Abstract 7554: The histone deacetylase inhibitor romidepsin is a potential therapeutic for metastatic osteosarcoma

Abstract Osteosarcoma predominately affects adolescents, young adults, and canines. For human patients, the five-year survival rate of those with detectable lung metastases is only 30% while most canine patients with metastatic disease die within 1-2 years. Standard therapy is not effective for this patient group, so it is therefore necessary to identify novel therapies that target the progression of lung metastases. Our lab previously screened 114 FDA-approved anti-cancer drugs to identify agents that decrease the growth of 3D spheroids (sarcospheres) generated from highly metastatic osteosarcoma cell lines. The top hits included both histone deacetylase inhibitors (HDIs) that were tested. In follow-up experiments measuring potency on sarcospheres and toxicity on non-transformed cells, romidepsin was the top hit of the 114-drug panel as well of the two additional FDA-approved HDIs and seven HDIs that are in clinical oncology trials. Our goal was therefore to further evaluate romidepsin as a potential therapy for metastatic osteosarcoma. Romidepsin potently decreased viability in sarcospheres from established highly metastatic osteosarcoma cell lines (relative ED50s = 3-36nM). About 50% of the patients (both canine and human) had similar responses to romidepsin (relative ED50s = 1- 18nM) suggesting that those patients might be good candidates for romidepsin therapy. This includes patients who had been heavily pretreated with standard-of-care osteosarcoma chemotherapeutics. Mechanistically, romidepsin blocks proliferation and causes a G2/M cell cycle arrest in fast growing sarcospheres (143B and MG63.3) while in slow growing sarcospheres (LM7 and K7M2) where primarily induces cytotoxicity and there is no cell cycle arrest. Patient-derived sarcospheres are slow growing, so we predict that the primary mechanism will be cytotoxicity. Using a tail vein injection model of osteosarcoma lung metastases, romidepsin dose dependently prolonged survival and reduced the area and number of lung metastases in immunodeficient mice injected with 143B cells and a syngeneic model using K7M2 cells. Romidepsin will be evaluated in mice with metastases from patient-derived cells and if effective, will be repurposed for canine and human clinical trials to improve outcomes in metastatic osteosarcoma without the associated costs and extensive timeframe of traditional drug discovery. Citation Format: Emily E. Seiden, Spencer M. Richardson, Shrey Ramnath, Tia Whiteside, Kathryn L. Coy, Anthony L. Sinn, Maegan L. Capitano, Karen E. Pollok, Chris D. Collier, Ed M. Greenfield. The histone deacetylase inhibitor romidepsin is a potential therapeutic for metastatic osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7554.