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

转录组学和金属组学生物标志物的组合用于局部区域透明细胞肾细胞癌的风险评估

基本信息

批准号：
10706315
负责人：
Shuchi Gulati
金额：
$ 26.11万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-16 至 2027-07-31
项目状态：
未结题

项目摘要

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.

项目概要 K08 指导职业发展提案的总体目标是为我提供必要的知识成为独立调查员所必需的指导和职业发展机会转化研究方面的专业知识。肾癌是十大最常见癌症之一，据估计美国每年新增病例 76,000 例。局部或局部晚期患者的管理透明细胞肾细胞癌（ccRCC）需要手术切除，之后一半的患者会出现五年内复发。由于不一致，采用辅助疗法来降低这种风险的效果一直很差。各个试验的结果。缺乏准确预测复发风险的生物标志物，这是治疗复发的一个关键障碍指导针对该组患者的辅助治疗。该提案将研究新颖的翻译方法识别手术切除原发性肾肿瘤后复发风险高的患者。在具体目标 1 中，我假设预后转录组特征由与电子传递相对应的基因组成链（ETC）、线粒体核糖体蛋白（MRP）和主要组织相容性复合物-II（MHC-II）将产生将局部 ccRCC 肿瘤分为两种亚型——有早期复发风险的与无早期复发风险的。具体来说目标 2，我假设 Cu 与线粒体细胞色素 c 氧化酶 (Cu-COX) 结合，通过大小测量排阻色谱法、电感耦合等离子体质谱法将指示线粒体呼吸并且可以预测早期复发，从而成为一种简单且廉价的生物标志物。在此外，我们将评估血清中不同铜池作为高铜血症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志物能够检测侵袭性 ccRCC。从该提案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规模的研究中，开发新的临床试验来指导生物标志物的辅助治疗特定的高复发风险人群，最终改善肾癌患者的预后。辛辛那提大学为我提供了与几位实验室和临床研究人员合作的机会，因此，这成为我进行研究的理想环境，同时提供临床和行政支持。我在临床和转化癌症研究方面的背景，包括与实验室合作的经验科学家并专注于生物标志物开发，将帮助我成功实现我的短期目标，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，我整理了一个导师和顾问团队，他们都是这些学科的专家研究人员。为了补充我的培训目标，我计划完成相关研讨会。通过K08职业发展奖励计划，我将生成数据，并增强转化研究方面的知识和技能，以提交 R01 申请，并最终转变为独立调查员。