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，侵略性，病态和可理解的疾病。许多患者未治愈 有了当前对局部肌肉侵入性尿路上皮癌的护理标准，这是新辅助 基于顺铂的联合化疗，然后进行根治性膀胱切除术。但是总体生存显着 在对新辅助化疗的病理完全反应的患者中，有更长的时间表明 全身疗法的强化将提高生存率。至关重要的是我们开发可靠的预测生物标志物 可以选择将分别接受或不会有完整的病理反应的患者接受 化学疗法或加强围手术治疗方案。尿路上皮癌和其他的初步证据 癌症表明，浸润的免疫细胞在治疗反应中起作用，但这并不是严格的 肌肉肌肉尿路上皮癌的研究。在这项研究中，我们将询问治疗前后 来自完整的关键II期临床试验的样本，利用我们在空间转录组学方面的专业知识 蛋白质组学在肿瘤，免疫和基质细胞中询问差异基因和蛋白质表达 带有或不使用检查点抑制剂的新辅助化学疗法之前和之后，注释的组织标本。 具体而言，我们将评估基线CD8：FOXP3比和对治疗的反应（AIM 1），确定效果 CD8：FOXP3比率（AIM 2）的Neoadjuvant疗法（AIM 2），并利用空间的全部容量 转录组/蛋白质组学测定，以开发和评估新型预测生物标志物的性能 对新辅助治疗的反应（AIM 3）。这项研究将导致预测生物标志物，同时同时 分析免疫浸润组合物以及如何受到治疗的影响。最终目标是设计 用于生物标志物驱动临床试验的合理组合或顺序围手术方案，以改善患者 生存和治愈率。该项目将提供候选人，凯瑟琳·科利尔（Katharine Collier），医学博士，MSC，MSE，MS， 在严格的定量方法，尖端的空间分子分析和高维的培训中培训 生物标志物开发。该提案大写了科利尔博士的化学定量背景 工程学，医学肿瘤学临床培训以及临床试验设计的正式培训，同时提供 在多摩斯技术和数据分析中获得其他技能和知识的机会，临床前 研究，领导，演讲和授予写作。科利尔博士长期致力于改善结果 对于泌尿生殖器癌作为翻译的身体科学家的患者。科利尔博士将得到 经验丰富的Menorship Team（Amir Mortazavi，医学博士，Zihai Li，医学博士，博士 博士学位），熟练的合作者，俄亥俄州立大学综合癌症的丰富学术环境 中心，并致力于为职业发展提供受保护的时间和资源 和研究。该奖项将确保科利尔博士成功过渡到独立的身体科学家 并翻译研究人员改善了泌尿生殖器癌患者的结局。