Romidepsin is a Potential Therapeutic to Treat Metastatic Osteosarcoma

Abstract

Osteosarcoma is the most common primary malignant bone tumor in children, adolescents, and dogs. Lethality is due to lung metastases. Despite standard of care, patients with lung metastases have a survival rate of only 25%. Therefore, our lab studied potential therapeutics to target lung metastases. To do this, our lab repurposed already FDA-approved oncology drugs, which saves on the extensive time and cost of traditional drug discovery. Our lab also used 3-D spheroids (sarcospheres) that mimic in vivo tumors. In initial drug screens, our lab identified romidepsin, a histone deacetylase inhibitor, as a potent inhibitor of viability of highly metastatic osteosarcoma sarcospheres that was non-toxic to normal cells. Romidepsin was additive-to-synergistic with standardof- care chemotherapy and inhibited viability in a subset of patient-derived sarcospheres. This thesis therefore focused on determining the mechanism of action of romidepsin in osteosarcoma sarcospheres and the efficacy of romidepsin in a mouse model of metastatic osteosarcoma. Romidepsin either blocked growth or increased cell death in a growth phenotype dependent manner. Sarcospheres that grow slowly showed an increase in cell death, while those that grow quickly showed a cell cycle arrest. This trend differs in patient-derived sarcospheres. Though they grow slowly, only the most sensitive patient sample showed an increase in cell death. Our sarcosphere assay may be able to be used clinically to identify which patients are most likely to respond to specific drugs. In a tail vein injection mouse model of metastatic osteosarcoma, romidepsin increased survival and reduced respiratory distress in immunocompetent mice, but not in immunocompromised mice. This indicated that romidepsin may act on the immune system to have an effect. Therefore, it may be essential to use a mouse model with an intact immune system for romidepsin to decrease tumor burden. Overall, romidepsin is a potential therapeutic to treat a subset of metastatic osteosarcoma patients.