Abstract A56: Targeting eIF4A dependent translation as therapeutics in pancreatic cancer

Abstract

Abstract Pancreatic cancer is one of the most aggressive cancers with no targeted therapy available. RNA translation is activated in aggressive pancreatic cancer and at the same time is also refractory to mTor inhibition. We have used a translation inhibitor for eIF4A, RNA helicase that is downstream of mTOR signaling and can be functionally targeted in pancreatic cancer. We establish that Silvestrol and its analog CR-31B showed potent anti-tumor activity in pancreatic cancer cell lines in vitro and in vivo. Silvestrol/CR-31B reduced pancreatic cancer cells and organoids growth derived from mouse model of pancreatic cancer and human patient samples in vitro. Further we identify the genome wide translational targets of Silvestrol in pancreatic cancer cell line that lacks response to mTOR signaling through loss of EIF4EBP1. Silvestrol down regulate translation of many key oncogenes and others cellular factors involved in oncogenic signaling in pancreatic cancer. Silvestrol targets were also enriched for G-quadruplex structure in their 5’UTR. With this study we establish a new mechanism of targeting pancreatic cancer cells through translation inhibition and identify more proteins as therapeutic targets that are regulated independent of mTOR signaling. Citation Format: Kamini Singh, Stefan G. Stark, Agnes Viale, Prathibha Mohan, Man Jiang, Gunnar Rätsch, Hans-Guido Wendel.{Authors}. Targeting eIF4A dependent translation as therapeutics in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A56.