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

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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.