Abstract 5197: Establishing patient-derived xenograft organoids (PDXOs) from renal cell carcinoma for drug screening and identification of treatment-induced vulnerabilities

Clear Cell Renal Cell Carcinoma (ccRCC) is the most prevalent urinary kidney malignancy, presenting significant challenges in disease control, particularly for patients with locally advanced or metastatic disease. The urgent need for more effective therapies remains unmet. Patient-derived models, including 3D patient-derived organoids (PDOs) and in vivo patient-derived xenografts (PDXs), faithfully recapitulate tumor histological morphology, genetic landscape, and therapeutic responses. The ACCamargo Cancer Center PDX Biobank includes several ccRCC cases and comprehensive patient clinical data supporting the generation of PDX organoids (PDXOs) for high-throughput drug screening and The present work aims to a) establish and validate ccRCC PDXO as predictive models for standard-of-care treatments and b) investigate drug vulnerabilities and synthetic lethality approaches in BAP1-mutated tumors. Twelve PDX samples (fresh and cryopreserved) were enzymatically digested, resuspended, seeded in growth factor-reduced Geltrex®, and cultured in a kidney organoid medium. PDXOs were assessed using histology and immunohistochemistry. Cell viability assays evaluated six PDXOs’ responses to Sunitinib (one of the stand-of-care drugs in RCC). Results were correlated with patients' clinical outcomes for three cases of PDXOs with BAP1 mutations (BAP1MUT) and wild-type BAP1 (BAP1WT ) were treated with Olaparib (Poly(ADP-ribose) polymerase (PARP) inhibitor) and Vorinostat (Histone deacetylase (HDAC) inhibitor). The success of PDXOs' growth and expansion efficiency, at approximately 60%, proves our research's reliability. Histology and immunohistochemistry c confirmed that five PDXOs and PDX matched the characteristics of the corresponding patient tumors. PDXOs treated with Sunitinib exhibited varied responses. In three out of the five cases, the sensitivity of PDXOs to Sunitinib aligned with the clinical outcomes of the respective patients. Preliminary data indicated that BAP1MUT PDXOs were more sensitive to Olaparib and Vorinostat treatments than BAP1WT PDXOs. The study demonstrated the predictive power of PDXOs in correlating therapeutic responses to Sunitinib with clinical outcomes. BAP1 mutations in PDXOs also revealed drug vulnerabilities, highlighting increased sensitivity to Olarapib and Vorinostat. These findings underscore the value of PDXOs as robust tools for predicting patient responses to therapy and exploring target treatments for ccRCC. Citation Format: Stefano Piatto Clerici, Adriano O. Beserra, Stephania M. Bezerra, Luciana M. Leite, Stênio C. Zequi, Tiago G. Santos, Vilma R. Martins. Establishing patient-derived xenograft organoids (PDXOs) from renal cell carcinoma for drug screening and identification of treatment-induced vulnerabilities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5197.