Abstract LB-B26: Novel eIF4A inhibitors target both cellular and microenvironment components in pancreatic ductal adenocarcinoma

Abstract

Abstract We are investigating the potential utility of targeting protein translation via inhibiting the translation initiation factor 4A (eIF4A) with a new class of Pateamine A derivatives to treat pancreatic ductal adenocarcinoma (PDAC). PDAC is one of the most refractory human malignancies with poor response to therapy and low survival rates. PDAC resistance to therapy is thought to comprise both cellular and microenvironment components. A key cellular aberration is thought to be the activating KRAS mutations found in over 90% of pancreatic cancers, signaling proliferation and survival. One postulated effect of KRAS mutation is to activate C-Myc, a central oncogene in PDAC, with elevated expression and high protein levels in over 40% of cases. A key microenvironment component is elevated hyaluronic acid content in the stroma of pancreatic cancers (4 to 12 times that of normal pancreatic tissues), which increases interstitial fluid pressure and is thought to impair drug perfusion efficiency, as well as the infiltration of immune cells. Here we report a promising therapeutic intervention for PDAC via targeting the eIF4A component of the translation initiation complex using a new class of Pateamine A derivatives, DMDA PatA and MZ735. Using cytotoxicity assays, immunoblotting, immunocytochemistry and confocal imaging we show activity of the Pateamine A derivatives on PDAC cell lines. Our primary data shows treatment with nanomolar concentrations of these compounds inhibits cell proliferation with IC50s ranging from 20 to 40nM for DMDAPatA and 5 to 20 nM for MZ735 in various PDAC cells. Immunoblotting shows a reduction in c-MYC, hyaluronic acid synthase HAS3, and hyaluronic acid receptor CD44 in PDAC cell lines following treatment with eIF4A targeting compounds. Finally, confocal imaging confirmed the reduction of hyaluronic acid and CD44 in the eIF4A inhibitor-treated PDAC cells. We believe Pateamine A derivatives represent a new class of anticancer agents that have the potential to address both altered cellular and microenvironment components in PDAC. Citation Format: Maryam Safari, Yu Ri Kim, Changchun Deng, Susan E. Bates. Novel eIF4A inhibitors target both cellular and microenvironment components in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B26.