Pd51-02 Integrative Molecular Profiling of Renal Cell Carcinoma Native Tissue and Patient Derived Organoids Identifies Predictive Markers of Drug Response

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology II (PD51)1 May 2024PD51-02 INTEGRATIVE MOLECULAR PROFILING OF RENAL CELL CARCINOMA NATIVE TISSUE AND PATIENT DERIVED ORGANOIDS IDENTIFIES PREDICTIVE MARKERS OF DRUG RESPONSE Daniel A. Triner, Trinh Pham, Srinivas Nallandhighal, Brittney Cotta, Zayne Knuth, Fengyun Sun, Aaron Udager, Saravana Dhanasekaran, Nathan Merrill, and Simpa S. Salam Daniel A. TrinerDaniel A. Triner , Trinh PhamTrinh Pham , Srinivas NallandhighalSrinivas Nallandhighal , Brittney CottaBrittney Cotta , Zayne KnuthZayne Knuth , Fengyun SunFengyun Sun , Aaron UdagerAaron Udager , Saravana DhanasekaranSaravana Dhanasekaran , Nathan MerrillNathan Merrill , and Simpa S. SalamSimpa S. Salam View All Author Informationhttps://doi.org/10.1097/01.JU.0001009360.84490.42.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The overall response rate of renal cell carcinoma (RCC) to systemic therapy is ∼30%. There is a critical need to identify effective treatment for each individual patient and identify novel therapeutic targets. To this end, we performed integrative molecular profiling of native tissue and patient derived organoids (PDOs) of RCC to identify predictive markers of drug responses. METHODS: We prospectively enrolled patients undergoing radical nephrectomy (RN) for RCC. Fresh tissue procured from normal (N) and two separate tumor (T1 and T2) areas were subjected to histological evaluation and molecular profiling. PDO cultures were established from various tissue samples from each patient to study their response to a library of 26 clinically available drugs, targeting genes and pathways implicated in RCC alongside appropriate experimental controls. Effects of drug exposure on PDOs and dose response curves obtained from IC50 experiments were also evaluated. Molecular profiling of PDOs before and after exposure to drugs to delineate mechanisms of drug resistance are in progress. RESULTS: Four patients with clear cell RCC (ccRCC) and one with chromophobe RCC (chRCC) have thus far been enrolled in this ongoing study. PDOs were successfully established for all patient's N samples and T1 and T2 samples of 3 patients (RCC #3-5). As shown in Figure 1, analysis of patient #3 with ccRCC demonstrated frameshift mutations in VHL and BAP1, and 3p loss in both T1 and T2. Single cell RNAseq revealed high CA9, VEGFA and EGFR expression. PDO cultures and drug testing experiments identified drugs targeting VEGFA and EGFR (i.e., Sunitinib and Neratinib) as effective therapies. Patient #3 had progressed while on Ipilimumab and Nivolumab and notably, their PDOs were differentially resistant to these therapies (T1 resistant to Nivolumab and T2 resistant to Ipilimumab). In patient #4 with chRCC, Sunitinib targeting c-KIT/PDGFR demonstrated efficacy in T1 and T2. CONCLUSIONS: Integration of PDOs, a clinically relevant 3D ex-vivo model system, with multi-omics can enable data-driven development of personalized kidney cancer therapies. Ongoing work will provide further insights into tumor heterogeneity, underlying mechanisms of tumor evolution, and therapeutic resistance. Download PPT Source of Funding: Rogen Scholar Award © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e1064 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Daniel A. Triner More articles by this author Trinh Pham More articles by this author Srinivas Nallandhighal More articles by this author Brittney Cotta More articles by this author Zayne Knuth More articles by this author Fengyun Sun More articles by this author Aaron Udager More articles by this author Saravana Dhanasekaran More articles by this author Nathan Merrill More articles by this author Simpa S. Salam More articles by this author Expand All Advertisement PDF downloadLoading ...