Abstract 4873: Pimavanserin suppresses glioblastoma progression by modulating the Akt/FOXO/Bim signaling axis

Abstract

Abstract Glioblastoma multiforme (GBM) is a highly aggressive grade IV malignant brain tumor with an average survival time of around 15 months; and a 5-year survival rate of 5%. Drug resistance, blood brain barrier (BBB) impermeability, and drug toxicity are some caveats in treating this malignancy. Current chemotherapeutic agents fail to address these challenges. In this study, we aim to repurpose an FDA-approved anti-psychotic agent Pimavanserin Tartrate (PVT), for the treatment of GBM and further delineate its mechanism. To unravel the oncolytic effects of PVT, cytotoxicity assay on several human (SF268, SF188, SF295, U251) and murine (CT2A-Luc) GBM cell lines was performed. Our results demonstrate that PVT inhibited the growth of various GBM cells with IC50 ranging 5 to 8 µM, contrary to Temozolomide (TMZ), a standard care therapy which has an IC50 ranging 600 to 1,300 µM after 48- and 72-hours of treatment. Moreover, PVT treatment enhanced the activity of TMZ when given in combination. Pro-apoptotic proteins such as cleaved caspase-3 and Bax were upregulated by PVT treatment as evaluated confirming apoptosis to be the mode of cell death. The apoptotic cell population increased in a dose-dependent fashion, for example, 10µM PVT exhibited 70% increase in apoptosis as observed in the annexin assay. PVT treatment suppressed the phosphorylation of PI3K and Akt, and increased the expression of FOXO proteins, which are the negative downstream regulators of Akt. FOXO proteins translocate to the nucleus leading to the enhanced transcription of Bim, a pro-apoptotic protein resulting in apoptosis. Oral administration of 10mg/kg PVT significantly suppressed the growth of intracranially implanted GBM tumors without any other organ toxicity. Our observations provide a robust foundation for PVT’s anti-cancer efficacy against GBM by modulating Akt/FOXO/Bim pathway. Citation Format: Manas Yogendra Agrawal, Sharavan Ramachandran, Carson Zabel, Sanjay K. Srivastava. Pimavanserin suppresses glioblastoma progression by modulating the Akt/FOXO/Bim signaling axis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4873.