
0
作者：
Gandhi, Jatin;Chen, Jie-Fu;Al-Ahmadie, Hikmat
通讯作者：
Al-Ahmadie, Hikmat

Clinical and Genomic Landscape of FGFR3-Altered Urothelial Carcinoma and Treatment Outcomes with Erdafitinib: A Real-World Experience.

FGFR3 改变的尿路上皮癌的临床和基因组景观以及 Erdafitinib 的治疗结果：真实世界的经验。

DOI：
10.1158/1078-0432.ccr-23-1283
发表时间：
2023
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Guercio,BrendanJ;Sarfaty,Michal;Teo,MinYuen;Ratna,Neha;Duzgol,Cihan;Funt,SamuelA;Lee,Chung-Han;Aggen,DavidH;Regazzi,AshleyM;Chen,Ziyu;Lattanzi,Michael;Al-Ahmadie,HikmatA;Brannon,ARose;Shah,Ronak;Chu,Carissa;Lenis,Andr
通讯作者：
Lenis,Andr

Molecular Pathology of Urothelial Carcinoma.

DOI：
10.1016/j.path.2021.05.005
发表时间：
2021-09
期刊：
Surgical pathology clinics
影响因子：
0
作者：
Al-Ahmadie, Hikmat;Netto, George J
通讯作者：
Netto, George J

CD274 (PD-L1) Copy Number Changes (Gain) & Response to Immune Checkpoint Blockade Therapy in Carcinomas of the Urinary Tract.

DOI：
10.3233/blc-201532
发表时间：
2021
期刊：
Bladder cancer (Amsterdam, Netherlands)
影响因子：
0
作者：
Gupta S;Vanderbilt CM;Zhang Y;Tickoo SK;Fine SW;Gopalan A;Chen YB;Sirintrapun SJ;Teo MY;Funt SA;Iyer G;Rosenberg JE;Bajorin DF;Bochner BH;Pietzak EJ;Ross DS;Ladanyi M;Cheville JC;Solit DB;Reuter VE;Al-Ahmadie HA
通讯作者：
Al-Ahmadie HA

A Phase I Trial of Intravesical Cabazitaxel, Gemcitabine and Cisplatin for the Treatment of Nonmuscle Invasive bacillus Calmette-Guérin Unresponsive or Recurrent/Relapsing Urothelial Carcinoma of the Bladder.

DOI：
10.1097/ju.0000000000000919
发表时间：
2020-08
期刊：
The Journal of urology
影响因子：
0
作者：
DeCastro GJ;Sui W;Pak JS;Lee SM;Holder D;Kates MM;Virk RK;Drake CG;Anderson CB;James B;Abate-Shen CT;McKiernan JM
通讯作者：
McKiernan JM