Abstract B139: 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 models included one inflammatory breast carcinoma from a pre-treated patient, as well as one pancreatic neuroendocrine cancer, one ovarian carcinosarcoma, one squamous cell vulvar cancer and two uterine carcinosarcomas from treatment naïve patients. Seven upper gastrointestinal models included one adenocarcinoma of the gastroesophageal junction, one stomach adenocarcinoma, one gastric exophytic adenocarcinoma, one intrahepatic cholangiocarcinoma and three small intestine adenocarcinomas. Seven head and neck models included one keratinizing squamous cell carcinoma, one laryngeal squamous cell carcinoma, one salivary gland cancer, and four Lip and oral cavity squamous cell carcinomas. Sarcoma models included one extraskeletal osteosarcoma, two spindle cell soft tissue sarcomas, one pleomorphic soft tissue sarcoma, and one Ewing sarcoma. 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 corresponding patient-derived organoids were highly responsive to these drugs at concentrations below the clinical Cmax. Organoid models derived from the other two patients who previously demonstrated a partial response to chemotherapy, were minimally sensitive to individual drugs from the regimens. However, those organoids were highly responsive to other drugs from the library. Altogether, these data underscore the potential utility of organoids for assessing tumor responses and exploring novel treatment modalities. Funded by NCI Contract No. 75N91019D00024 & 75N91020F00032 Citation Format: Nathan P. Coussens, Thomas S. Dexheimer, Zahra Davoudi, Thomas Silvers, Eric M. Jones, Bryce M. N. Butler, John R. Britt, Luke Stockwin, Dianne Newton, Carmen Allegra, James H. Doroshow, Beverly A. Teicher. A panel of patient-derived organoid models from rare cancers for high-throughput preclinical pharmacology studies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B139.