Characterizing the immune infiltrate in muscle-invasive urothelial carcinoma

项目摘要 尿路上皮癌是一种常见的、侵袭性的、病态的、未被研究的疾病。许多患者没有被治愈 根据目前对局部肌肉浸润性尿路上皮癌的护理标准，这是一种新的辅助手段 以顺铂为主的联合化疗后行根治性膀胱切除术。但总体存活率显著 对新辅助化疗取得病理完全反应的患者的时间更长，这表明 加强系统治疗将提高存活率。我们开发可靠的预测生物标志物是至关重要的 可以选择将会或不会有完全病理应答的患者分别接受 化疗或强化的围手术期方案。尿路上皮癌和其他疾病的初步证据 癌症提示，渗入的免疫细胞在治疗反应中发挥作用，但这一点并不严格。 肌肉浸润性尿路上皮癌的研究。在这项研究中，我们将询问治疗前后的情况 来自完成的关键II期临床试验的样本，利用我们在空间转录和 蛋白质组学在肿瘤、免疫和间质细胞中的差异基因和蛋白表达 使用或不使用检查点抑制剂的新辅助化疗前后的注解组织标本。 具体地说，我们将评估基线CD8：Foxp3比率和治疗反应(目标1)，确定疗效 新辅助治疗对CD8：Foxp3比率的影响(目标2)，并充分利用空间 转录/蛋白质组学分析开发和评估新的预测生物标记物的性能 对新辅助治疗的反应(目标3)。这项研究将导致预测性生物标志物的同时 分析免疫渗出成分以及治疗对其的影响。最终目标是设计 以生物标记物为导向的临床试验的围手术期合理组合或序贯方案以改善患者 存活率和治愈率。该项目将为候选人，凯瑟琳科利尔，医学博士，硕士， 严格的定量方法、尖端的空间分子分析和高维的培训 生物标记物的开发。该提案充分利用了科利尔博士在化学方面的量化背景 工程，医学肿瘤学的临床培训，以及临床试验设计的正式培训，同时提供 获得多组学技术和数据分析方面的额外技能和知识的机会，临床前 学习、领导力、演示文稿和助学金写作。科利尔博士长期致力于改善结果 为泌尿生殖系癌症患者担任翻译内科医生兼科学家。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、Daniel Stover医学博士、Steven Clinton医学博士、 博士)，熟练的合作者，俄亥俄州立大学综合癌症丰富的学术环境 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 和研究。这一奖项将确保科利尔博士成功地过渡到作为一名内科科学家的独立 和翻译研究人员改善泌尿生殖系癌症患者的预后。

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.