Combination of Transcriptomic and Metallomic Biomarkers for Risk Assessment in Locoregional Clear Cell Renal Cell Carcinoma

项目摘要 本K 08指导式职业发展提案的总体目标是为我提供基本的 导师和职业发展机会，成为独立调查员所必需的， 翻译研究的专业知识。肾癌是十大最常见的癌症之一，估计 在美国每年有七万六千个新病例。局部或局部晚期乳腺癌患者的管理 透明细胞肾细胞癌（ccRCC）涉及手术切除，随后，一半的患者将 五年内复发。采用辅助治疗来降低这种风险一直很差，因为不一致的 试验结果。缺乏生物标志物来准确预测复发风险，这是治疗复发的关键障碍。 为这组患者提供辅助治疗。这项提案将探讨新的翻译方法 以确定原发性肾脏肿瘤手术切除后复发风险高的患者。在具体目标1中， 假设由对应于电子传递的基因组成的预后转录组标记 链（ETC）、线粒体核糖体蛋白（MRP）和主要组织相容性复合物-II（MHC-II）将导致 将局部ccRCC肿瘤分层为两种亚型-有早期复发风险的亚型与无早期复发风险的亚型在特定 目的2，我假设铜结合到线粒体细胞色素c氧化酶（Cu-COX），测量的大小 排阻色谱电感耦合等离子体质谱法将指示线粒体 呼吸，并将预测早期复发，从而成为一个简单和廉价的生物标志物。在 此外，我们将评估血清中不同铜池的临床相关性，作为高铜血症的预测因子。 相应的ccRCC肿瘤中的铜含量，从而使基于血清的生物标志物能够检测侵袭性 ccRCC。从本提案中生成的数据将使我能够进行额外的研究，包括验证 这些生物标志物在更大的研究中，开发新的临床试验，以指导生物标志物中的辅助治疗 特定人群的复发风险高，并最终改善肾癌患者的预后。 辛辛那提大学为我提供了与几位实验室和临床研究人员合作的机会， 因此，这是一个理想的环境，进行我的研究，同时提供临床和行政支持。 我的临床和转化癌症研究背景，包括与实验室合作的经验 科学家和专注于生物标志物的发展，将帮助我成功地实现我的短期目标，包括 癌症生物学、功能基因组学和生物信息学领域的培训。为此目的，我召集了一个 导师和顾问团队，他们都是这些学科的专家调查员。来补充我 培训目标，我计划完成相关的研讨会。通过K 08职业发展奖励计划， 我将生成数据，并提高翻译研究的知识和技能，以提交R 01申请， 最终转变为独立调查员

PROJECT SUMMARY The overall goal of this K08 Mentored Career Development proposal is to provide me with the essential mentorship and career development opportunities, necessary to become an independent investigator with expertise in translational research. Kidney cancer is among the top ten most common cancers, with an estimated 76,000 new cases every year in the Uniter States. Management of patients with localized or locally advanced clear cell renal cell carcinoma (ccRCC) involves surgical resection, following which, half of the patients will have a recurrence within five years. Adoption of adjuvant therapies to lower this risk has been poor due to inconsistent results across trials. There is a lack of biomarkers to predict the recurrence risk accurately, a critical barrier in directing adjuvant therapies to this group of patients. This proposal will investigate novel translational approaches to identify patients at high risk of relapse after surgical removal of the primary kidney tumor. In Specific Aim 1, I hypothesize that a prognostic transcriptomic signature comprised of genes corresponding to electron transport chain (ETC), mitochondrial ribosomal proteins (MRP) and major histocompatibility complex-II (MHC-II) will result in stratification of localized ccRCC tumors into the two subtypes- those at risk of early relapse vs. not. In Specific Aim 2, I hypothesize that Cu-bound to mitochondrial cytochrome c oxidase (Cu-COX), measured by size exclusion chromatography inductively coupled plasma mass spectrometry will be indicative of mitochondrial respiration and will be predictive of early relapse, thus making for a simple and inexpensive biomarker. In addition, we will be evaluating the clinical relevance of different pools of copper in serum as predictors of high copper content in corresponding ccRCC tumors, thus enabling a serum-based biomarker to detect aggressive ccRCC. Data generated from this proposal will allow me to perform additional research, including validation of these biomarkers in larger studies, development of novel clinical-trials to direct adjuvant therapies in a biomarker specified population at high risk of relapse, and ultimately improve outcomes for patients with kidney cancer. University of Cincinnati, provides me collaborative opportunities with several laboratory and clinical researchers, thus making this an ideal environment to conduct my research while providing clinical and administrative support. My background in clinical and translational cancer research, including experience in collaborating with laboratory scientists and focus on biomarker development, will help me to successfully attain my short-term goals including training in the fields of cancer biology, functional genomics and bioinformatics. To this end, I have assembled a team of mentors and advisors, all of whom are expert investigators in these disciplines. To supplement my training aims, I plan on completing relevant workshops. Through the K08 Career Development Award Program, I will generate data, and enhance knowledge and skills in translational research to submit an R01 application, and ultimately transition to an independent investigator.