Abstract 2819: Targeting inflammation and pancreatitis blocks tumor-initiating stem cells and pancreatic cancer progression
Authors: Mohammed Altaf , Janakiram Naveena B. , Madka Venkateshwar , Brewer Misty , Ritchie Rebekah L. , Lightfoot Stan , Kumar Gaurav , Sadeghi Michael , Patlolla Jagan Mohan R , Yamada Hiroshi , Cruz-Monserrate Zobeida , Houchen Courtney W. , Steele Vernon E. , Rao Chinthalapally V. 
Published: August 2015

Pancreatic cancer (PC) is a deadly disease with the lowest survival of all cancers. Recent development of genetically engineered mouse models (GEMs) for PC that recapitulate human disease progression has enabled development of new strategies to delay or inhibit pancreatic cancer and testing of experimental interventions in preclinical trials. Pancreatic tumor-initiating or cancer stem cell (CSC) populations contribute to tumor growth, metastasis, and resistance to therapy. We first found that expression of the CSC marker DclK1 occurs at an early stage of PC in both early and late pancreatic intraepithelial neoplasia (PanINs) and increases as the disease progresses. Genome-wide next generation sequencing of pancreatic ductal adenocarcinoma (PDAC) from GEMs revealed significantly increased DclK1 along with inflammatory genes. Genetic ablation of cyclo-oxygenase (COX)-2 decreased the DclK1 in GEMs. Induction of inflammation with cerulein induced pancreatitis in GEMs increased DclK1, and Dclk1 was reduced by the novel anti-inflammatory dual COX/5-lipoxygenase (5-LOX) inhibitor licofelone. We investigated the long term pharmacologic inhibitory efficacy of licofelone on PDAC in vivo using a GEM model. GEM (n = 86) and wild type mice (n = 24) were fed a diet containing different doses of licofelone for 300 days and evaluated for formation of PanINs and for their progression to PDAC. Dietary licofelone at tested doses significantly inhibited the incidence of PDAC (60-90%; p&lt;0.0001) with a profound suppression of carcinoma in situ (35-60%; p&lt;0.001) in male and female GEMs. Licofelone caused a dose-dependent suppression of pancreatic tumor COX-2 and 5-LOX activities and modulated miRNAs for inflammation markers and CSCs, including DclK1, CD133, CD44, and Lgr5 (p&lt;0.001) in correlation with the PDAC inhibition. Licofelone also inhibited inflammation-induced CSCs in vitro. These studies provide the first evidence that modulation of inflammation with a dual COX-LOX inhibitor effectively blocks CSCs and inhibits pancreatic tumorigenesis. In summary, our preclinical data indicate that licofelone has potential for chemoprevention of PC and should be evaluated in other PDAC models in anticipation of future clinical trials. {Supported by NCI-CN-53300}

Citation Format: Altaf Mohammed, Naveena B. Janakiram, Venkateshwar Madka, Misty Brewer, Rebekah L. Ritchie, Stan Lightfoot, Gaurav Kumar, Michael Sadeghi, Jagan Mohan R Patlolla, Hiroshi Yamada, Zobeida Cruz-Monserrate, Courtney W. Houchen, Vernon E. Steele, Chinthalapally V. Rao. Targeting inflammation and pancreatitis blocks tumor-initiating stem cells and pancreatic cancer progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2819. doi:10.1158/1538-7445.AM2015-2819