Abstract 4807: Pimavanserin suppresses pancreatic tumor growth and resistance to gemcitabine by inhibiting Akt/Gli1 signaling

Abstract

Abstract Despite major advances in cancer treatment, pancreatic cancer is still incurable and the treatment outcomes are limited. In the current study, we evaluated the anti-cancer effects of pimavanserin tartrate (PVT), a drug used for the treatment of Parkinson’s disease psychosis. Our observations indicated that, PVT significantly suppressed the proliferation of pancreatic cancer cells by inducing apoptosis without exerting any cytotoxic effects in normal human pancreatic ductal epithelial (HPDE-6) cells. The colony forming ability of pancreatic cancer cells was significantly inhibited with PVT treatment. Anti-proliferative and apoptosis inducing effects of PVT were mediated by the inhibition of pAkt (Ser473), Akt, Gli1, Oct-4, SOX-2, NANOG and c-Myc. Akt and Oct-4 inhibition by PVT treatment was further validated by immunofluorescence analysis. Moreover, PVT inhibited the formation of tumorspheres in PANC1 pancreatic cancer cells. Pharmacologically inhibiting or genetically knocking out Akt or Gli1 enhanced the growth suppressive effects of PVT in pancreatic cancer cells. Subsequently, we evaluated the effects of PVT in gemcitabine resistant cells. Our results demonstrated that, PVT reduced the survival of MIAPaCa2 gemcitabine resistant cells in a concentration and time-dependent manner. Further mechanistic analysis indicated that, PVT suppressed the phosphorylation of Akt at Ser 473 and inhibited the expression of Gli1, Oct-4 and c-Myc in MIAPaCa2 gemcitabine resistant cells. Moreover, PVT increased the cleavage of caspase-3 and PARP as an indicator of apoptosis. Oral administration of PVT suppressed BxPC3 tumor xenografts by 50% in athymic nude mice. In another in vivo experiment, PVT treatment inhibited the growth of orthotopically implanted PANC1 tumors by 75%. Chronic administration of PVT did not exhibit any general signs of toxicity or behavioral side effects in mice. Taken together, our results indicate that pancreatic tumor growth suppression by PVT is orchestrated by inhibition of Akt/Gli-1 signaling. Since PVT is already available in the clinic with an established safety profile, our results will accelerate its clinical development for the treatment of patients with pancreatic cancer. Citation Format: Sharavan Ramachandran, Sanjay K. Srivastava. Pimavanserin suppresses pancreatic tumor growth and resistance to gemcitabine by inhibiting Akt/Gli1 signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4807.