Characterizing the immune infiltrate in muscle-invasive urothelial carcinoma

肌层浸润性尿路上皮癌免疫浸润的特征

• 批准号: 10738992
• 负责人: Katharine A. Collier
• 金额: $ 27.36万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-04 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10738992
• 关键词: Achievement; Address; Adjuvant Chemotherapy; Affect; Aftercare; Award; Biological Assay; Bladder; Bladder Neoplasm; CD8-Positive T-Lymphocytes; CD8B1 gene; Chemical Engineering; Cisplatin; Clinical; Clinical Trials; Clinical Trials Design; Complement; Comprehensive Cancer Center; Cystectomy; Data; Data Analyses; Disease; Doctor of Philosophy; Ensure; Environment; Excision; FOXP3 gene; Future; Gene Expression Profile; Genes; Goals; Grant; Immune; Immune checkpoint inhibitor; In complete remission; Individual; Institution; Investigation; Investments; Knowledge; Leadership; Malignant Neoplasms; Measures; Medical Oncology; Mentors; Mentorship; Methods; Modernization; Molecular Analysis; Muscle; Neoadjuvant Therapy; Ohio; Outcome; Pathologic; Patient Selection; Patient-Focused Outcomes; Patients; Performance; Perioperative; Phase II Clinical Trials; Physicians; Preclinical Testing; Proteins; Proteomics; Radical Cystectomy; Regimen; Regulatory T-Lymphocyte; Research; Residual Neoplasm; Resources; Sampling; Scientist; Specimen; Stromal Cells; Systemic Therapy; T cell infiltration; Techniques; Time; Tissue Sample; Tissue-Specific Gene Expression; Tissues; Training; Transitional Cell Carcinoma; Treatment Protocols; Tumor-infiltrating immune cells; Universities; Urethra; Urogenital Cancer; Writing; biomarker development; biomarker driven; biomarker performance; biomarker validation; career development; chemotherapy; clinical training; cohort; design; differential expression; experience; gemcitabine; high dimensionality; immune cell infiltrate; improved; improved outcome; multiple omics; novel; overtreatment; phase II trial; preclinical study; predictive marker; prevent; prospective; protein expression; rational design; research and development; responders and non-responders; response; response biomarker; skills; standard of care; therapy resistant; transcriptomics; translational physician; translational scientist; treatment response; treatment stratification; tumor; tumor immunology; tumor microenvironment

Project Summary Urothelial carcinoma is a common, aggressive, morbid, and understudied disease. Many patients are not cured with the current standard of care for localized muscle-invasive urothelial carcinoma, which is neoadjuvant combination cisplatin-based chemotherapy followed by radical cystectomy. But overall survival is significantly longer in patients who obtain a pathologic complete response to neoadjuvant chemotherapy, suggesting that intensification of systemic therapy will improve survival. It is critical that we develop reliable predictive biomarkers that can select patients that will or will not have a complete pathologic response to receive, respectively, either chemotherapy or an intensified peri-operative regimen. Preliminary evidence in urothelial carcinoma and other cancers suggests that infiltrating immune cells play a role in treatment response, but this has not been rigorously studied in muscle-invasive urothelial carcinoma. In this study, we will interrogate pre- and post-treatment samples from a completed, pivotal phase II clinical trial, harnessing our expertise in spatial transcriptomics and proteomics to interrogate differential gene and protein expression in tumor, immune, and stromal cells in annotated tissue specimens before and after neoadjuvant chemotherapy with or without a checkpoint inhibitor. Specifically, we will evaluate baseline CD8:FOXP3 ratio and responses to therapy (Aim 1), determine the effect of neoadjuvant therapy on CD8:FOXP3 ratio (Aim 2), and leverage the full capacity of spatial transcriptomic/proteomic assays to develop and evaluate the performance of novel predictive biomarkers of response to neoadjuvant therapy (Aim 3). This study will result in predictive biomarkers while concurrently profiling the immune infiltrate composition and how it is influenced by treatment. The ultimate goal is to design rational combination or sequential peri-operative regimens for biomarker-driven clinical trials to improve patient survival and cure rates. The project will provide the candidate, Katharine Collier, MD, MSc, MSE, MS, with training in rigorous quantitative methods, cutting-edge spatial molecular analyses, and high-dimensional biomarker development. The proposal capitalizes on Dr. Collier’s quantitative background in Chemical Engineering, clinical training in Medical Oncology, and formal training in clinical trial design, while providing an opportunity to gain additional skills and knowledge in multi-omics techniques and data analyses, preclinical studies, leadership, presentations, and grant writing. Dr. Collier is committed long-term to improving outcomes for patients with genitourinary cancers as a translational physician-scientist. Dr. Collier will be supported by an experienced mentorship team (Amir Mortazavi, MD, Zihai Li, MD, PhD, Daniel Stover, MD, Steven Clinton, MD, PhD), skilled collaborators, the rich academic environment of the Ohio State University Comprehensive Cancer Center, and an invested institution committed to providing protected time and resources for career development and research. This award will ensure Dr. Collier’s successful transition to independence as a physician-scientist and translational researcher improving outcomes for patients with genitourinary cancers.

项目摘要 尿路上皮癌是一种常见的、侵袭性的、病态的和研究不足的疾病。很多病人没有治愈 与目前的标准治疗局部肌肉浸润性尿路上皮癌，这是新辅助治疗， 联合顺铂为基础的化疗，然后进行根治性化疗。但总体生存率 在对新辅助化疗获得病理完全缓解的患者中， 加强全身治疗将提高存活率。我们开发可靠的预测生物标志物是至关重要的 可以选择将或将不会有一个完整的病理反应的患者，分别接受， 化疗或强化围手术期方案。尿路上皮癌和其他 癌症表明浸润性免疫细胞在治疗反应中起作用，但这并没有得到严格的证实。 在肌层浸润性尿路上皮癌中进行了研究。在这项研究中，我们将询问治疗前后 从已完成的关键II期临床试验中提取样本，利用我们在空间转录组学方面的专业知识， 蛋白质组学，以询问肿瘤，免疫和基质细胞中的差异基因和蛋白质表达， 在有或没有检查点抑制剂的新辅助化疗之前和之后的注释组织标本。 具体而言，我们将评估基线CD 8：FOXP 3比率和对治疗的反应（目的1），确定 新辅助治疗对CD 8：FOXP 3比率的影响（目标2），并充分利用空间 转录组学/蛋白质组学测定，以开发和评估新的预测生物标志物的性能， 对新辅助治疗的反应（目的3）。这项研究将产生预测性生物标志物，同时 分析免疫浸润物组成以及它如何受治疗影响。最终目标是设计 生物标志物驱动的临床试验的合理组合或序贯围手术期方案，以改善患者 存活率和治愈率。该项目将提供候选人，凯瑟琳科利尔，医学博士，理学硕士，MSE，MS， 严格的定量方法，尖端的空间分子分析和高维 生物标志物开发。该提案利用了Collier博士在化学领域的定量背景， 工程、肿瘤内科临床培训和临床试验设计的正式培训，同时提供 有机会获得多组学技术和数据分析，临床前 学习、领导力、演讲和赠款写作。科利尔博士长期致力于改善结果 作为一名转化医学科学家，为泌尿生殖系统癌症患者提供服务。科利尔博士将由一名 经验丰富的导师团队（Amir Mortazavi，医学博士，Zihai Li，医学博士，哲学博士，丹尼尔秸秆，医学博士，Steven Clinton，医学博士， 博士）、技术娴熟的合作者、俄亥俄州州立大学综合癌症所丰富的学术环境 中心，以及致力于为职业发展提供受保护的时间和资源的投资机构 与研究该奖项将确保科利尔博士成功过渡到独立作为一个医生，科学家 和转化研究人员改善泌尿生殖系统癌症患者的预后。