(P 14) EVALUATING THE COMBINATION OF DISULFIRAM AND ENZALUTAMIDE IN OSTEOSARCOMA

Objective: Despite treatment advances in primary disease, survival rates for patients with metastatic osteosarcoma (OS) have remained dismal. Recent studies have suggested Targeting aldehyde dehydrogenase 1A1 (ALDH1A1) and androgen receptor (AR) as possible targets. Both targets have FDA-approved targeted agents available that can be repurposed for used in OS.

Methods: We evaluated disulfiram, enzalutamide, or combination across a range of concentrations in primary SaOS-2 and metastatic SaOS-LM2 OS cells in vitro using cytotoxic, clonogenic, migration, and proliferation assays. Tumor cell migration was evaluated using scratch assays while proliferation was established using the Incucyte cell imaging system.

Results: Both disulfiram and enzalutamide reduce tumor cell proliferation and survival although the effect was significantly larger in response to disulfiram. We observed a biphasic effect of disulfiram treatment where low concentrations have a profoundly higher efficacy than high concentrations. Similar results were observed across assays. While the low dose combination of disulfiram and enzalutamide displayed mild additive effects, we did not observe significant differences to disulfiram monotherapy. These effects were consistently observed across assays.

Conclusion: The combination of disulfiram and enzalutamide successfully targets OS cells across multiple assays; however, these responses are driven by disulfiram, suggesting that AR inhibition may not add a benefit that is of significant enough magnitude to warrant the side effects of Enzalutamide treatment. Nevertheless, our observations suggest an underlying mechanistic interaction between the pathways that may be exploited in the future.