Abstract 2926: The synthetic triterpenoid CDDO-methyl ester and the rexinoid LG100268 extend survival in the KPC transgenic mouse model of pancreatic cancer

Abstract

Abstract Pancreatic cancer is the fourth leading cause of cancer-related deaths in the U.S. and is almost always fatal. While prevention offers the most promising approach for reducing the mortality of this disease, there is still a need to develop effective drugs for the prevention and treatment of pancreatic cancer. We have previously reported that the triterpenoid CDDO-methyl ester (CDDO-Me) and the rexinoid LG100268 (268) can prevent and treat experimental lung and breast cancer in rodents. These drugs also inhibit proliferation and induce apoptosis in human pancreatic cancer cells but have not been tested in vivo against pancreatic cancer. Hingorani et al have developed the autochthonous LSL-KrasG12D/+;LSL-Trp53R127H/+;Pdx-1-Cre (KPC) mouse model of pancreatic cancer. These KPC transgenic mice closely replicate the genetic mutations, clinical symptoms, and histopathology found in human pancreatic cancer. We have generated pancreatic cancer cell lines from a solid pancreatic tumor and from ascites of KPC mice. The triterpenoid CDDO-Me directly interacts with both STAT3 and IKK in these cells. As a result, CDDO-Me (0.3-1 μM) decreases constitutive IL-6 secretion, inhibits constitutive and IL-6 inducible STAT3 phosphorylation, and blocks the degradation of IKBα in cells challenged with TNFα. CDDO-Me also inhibits proliferation and induces apoptosis of these pancreatic cancer cell lines. Although the rexinoid 268 has little effect on epithelial cells in vitro, it regulates macrophages and other immune cells that drive tumorigenesis in the KPC mice. In order to test these drugs in vivo, KPC mice were fed powdered control diet or diet containing CDDO-Me (50 mg/kg diet), 268 (30 mg/kg diet) or the combination, beginning at 4 weeks of age until the mice displayed overt symptoms (cachexia, abdmonial distension) of pancreatic cancer. CDDO-Me, 268, and the combination (n = 25 per group) all significantly (P < 0.05) increased survival compared to the controls (n = 81), although only by 3-4 weeks (control 20.1 wks, CDDO-Me 23.5 wks, 268 23 wks, and CDDO-Me + 268 24.1 wks). Notably, Olive et al have recently shown that gemcitabine, the current standard of care for human pancreatic cancer even though it is only marginally effective, does not extend survival in KPC mice. These results suggest that drugs with promising in vitro effects on human pancreatic cell lines or in xenograft models should be evaluated in the challenging, yet highly relevant, KPC model before entering clinical trials and that additional drugs and drug combinations need to be developed for pancreatic cancer. Supported by the Sidney Kimmel Foundation for Cancer Research, NIH grant RO1 CA101207 and Reata Pharmaceuticals, Inc. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2926.