Abstract B41: The angiotensin receptor blocker telmisartan inhibits the growth of pancreatic ductal adenocarcinoma and improves survival

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer with a 5-year survival rate of less than 5%. PDAC is highly resistant to chemotherapy, which impels search for novel approaches for treatment. Our group has previously shown in PDAC models that the angiotensin II type 1 receptor (AT1R) blocker losartan decreases desmoplasia and solid stress, which enhances blood flow, and improves the delivery and effectiveness of cytotoxic agents (Chauhan et al, Nature Comm 2013). In contrast to losartan, which had no effects on the growth of primary PDAC, we recently found that the AT1R blocker telmisartan significantly reduces the growth of PDAC. In addition to inhibiting AT1R activity telmisartan is also a partial agonist of Peroxisome Proliferator Activated Receptor γ (PPARγ). We determined in a panel of PDAC cell lines the effects of telmisartan on cellular viability. Our findings suggest that the sensitivity to telmisartan treatment correlates with low steady-state expression of PPARγ and a mesenchymal morphology. Furthermore, telmisartan induced a transcriptional profile distinct from the response to the direct PPARγ agonist pioglitazone. In support of our correlative results, the genetic knockdown of PPARγ increased the sensitivity to telmisartan and stimulated epithelial to mesenchymal transition (e.g. decreased expression of E-cadherin, increased expression of the mesenchymal markers Snail and N-cadherin). We also tested the effects of telmisartan in orthotopically implanted and genetically engineered mouse models of PDAC. Telmisartan inhibited the growth of primary tumors, decreased the incidence of metastasis and improved mice survival. In summary, our findings show that telmisartan reduces the viability of PDAC cells with a mesenchymal morphology and low expression of PPARγ, inhibits PDAC growth and improves the survival of mice. Citation Format: Jelena Grahovac, Shiwei Han, Hao Liu, Rakesh Jain, Yves Boucher.{Authors}. The angiotensin receptor blocker telmisartan inhibits the growth of pancreatic ductal adenocarcinoma and improves survival. [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 B41.