Abstract B033: Patient-derived 3D organoids for drug screening in cutaneous neurofibroma: A personalized approach to treatment discovery

Abstract Neurofibromatosis type 1 (NF1) is a common genetic disorder, affecting approximately 1 in 3,500 individuals worldwide. Mutations in the NF1 gene impair the function of the tumor suppressor protein neurofibromin, which plays a crucial role in regulating cell proliferation and differentiation. Alterations of NF1 lead to dysregulation of the RAS signaling pathway and uncontrolled cell proliferation. Approximately 90% of NF1 patients develop cutaneous neurofibromas (cNFs)—benign skin tumors Although benign, cNFs cause substantial morbidity and quality of life deterioration for affected individuals. No approved therapies for cNFs currently exist, with surgery as the only non-curative treatment option. Drug development for cNFs is complicated by a lack of models that recapitulate the complexity of their composition. We have developed a platform to rapidly establish and screen patient-derived 3D cNF organoids. By mirroring key characteristics of the original tumors, including cellular complexity and heterogeneity, cNF organoids match patient tumor’s characteristics at the cellular and molecular level. We are conducting drug screenings on individual tumor from every patient to identify compounds that inhibit cNF tumor cell proliferation, and identifying biomarkers predictive of drug response. We have enrolled 22 NF1 patients undergoing cNF removal as part of their clinical care. Preliminary drug screening results indicate variable drug sensitivities among patients, with notable dose-dependent responses to Onalespib (an Hsp90 inhibitor) and Digoxin (a Na+/K+ ATPase inhibitor). By integrating drug response data with proteogenomic profiles, we aim to leverage a machine learning-based biomarker discovery pipeline, to identify specific transcripts, proteins, and phosphosites associated with drug sensitivities. Citation Format: Huyen Thi Lam Nguyen, Alberto Mendoza Valderrey, Summer Norris, Andre Panossian, Sara Gosline, Paul Piehowski, Hutchinson Chelsea, Alice Soragni. Patient-derived 3D organoids for drug screening in cutaneous neurofibroma: A personalized approach to treatment discovery [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B033.