Abstract A26: Pimozide, an antipsychotic derivative, targets the STAT signaling pathway in osteosarcoma

Objective: Osteosarcoma (OS) is the most common pediatric bone cancer worldwide with an annual US incidence of 800. Chemotherapy and surgery have resulted in a marginal increase in survival of localized OS. However, that same treatment regimen has not been as successful for improving metastatic OS, as it yields an abysmal 5-year overall survival of less than 30% in patients afflicted with the disease. There have not been new successful standardized treatment agents in the last 2 decades for OS. Current standard practice still implements the same chemotherapeutic agents: cisplatin, doxorubicin, and methotrexate. These nonspecific agents have failed to yield optimal survival in metastatic OS patients. Hence, there is a need to utilize different agents that can specifically target signaling pathways involved in the pathogenesis of OS. One such pathway that has been found to be instrumental in the pathogenesis of OS is the JAK/STAT pathway, and the antipsychotic medication pimozide appears to be able to halt OS growth through inhibiting this pathway. Herein, we investigated the effects of pimozide on OS cancer growth and elucidated its mechanistic action through STAT signaling pathway. Methods: Human OS cell lines KHOS, MG63, and SJSA cell lines and normal osteoblast cells were used in the study. The effects of pimozide on cell proliferation were assessed by hexosaminidase and clonogenicity assays. Effects of pimozide on stem cells were evaluated by colonosphere formation. Furthermore, the effect of pimozide on OS cells was evaluated by live cell fluorescent staining. Western blot was utilized to evaluate the effect on STAT protein expression. Results: Pimozide treatment resulted in a dose- and time-dependent inhibition of proliferation and colony formation in all three osteosarcoma cell lines but not in osteoblast cells. It induces caspase 3 and 7 activity. Pimozide also showed reduced live cell fluorescent staining. Pimozide significantly reduced the number and size of spheroid formation. In addition, pimozide inhibits OS stem cell marker protein CD44 expression. Moreover, pimozide treatment decreased the expression of STAT5 signaling proteins on Western blot, which suggests that pimozide inhibits OS growth through STAT signaling pathway. Conclusion: Together, these data suggest that pimozide inhibits OS cancer growth by inhibiting the STAT signaling pathway. Pimozide could serve as a potential therapeutic agent for OS. Citation Format: Pablo Angulo, Katherine Chastain, Dharmalingam Subramaniam, Shrikant Anant. Pimozide, an antipsychotic derivative, targets the STAT signaling pathway in osteosarcoma [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr A26.