Abstract 4857: A panel of patient-derived organoid models from rare cancers for high-throughput preclinical pharmacology studies

Abstract Twenty-five patient-derived organoid models from rare cancer types were selected from the NCI’s Patient-Derived Models Repository (https://pdmr.cancer.gov) to serve in a high-throughput screening panel for preclinical pharmacology studies. The models were derived from primary (16; 64%) or metastatic (9; 36%) tumors of patients (56% female, 44% male) with varied ancestries, ranging in age from 32-87 yrs, that were either previously treated (13; 52%) or treatment naïve (12; 48%). The panel included a range of cancer types, including one breast, seven digestive/gastrointestinal, one neuroendocrine, four gynecologic, seven head and neck, and five musculoskeletal. Variations were determined in microsatellite stability and genetics, including clinically relevant oncogenic variants of RAS, BRAF, and PIK3CA. A high-throughput pilot screen was conducted with a library of 166 FDA-approved oncology drugs tested at five concentrations with a 1-log dilution series ranging from 0.01 µM to 100 µM. After a seven-day drug exposure period, cell viability was determined by the CellTiter-Glo 3D endpoint assay. The overall assay performance was excellent with average Z’-factor values from nine microplates per organoid model ranging between 0.54 (0.49 - 0.63) to 0.89 (0.86 - 0.91), with an overall average of 0.67 (0.44 - 0.91). Under assay conditions, the organoid models exhibited diverse morphologies and varied growth kinetics with doubling times ranging from 48 - 363 h with an average of 129 h. Among the patients that received prior chemotherapy, four had a partial response as the best outcome, two of which were sarcoma patients treated with regimens including doxorubicin, vincristine, and etoposide. Interestingly, the organoids derived from the two patients demonstrated ≥1 log of cytotoxicity following exposure to these drugs and others at concentrations below the clinical Cmax. A patient with lip/oral cavity squamous cell carcinoma partially responded to a regimen including temozolomide and the corresponding organoid demonstrated ≥1 log of cytotoxicity following exposure to temozolomide and other drugs below the clinical Cmax. A patient with stomach adenocarcinoma partially responded to a regimen with 5-fluorouracil and cisplatin, but the organoid was minimally sensitive to these drugs. However, genomic characterizations of the tumor tissue indicated an amplification of ERBB2 and the organoid demonstrated sensitivity to the ERBB2 inhibitors neratinib, dacomitinib, and lapatinib below their respective clinical Cmax value. Altogether, these data underscore the potential utility of organoids for assessing tumor responses and exploring novel treatment modalities for underserved malignancies. Funded by NCI Contract No. 75N91019D00024 Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4857.