Abstract 3155: High-throughput drug repositioning identifies dinaciclib as a potent osteosarcoma inhibitor

Abstract Background: Osteosarcoma (OS) is the most common primary malignant bone tumor, predominantly affecting adolescents and young adults. Despite multimodal treatment combining chemotherapy and surgical resection, survival rates for metastatic OS remain below 20%, underscoring the urgent need for novel therapies. Recent studies implicate chromothripsis, a phenomenon of chromosomal shattering and reassembly, in OS pathogenesis, contributing to its aggressive behavior and treatment resistance. However, therapeutic options for OS have remained largely stagnant over the past two decades. Advancing our understanding of OS biology and identifying new therapeutic approaches are essential to improving outcomes for patients with metastatic and relapsed disease. Methods and Findings: We conducted a high-throughput screen of 3, 800 compounds across eight OS cell lines. Two-thirds of the drug library consists of FDA approved drugs and one-third consists of drugs in early phase clinical trials. Each compound was tested in five concentrations (1 nM to 10, 000 nM), generating over 200, 000 data points to identify active single agents. Dinaciclib, a CDK1/2/5/9 inhibitor, emerged as one of the top-performing agents, ranking in the top 0.5% based on cytotoxicity across all cell lines. Notably, clinically relevant agents Gemcitabine and Docetaxel, components of active retrieval regimens for relapsed OS, also ranked in the top 0.5%. To investigate drug synergy, combinations of Gemcitabine and Docetaxel were tested at varying molar ratios (1:10, 10:1, 1:5, 5:1, and 1:1) across the eight cell lines. The 1:10 molar ratio demonstrated the highest cytotoxicity, consistent with the clinically established 1:9 ratio. Subsequently, an iterative screen assessed the synergy of third agents with the Gemcitabine+Docetaxel regimen in the MG-63 OS cell line. Dinaciclib exhibited additive effects when layered onto this regimen, further supporting its therapeutic potential. Conclusions: This study identifies Dinaciclib as a potent inhibitor of osteosarcoma, with additive cytotoxicity when combined with the clinically relevant Gemcitabine+Docetaxel regimen. These findings, coupled with prior evidence of Dinaciclib's efficacy in reducing metastatic burden in OS patient-derived xenograft models, highlight its potential as part of a triple combination therapy. This research underscores the value of high-throughput drug repurposing in identifying innovative treatment strategies for osteosarcoma and supports further preclinical and clinical evaluation of Dinaciclib to improve outcomes for patients with metastatic or treatment-resistant disease. Citation Format: Mithun Sarangdhar, Jonah Snyder, Eric O'Brien, Brett VanCauwenbergh, Mitali Basu, Joseph Pressey, John Perentesis. High-throughput drug repositioning identifies dinaciclib as a potent osteosarcoma inhibitor [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 3155.