Abstract 2585: Snail-p53 interaction inhibitor GN25 and its combination with Oxaliplatin targets both hedgehog signaling and K-ras pathway in pancreatic cancer

Abstract

Abstract Activation of hedgehog (Hh) signaling is widely observed in human cancers including pancreatic cancer (PC). Similarly, mutations in K-Ras gene is found in >80% of PC. Constitutive activation of Hh signaling component Gli in turn enhances p53 suppressor Snail. Studies from our group have revealed that p53 is further suppressed by direct binding with oncogenic K-Ras-induced Snail. Therefore in order to target combined suppressive effects of Hh signaling and K-Ras-induced snail on p53 pathway, a specific inhibitor of the p53-Snail binding (GN25) was developed. This inhibitor can induce p53 expression and functions in K-Ras-mutated cells, with no toxicity to normal cells (Oncogene 2010). Here we show that GN25 when combined with Oxaliplatin induces synergistically (combination index CI<1) enhanced growth inhibition (MTT) and apoptosis (Histone DNA ELISA and Annexin V FITC) in multiple PC cell lines (AsPC-1, Capan-2, BxPC-3 and Colo-357) irrespective of the mutational or functional status of both p53 and K-Ras. Interestingly, we found that some of the above cell lines have hyper activation of Hh signaling that results in constitutively over activation of Gli. Western blot analysis demonstrated that GN25/oxaliplatin re-activated the p53 protein and downstream effector molecules such as pro-apoptotic Bax and cell cycle regulator p21. Further analysis showed that GN25/oxalipltin interferes with the Hh signaling and suppresses Snail. In SCID mice studies in vivo, the maximum tolerated dose of GN25 was found to be 35 mg/kg i.v. In addition, it can be given in combination with oxaliplatin at 5 mg/kg i.p twice a week for two weeks. The combination studies of GN25/oxaliplatin in multiple tumor xenografts (wt-k-Ras BxPC-3 and AsPC-1 mut-p53 k-Ras) are ongoing. So far our results suggest that GN25/oxaliplatin is a strong combination against hyper activated Hh and mutant K-Ras-initiated human pancreatic cancer irrespective of mutational status of p53. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2585. doi:10.1158/1538-7445.AM2011-2585