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

项目总结 这份由K08指导的职业发展提案的总体目标是为我提供必要的 导师和职业发展机会，成为一名独立调查员所必需的 翻译研究方面的专业知识。肾癌是最常见的十种癌症之一，据估计 在美国，每年有76,000个新病例。本地化或局部进展期患者的处理 肾透明细胞癌(CcRCC)包括手术切除，之后，一半的患者将有 五年内复发。由于不一致，采用辅助疗法来降低这种风险的效果很差。 所有试验的结果。缺乏准确预测复发风险的生物标记物，这是 将辅助治疗引导到这一组患者。这项提案将研究新颖的翻译方法。 目的：识别原发肾肿瘤手术切除后复发的高危患者。在具体目标1中，我 假设由对应于电子传递的基因组成的预后转录标记 链(ETC)、线粒体核糖体蛋白(MRP)和主要组织相容性复合体-II(MHC-II)将产生 将局限性肾细胞癌肿瘤分成两种亚型--有早期复发风险的肿瘤和无复发风险的肿瘤。具体而言 目的2，我假设铜结合到线粒体细胞色素C氧化酶(铜-COX)，以大小衡量 排除层析电感耦合等离子体质谱检测线粒体 呼吸作用，并将预测早期复发，因此成为一个简单和廉价的生物标志物。在……里面 此外，我们将评估血清中不同铜库作为高血压病预测因子的临床相关性。 相应ccRCC肿瘤中的铜含量，从而使基于血清的生物标记物能够检测侵袭性 中国铁路总公司。此提案生成的数据将使我能够执行其他研究，包括验证 这些生物标记物在更大的研究中，开发新的临床试验来指导生物标记物的辅助治疗 特定人群是复发的高危人群，最终改善肾癌患者的预后。 辛辛那提大学为我提供了与几个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来进行我的研究，同时提供临床和管理支持。 我的临床和转化性癌症研究背景，包括与实验室合作的经验 科学家和专注于生物标记物开发，将帮助我成功实现我的短期目标，包括 在癌症生物学、功能基因组学和生物信息学领域的培训。为此，我已经组建了一个 由导师和顾问组成的团队，他们都是这些学科的专家调查人员。来补充我的 培训目标，我计划完成相关的工作坊。通过K08职业发展奖励计划， 我将生成数据，并增强翻译研究方面的知识和技能，以提交R01申请， 并最终转变为一名独立的调查员。

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.