Sex, Chromosomes, and Immunity in Bladder Cancer

膀胱癌中的性别、染色体和免疫

• 批准号: 10629077
• 负责人: Xue Sean Li
• 金额: $ 227.23万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629077
• 关键词: Affect; Anatomy; Androgen Receptor; Androgens; Applications Grants; Automobile Driving; B-Lymphocytes; Benchmarking; Biological; Biology; Bladder; Bladder Neoplasm; CD8-Positive T-Lymphocytes; Cancer Biology; Cancer Center; Cancer Patient; Chromosomes; Clinical; Clinical Management; Collaborations; Communication; Comprehensive Cancer Center; Consultations; Data; Data Science Core; Development; Disease; Doctor of Philosophy; Environmental Risk Factor; Epigenetic Process; Estrogens; Experimental Designs; Female; Foundations; Gene Targeting; Genetic; Genetic Transcription; Goals; Gonadal Steroid Hormones; Growth; Hormonal; Image Analysis; Immunity; Immunocompetent; Immunologic Monitoring; Immunologics; Immunology; Incidence; Infection; Institution; Joints; Knowledge; Laboratories; Link; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Medical Oncology; Medical center; Medicine; Molecular; Mus; Natural Killer Cells; Neoplasm Metastasis; Ohio; Paper; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Physicians; Play; Prevalence; Program Research Project Grants; Publications; Publishing; Receptor Signaling; Recording of previous events; Reporting; Research; Research Personnel; Resistance; Resource Sharing; Risk Factors; Role; Science; Services; Sex Bias; Sex Chromosomes; Sex Differences; Signal Transduction; Smoking; System; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Tumor Suppression; Tumor Suppressor Proteins; Universities; Urology; X Chromosome; Y Chromosome; biological sex; cancer initiation; cancer therapy; cancer type; chromosome Y loss; clinical development; computerized data processing; data integration; data repository; design; digital pathology; druggable target; epigenome; exhaustion; expectation; experience; functional genomics; immune checkpoint blockade; improved; innovation; insight; interest; male; men; mortality; mouse model; neoplastic cell; novel; occupational hazard; programs; response; sex; sex disparity; success; symposium; targeted treatment; translational potential; treatment response; tumor; tumor growth; tumor immunology; tumor initiation; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenesis

OVERALL – SUMMARY Bladder cancer (BC) is 3-5 times more common in men even when adjusted for environmental factors such as smoking, the primary risk factor for this disease. The goal of this Program Project Grant (PPG) is to advance our knowledge of “sex as a biological variable (SABV)” in BC, with the ultimate objective of improving patient outcomes by discovering sex-specific drivers that can be targeted therapeutically. Benchmarks of Success and Impact for the Program include identification of key immunological, hormonal, chromosomal, genetic, and epigenetic pathways responsible for sex-driven biological phenotypes in BC to inspire the design of a novel line of BC therapeutics based on each patient’s biological sex. To this end, the PPG will unite three leading laboratories in their respective fields, each tackling the problem of SABV from a unique and complementary standpoint of expertise: immunology, cancer biology/functional genomics, and epigenetics. These three research groups, supported by Cedars-Sinai Medical Center Cancer Center and the Ohio State University Comprehensive Cancer Center, have a proven history of collaboration, with nine joint publications since 2017 and multiple co- authored papers in the pipeline. Project 1 aims to uncover the immunological basis of sex differences in BC, taking advantage of a recent discovery in T cell intrinsic androgen receptor signaling in CD8+ T cell exhaustion. Project 2 will focus on the role of the Y chromosome and the Y-lined epigenetic regulators in driving BC progression and resistance to immune checkpoint blockade (ICB); and Project 3 will investigate tumor suppressing activity of the X chromosome-linked epigenetic regulator and the roles of androgen and estrogen- dependent sex hormone pathways, aiming to elucidate the epigenetic basis of sex differences in BC. All three Projects will be supported by an Administrative Core (Admin Core) and two shared resource Cores – the Systems Pathology Core (Core 1) and the Data Science Core (Core 2). Admin Core will manage and support the entire program by offering administrative and fiscal management support and facilitating communication and scientific interactions. Core 1 will provide state-of-the-art digital pathology services, automated and personalized image analyses, and multiparameter immune monitoring. Core 2 will provide unified data processing, analytical pipelines, data integration, data repository, and statistical consultation. Because male prevalence in cancer incidence and mortality is observed across many other cancer types, our scientific findings will likely have broad implications in cancer medicine far beyond BC.

Overall—概要