Abstract 3083: A novel hedgehog signaling inhibitor for targeting pancreatic ductal adenocarcinoma

Abstract

Abstract Sonic Hedgehog (Shh) signaling is deregulated in pancreatic cancer and can drive tumor onset and progression. Previous attempts to block Shh signaling used Smoothened (Smo) inhibitors, which target canonical Shh signaling. These approaches met with limited success, due to development of resistance, and contributions from non-canonical, Smo-independent signaling pathways that operate within tumor epithelial cells. Here, we show that Hedgehog acyltransferase (Hhat), the enzyme responsible for palmitoylation of Shh, is a novel target for inhibition of Shh signaling in human and mouse pancreatic cancer cells and tumors. TDI-003410, a small molecule inhibitor of Hhat recently developed by our group, reduced proliferation of AsPC1 cells, a human pancreatic cancer cell line, in vitroand in subcutaneous xenografts in mice in vivo. The mechanism is via induction of a G2/M cell cycle arrest leading to apoptosis. We next used cell lines isolated from tumors formed in KPC (K-RasG12D/p53R172H) mice, a genetically engineered mouse model of pancreatic cancer.TDI-003410 inhibited the growth of KPC cell linesand also reduced Gli1 levelsin vitro. Neither LDE225, a Smo inhibitor, nor SAG, a Smo activator, had any effect on KPC cell proliferation or Gli1 levels in vitro. In orthotopic xenografts using KPC cells implanted into the pancreas, TDI-3410 treatment significantly reducedin vivotumor burden. No significant changes in CD31 or Trichrome (collagen) stainingwith TDI-3410 were detected in KPC orthotopic tumor tissue. However, Gli-1 levels in tumor tissue from TDI-3410 treated mice were significantly reduced compared to the vehicle controls. These findings provide proof of concept for the potential therapeutic efficacy of Hhat inhibition in pancreatic cancer. The concept of using an Hhat inhibitor is unique: Hhat is a novel target that hits upstream, directly at hedgehog ligands. This approach can inhibit both canonical and non-canonical (Smo-independent) as well as autocrine and paracrine Shh signaling. Citation Format: Atul Khire, Yi Zhong, Kalpana Rajanala, Christine Iacobuzio-Donahue, Marilyn D. Resh. A novel hedgehog signaling inhibitor for targeting pancreatic ductal adenocarcinoma [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 3083.