Renal cell carcinoma is a cancer with major unmet clinical needs for which the incidence is steadily rising, and which is increasingly becoming a multidisciplinary disease. Our understanding of the underlying genetic and molecular factors which shape the clinical outcomes for patients with this cancer has advanced to a stage where application to clinical decision-making is imperative. An enhanced understanding of the molecular and genetic events which contribute to disease recurrence and death would significantly improve our ability to stratify patients into clinically relevant classes, devise strategies to achieve risk reduction and identify novel methods to treat patients with this cancer. We have previously identified several important biological features of these cancers through our translational efforts, which are instructional in discriminating the pathways to cancer in the kidney. I propose to extend these features as biomarkers in four projects in various stages of development as vehicles to introduce junior members of our clinical team to the unique potential of prospective investigation. In brief, the four projects are: 1) Prospective biomarker assessment and longitudinal clinical data collection for prognostic biomarker validation. 2) Evaluation of clinical benefit to neoadjuvant treatment with pazopanib prior to nephrectomy, with prospective development of response - predictive biomarkers. 3) Elucidation of the functional relationship of genomic intratumoral heterogeneity with tumor perfusion and metabolic properties using MR-PET. 4) Evaluation of a kinase biomarker expression profile to stratify patients for response to dasatinib. This proposal will provide a series of optimal clinically annotated datasets for developing biological and pharmacological relationships as well as serving as a platform for developing a multidisciplinary cadre of established investigators through the involvement of junior faculty and fellow mentoring relationships. In addition to providing ground-level support fo this endeavor, the support of this proposal will allow me to have the protected time and a platform from which to continue and expand my current patient-oriented research efforts as well as the mentoring efforts of junior faculty, fellows and residents, as well as post-graduate students, focusing on MD-PhD student preparation for the physician- scientist career path. This work will provide key insights to enable drug development, more accurate disease risk assessment, suggest possible therapeutic strategies, and model the biology of common molecular and genetic changes responsible for renal oncogenesis while continuing to build a robust multidisciplinary team. Further, these studies are ideally suited for developing the careers of junior faculty and clinical trainees, and will serve as the launching point for studies to be implemented by my mentees.

Public Health Relevance

Clear cell renal cell carcinoma is a heterogeneous cancer in spite of apparently homogeneous genetics. We propose to harness the potential of three unique molecular profiles we have identified, which stratify these tumors into distinct classification subsets, to identify and model molecular pathways that contribute to tumor behavior. This work will shed light on the events causing progression in renal cell carcinoma and reveal the genetic and molecular biomarkers which contribute to tumor characteristics such as metabolic activity, risk for disease recurrence, and response to targeted therapy. It will also suggest novel targets for diagnostic or therapeutic development, and serve as a resource for specific mentored research projects for students of patient oriented research ranging from graduate level to junior faculty. In addition, my mentoring roles extend well beyond my own interests in renal cell carcinoma, encompassing roles in housestaff and fellowship research advising, and mentoring junior faculty from a broad cross-section of the multidisciplinary program pursuing patient-oriented research careers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Midcareer Investigator Award in Patient-Oriented Research (K24)
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Subcommittee B - Comprehensiveness (NCI)
Program Officer
Lim, Susan E
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University of North Carolina Chapel Hill
Internal Medicine/Medicine
Schools of Medicine
Chapel Hill
United States
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Ricketts, Christopher J; De Cubas, Aguirre A; Fan, Huihui et al. (2018) The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma. Cell Rep 23:313-326.e5
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Beckermann, Kathryn E; Jolly, Pradeep C; Kim, Ju Y et al. (2017) Clinical and immunologic correlates of response to PD-1 blockade in a patient with metastatic renal medullary carcinoma. J Immunother Cancer 5:1

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