Abstract 7200: PREMOST: an organoid-based functional precision medicine trial in osteosarcoma

Abstract Pediatric sarcomas are a diverse group of malignancies accounting for ∼15% of all childhood solid tumors. Osteosarcomas constitute the most common bone tumor in the pediatric patient population. There are about 1, 000 new cases diagnosed each year in the United States, with greatest incidence in adolescence and in the sixth decade of life. Overall, 5-year survival rates are ∼60% and as low as ∼20-30% for metastatic disease. In the primary setting, neoadjuvant MAP chemotherapy including methotrexate, adriamycin (doxorubicin), and cisplatin combination therapy is the standard of care. However, ∼30% of all patients are resistant to MAP therapy, resulting in low degree of necrosis at time of surgery, and rapid recurrences. For recurrent and metastatic disease, NCCN guidelines include several different possible regimens, which have shown some activity in the clinic. For both the neoadjuvant MAP setting and second line therapies, there is no clinically validated biomarker of response to help stratify patients and improve outcomes by selecting the most effective therapy. Our overarching goal is to leverage short-term, patient-derived sarcoma organoids to provide actionable information for treatment guidance. Patient-derived organoids (PDOs) are increasingly used both to investigate tumor growth and for precision medicine, as they recapitulate patients drug responses in many settings (Zhao et al, Nature Reviews Methods Primers 2022). We have an established pipeline to establish and characterize sarcoma patient-derived organoids using an approach that allows us to perform high throughput drug screenings to find individual susceptibilities (Al Shihabi et al, Science Advances 2022; Al Shihabi et al, Cell Stem Cell 2024). Our preliminary correlative studies highlight how sarcoma PDOs can recapitulate therapy outcomes (Al Shihabi et al, Cell Stem Cell 2024). In a small dataset, responses of osteosarcoma organoids established from diagnostic biopsies to MAP neo-adjuvant therapy were found to correlate with both short-term histologic response (necrosis at time of surgery) and long-term patient outcomes (progression-free survival). As such, we have initiated a clinical trial to evaluate the feasibility of developing organoids from these cases and to assess the prognostic accuracy of our platform in predicting treatment outcomes. Here we will discuss the design and preliminary findings of PREMOST (An Organoid-based Functional Precision Medicine Trial in Osteosarcoma, NCT06064682), currently open to patients either suspected of having osteosarcoma (Arm 1) or who have recurrent/metastatic osteosarcoma (Arm 2). Clinical validation of organoid-based platforms is a critical step to deploy these technologies for therapy guidance in the future. Citation Format: Rina Kuznets, Maite Calucho, Huyen T. Nguyen, Scott D. Nelson, Sarah M. Dry, Jane Yanagawa, Arun S. Singh, Joseph G. Crompton, Lauren E. Wessel, Alexander B. Christ, Nicholas M. Bernthal, Noah C. Federman, Bartosz Chmielowski, Alice Soragni. PREMOST: an organoid-based functional precision medicine trial in osteosarcoma [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 7200.