Abstract 3262: Notch signaling pathway-targeted therapy suppresses tumor progression and prevents metastatic spread in pancreatic cancer
Authors: Yabuuchi Shinichi , de Wilde Roeland F. , Campbell Nathaniel , Oliveira Elizabeth De , Rasheed Zeshaan , Maitra Anirban , Rajeshkumar N.V. 
Published: August 2012

Background: Pancreatic ductal adenocarcinoma (PDA) has the highest mortality rate of any cancer type. The 5-year survival rate of 5% remained largely unchanged in the last three decades. The paucity of breakthroughs in treatment regimens and continued poor survival demonstrates an acute need for improvement in therapy for this lethal malignancy. Mounting evidence suggest that sustained re-activation of Notch signaling pathway contributes to the initiation, progression and maintenance of PDA. Recently, Notch signaling has been linked to the viability of putative tumor initiating cancer stem cell populations in pancreatic cancer. PF-03084014 is a selective γ-secretase inhibitor developed by Pfizer. The present study was conducted to determine the effect of PF-03084014 monotherapy and in combination with gemcitabine (GEM) to suppress tumor progression and prevent metastatic spread in preclinical models of pancreatic cancer. Methods: NOTCH-1 gene expression was determined in a panel of 30 human pancreatic cancer xenografts by Affymetrix gene array. We investigated the efficacy of PF-03084014 and in combination with GEM in subcutaneously (s.c) implanted as well as orthotopic models of pancreatic cancer. We also determined the treatment effect on putative pancreatic cancer stem cell (CSC) populations. TUNEL and Ki-67 staining were performed to determine whether the therapy induce apoptosis and suppresses tumor cell proliferation. Results: A combination of PF-03084014 and GEM is highly effective in producing durable tumor regression compared to GEM in subcutaneously implanted pancreatic cancer xenografts. Tumor re-growth curves plotted after 4 weeks of drug treatment demonstrate that the effect of the combination therapy is longer lasting than that of GEM. Notably, in a highly aggressive Panc265 orthotopic model, PF-03084014 and GEM combination was effective in controlling the primary tumor growth as well as preventing metastatic dissemination to organs as compared to GEM treatment. Flow cytometry of sorted tumor cells from Panc215 (after 4 weeks of treatment) showed that GEM treatment was not capable of diminishing the CSC pool as compared to the vehicle treated mice. However, PF-03084014 alone, and the combination of GEM with PF-03084014 resulted in a 3.72 and 3.04-fold decrease in CD24+CD44+ tumor cells compared with GEM treatment, respectively. TUNEL and Ki-67 staining demonstrated that combination therapy induced apoptosis and suppresses cell proliferation. Conclusions: The findings presented here provide strong rationale for the clinical investigation on notch inhibition as a chemotherapeutic strategy to combat pancreatic cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3262. doi:1538-7445.AM2012-3262