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.

项目摘要这项K08指导职业发展建议的总体目标是为我提供必不可少的指导和职业发展机会，成为成为独立调查员的必要翻译研究专业知识。肾癌是最常见的十大癌症之一，据估计 Uniter州每年有76,000个新案件。管理局部或局部先进的患者透明细胞肾细胞癌（CCRCC）涉及手术切除，随后，一半的患者将五年内复发。由于不一致而采用辅助疗法以降低这种风险是很差的跨试验的结果。缺乏生物标志物无法准确预测复发风险，这是一个关键的障碍将辅助疗法指向这组患者。该建议将调查新颖的翻译方法确定手术去除原发性肾脏肿瘤后有高复发风险的患者。在特定的目标1中，我假设的预后转录组特征由对应于电子传输的基因组成链（ETC），线粒体核糖体蛋白（MRP）和主要的组织相容性II（MHC-II）将导致在将局部CCRC肿瘤分层为两个亚型的肿瘤中，有早期复发风险的肿瘤与不风险。具体 AIM 2，我假设Cu结合到线粒体细胞色素C氧化酶（Cu-Cox），以大小测量排除色谱分感耦合等离子体质谱法将表示线粒体呼吸并将预测早期复发，从而使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检测到侵略性 CCRCC。该提案产生的数据将使我能够进行其他研究，包括验证这些生物标志物在较大的研究中，开发新型临床试验以指导生物标志物中的辅助疗法指定的人群有高度复发的风险，并最终改善了肾癌患者的预后。辛辛那提大学，为我提供了与几个实验室和临床研究人员的合作机会，因此，这使这是进行我的研究的理想环境，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发展，将帮助我成功实现我的短期目标在癌症生物学，功能基因组学和生物信息学领域的培训。为此，我已经组装了导师和顾问团队，他们都是这些学科的专家调查员。补充我培训目的，我计划完成相关的研讨会。通过K08职业发展奖计划，我将生成数据，并增强转化研究的知识和技能，以提交R01应用程序，并最终过渡到独立研究者。