Comprehensive Liquid Biomarkers to Personalize Therapy in Renal Cell Carcinoma

/ABSTRACT Combination immune-oncology (IO) using immune checkpoint blockers (ICB) with or without vascular endothelial growth factor (VEGF) targeting agents have emerged as first-line treatments for patients with advanced renal cell carcinoma (RCC). Although the initial response rates to treatment range from 40%–60%, the rates of treatment resistance are high. Given the need to better optimize therapy selection for patients and minimize exposure to ineffective treatments, identifying which patients are destined to progress on treatment and those who can obtain long-term benefit and potentially cure is an urgent need plaguing clinical practice. Currently, no biomarkers are used in the clinic to help inform therapy selection for patients. Against this backdrop, we have pioneered a minimally invasive comprehensive blood-based liquid biopsy platform that can integrate analysis of CTC protein and DNA—necessary for improved treatment selection for patients with RCC and other cancers. The key aims of this project are to: 1) clinically validate early on-treatment CTC dynamics as prognostic biomarkers in metastatic RCC, 2) clinically validate early on-treatment CTC dynamics as predictive biomarkers to IO therapy in metastatic RCC, and 3) determine if early on-treatment CTC dynamics predict benefit to stereotactic ablative radiotherapy (SABR), which is increasing being utilized in RCC management. We will use our liquid biopsy platform to identify predictors of response and resistance to systemic therapy and radiotherapy among two clinical groups of advanced RCC patients: (1) a multi-institutional cohort of patients with RCC from University of California San Diego Moores Cancer Center, University of Wisconsin Carbone Cancer Center, and University Hospitals Seidman Cancer Center, and (2) RCC patients enrolled on a nationally-accruing, National Cancer Institute Cooperative Group trial of IO combination therapy with or without SABR. The outcomes of this project will transform how we select patients for treatment and monitor for resistance in metastatic RCC. Our team is led by Dr. Rana R. McKay, an early-stage investigator and medical oncologist at the University of California San Diego. Together with Dr. Zhao, Lang, and Emamekhoo from the University of Wisconsin, and Dr. Barata from University Hospitals, we have the clinical and translational expertise necessary to lead the studies featured in this project. We are confident that our innovative, minimally invasive, liquid biopsy approach will provide real-time molecular information for clinical decision-making that will optimize therapy selection of patients and improve patient well-being by maximizing the therapeutic benefit of treatment and limiting exposure to ineffective treatments. Additionally, our approach is scalable allowing for broad clinical application. Our proposed comprehensive clinical-grade liquid biopsy platform will revolutionize developing biomarkers for RCC and can serve as a roadmap for other cancers. Project Number: 1R01CA292799-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Rana McKay | Institution: UNIVERSITY OF CALIFORNIA, SAN DIEGO, LA JOLLA, CA | Award Amount: $2,984,495 | Activity Code: R01 | Study Section: Molecular Cancer Diagnosis and Classification Study Section[MCDC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11134196