Therapeutic implication of RB1 loss in bladder cancer

RB1 缺失对膀胱癌的治疗意义

基本信息

批准号：
10580816
负责人：
Qiang Li
金额：
$ 28.57万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
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：
2021-03-05 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10580816
关键词：
Acceleration Adenoviruses Adjuvant Chemotherapy Basal Cell Bioinformatics Biological Bladder Bladder Neoplasm Bladder Urothelium Cancer Biology Cancer Model Cancer Patient Cell Cycle Regulation Cells Characteristics Cisplatin Clinical Clinical Research Clinical Trials Clonal Evolution Comprehensive Cancer Center DNA Repair Data Development Disease Doxycycline Drug resistance Engineering Experimental Models Foundations Future Genes Genetically Engineered Mouse Genomics Goals Histologic Histology Human Incidence Intravesical Administration Keratin Knock-out Knockout Mice Knowledge Link Lung Malignant Neoplasms Malignant neoplasm of urinary bladder Mentors Modeling Molecular Molecular Probes Mus Muscle Cells Mutation Neoadjuvant Therapy Neoplasm Metastasis Nucleotide Excision Repair Oncology Operative Surgical Procedures Organoids PI3K/AKT PTEN gene Papillary Neoplasm Pathogenesis Pathologic Pathway interactions Patients Phase Phenotype Physicians Pre-Clinical Model Program Development Prostate RB1 gene Research Research Project Grants Resistance Role Scientist Signal Pathway Signal Transduction System TP53 gene Techniques Testing Tetracyclines Therapeutic Training Trans-Activators Transgenic Mice Tumor Promotion Tumor Suppressor Genes Tumor-Derived UPK2 gene Urology Urothelium Vision Work acquired drug resistance analysis pipeline anticancer research cancer cell cancer subtypes cancer type career career development chemotherapy clinically relevant driver mutation experience experimental analysis experimental study gene repair genetic manipulation human old age (65+)in vivo keratin 5 molecular subtypes mouse model muscle invasive bladder cancer mutational status novel novel therapeutic intervention potential biomarker pre-clinical professor programs promoter response standard care therapy resistant tool translational cancer research treatment response tumor tumor heterogeneity tumor initiation tumor progression tumorigenesis

项目摘要

Abstract This proposal describes a 5-year research career development program focused on a non-canonical role of RB1 loss in bladder cancer. Dr. Qiang Li is an Assistant Professor of Oncology at Roswell Park Comprehensive Cancer Center in the Department of Urology. The proposal builds on the candidate’s previous experience and current research projects using genetically engineered mouse models (GEMMs) and organoids. The proposed experiments and training will enable his transition to independence as a physician scientist in bladder cancer translational research. He will be mentored primarily by Dr. David Goodrich. Dr. Goodrich is an expert in RB1 cancer biology, genetically engineered mouse models, acquired drug resistance and cancer cell plasticity. The training plan includes the following goals: (1) Enhance expertise in preclinical cancer modeling (GEMM and organoids); (2) Probe the molecular mechanisms of bladder cancer cellular plasticity and drug resistance; and (3) Gain expertise in bioinformatic analysis. RB1 mutations are predictive of pathologic response after neoadjuvant chemotherapy in bladder cancer. Other clinical observations suggest that the basal type of bladder cancer is more likely to respond to chemotherapy than the luminal type. However, the biological impact of RB1 loss on molecular subtypes of bladder cancer pathogenesis and chemotherapy response has not been investigated. Newly discovered features of the RB1 pathway in other cancer types suggest that RB1 loss promotes lineage plasticity and acquired therapy resistance. Thus, we hypothesize that RB1 loss promotes bladder cancer progression, metastasis, and cellular plasticity (luminal to basal, and therapeutic resistance). We use two transgenic mouse systems (Uroplakin II driven reverse tetracycline trans-activator, TRE-Cre) to investigate the role of RB1 loss in bladder urothelium by facilitating deletion of tumor suppressor genes (Trp53, Pten, Rb1) under control of doxycycline administration. We engineered doxycycline inducible triple knockout mice Trp53-/-: Pten-/-: Rb1-/- (referred as TKO) and double knockout mice Trp53-/-: Pten-/- (referred as DKO). We propose the following Specific Aims: (1) Define the function of RB1 loss in accelerating tumor progression, metastasis, and cellular plasticity in bladder cancer GEMMs; (2) Dissect the impact of cell-of-origin on bladder tumorigenesis, metastasis and response to chemotherapy in TKO tumors derived from basal cells versus luminal cells. Successful completion of this proposal will allow the candidate to gain valuable technical knowledge and expertise in preclinical modeling of advanced bladder cancer and further his development as an independent physician scientist. The work will also establish experimental models and analysis pipelines that will provide the foundation for the candidate’s independent research program.

抽象的该提案描述了一个为期 5 年的研究职业发展计划，重点关注 RB1 的非规范角色李强博士是罗斯威尔公园综合医院肿瘤学助理教授。该提案建立在候选人之前的经验和基础上。目前的研究项目使用基因工程小鼠模型（GEMM）和类器官。实验和培训将使他能够独立地成为一名膀胱癌医师科学家他将主要由 David Goodrich 博士指导。Goodrich 博士是 RB1 领域的专家。癌症生物学、基因工程小鼠模型、获得性耐药性和癌细胞可塑性。培训计划包括以下目标：（1）增强临床前癌症模型（GEMM和 (2) 探讨膀胱癌细胞可塑性和耐药性的分子机制； (3) 获得生物信息分析方面的专业知识。 RB1 突变可预测膀胱癌新辅助化疗后的病理反应。临床观察表明，基底型膀胱癌更可能对化疗产生反应然而，RB1 缺失对膀胱癌分子亚型的生物学影响。 RB1 的发病机制和化疗反应尚未得到研究。其他癌症类型中的通路表明 RB1 丢失促进谱系可塑性和获得性治疗因此，我们发现 RB1 缺失会促进膀胱癌的进展、转移和细胞增殖。可塑性（管腔到基础、治疗抗性）我们使用两种转基因小鼠系统（Uroplakin II）。驱动反向四环素反式激活剂（TRE-Cre）通过以下方法研究 RB1 丢失在膀胱尿道上皮中的作用：在多西环素给药的控制下促进肿瘤抑制基因（Trp53、Pten、Rb1）的删除。我们设计了强力霉素诱导的三重敲除小鼠Trp53-/-: Pten-/-: Rb1-/-（简称TKO）和双敲除小鼠敲除小鼠Trp53-/-: Pten-/-（简称DKO）我们提出以下具体目标：（1）定义功能。 RB1 丢失加速膀胱癌 GEMM 的肿瘤进展、转移和细胞可塑性 (2) 剖析 TKO 中来源细胞对膀胱肿瘤发生、转移和化疗反应的影响源自基底细胞与管腔细胞的肿瘤的成功完成将允许候选人将获得晚期膀胱癌临床前建模方面宝贵的技术知识和专业知识这项工作还将建立实验性的基础，进一步促进他作为一名独立医师科学家的发展。模型和分析流程将为候选人的独立研究项目提供基础。