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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：
10366068
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/10366068
关键词：
Adenoviruses 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 Research Training Resistance Role Scientist Signal Pathway Signal Transduction System TP53 gene Techniques Testing Tetracyclines Therapeutic Training Trans-Activators Transgenic Mice Tumor Suppressor Genes Tumor-Derived UPK2 gene Urology Urothelium Vision Work acquired drug resistance analysis pipeline anticancer research base 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.

摘要