A PROGNOSTIC ASSAY FOR METASTATIC CLEAR CELL RENAL CELL CARCINOMA

ABSTRACT An estimated 79,000 Americans were diagnosed with renal carcinoma in 2022 and approximately 13,920 died, primarily as a result of metastasis. First line treatment involves localized surgical removal of the primary tumor as systemic therapies are generally reserved for metastatic dissemination. While ccRCC surveillance protocols have improved over recent years, aggressive management with immunomodulators and chemotherapeutic agents is generally withheld until after significant recurrence or metastasis is identified; although this is generally too late to effectively manage or deter advanced cancerous spread, which is reflected by a post-metastasis 5-year survival rate of just 14%. The goal of this Phase II SBIR is to further address the absence of quantifiable targeted metabolite biomarkers in ccRCC tissues that accurately and specifically predict early disease progression to metastasis. Ultimately, we seek to identify those patients that express aggressive subtype(s) of renal cancer that would benefit from earlier initiation of systemic therapy. Likewise, evaluation of this newly identified 12-marker panel can determine those patients who will have metastatic disease with 100% specificity and may confidently choose a more conservative management approach. There is a clear unmet clinical need to stratify aggressive cancer subpopulations within certain malignancies like ccRCC, yet, there are currently no prognostic or diagnostic tests on the market that predict metastasis. In pilot studies, LAGRANGE SCIENTIFIC was able to overcome major problems that encumbered previous metabolic studies, such as primary tumor tissue heterogeneity and day-to-day, as well as lab-to-lab, MS variability. Additionally, further refinement of our pre-analytical and post-acquisition normalization techniques, in addition to metabolite quantification methods, have demonstrated stronger accuracy and higher robustness. Indeed, we have identified in our feasibility studies a panel of metabolite markers that are 100% specific and 83% sensitive – with 100% PPV and 94% NPV – in identifying ccRCC patients that progress to metastasis at the time of primary ccRCC tumor resection (1.7 - 4.6 years sooner than standard of care). In order to help validate our prototype, we will utilize the ccRCC biorepositories from the Eastern Virginia Medical School PROBE cohort, Ontario Institute for Cancer Research Tumor Bank, University of Florida, University of Virginia, and UT Health San Antonio; which account for over 894 renal tumors with associated patient data and follow-up. We will begin prospective tissue collection at the University of Florida, Jacksonville, and continue collection at UT Health San Antonio, which are accompanied by updated databases that further allow us to identify patients who underwent a primary ccRCC tumor and metastasized (Cases) vs patients who did not progress to metastasis (Controls). Paired “Normal” adjacent tissue will be obtained when feasible. For this Phase II R&D, we will expand upon our extremely successful results from our pilot proof-of-concept studies and further develop our prototype and commercialization strategies.