Abstract 1205: Identification of a novel adjuvant therapeutic agent for obesity related pancreatic cancer

Abstract

Abstract PURPOSE: Pancreatic cancer (PC) is an aggressive disease that develops in a symptom-free manner and is usually advanced at the time of diagnosis; the overall 5 year survival rate is less than 5%. Obesity is pandemic in the US and strongly linked to higher incidence of many cancer types. Obese people are 20% more likely to develop PC. We hypothesize that high level of leptin shown by obese PC patients could increase tumor progression and drug resistance. METHODS: A panel of PC cell lines (Panc-1, BxPC-3 and MiaPaCa-2) was challenged with leptin, a specific leptin inhibitor coupled with nanoparticles (IONP-LPrA2) and various chemotherapeutic agents (Gemcitabine, Cisplatin, Paclitaxel and Sunitinib). Cell viability, proliferation and the expression levels of molecular markers were analyzed. Further, we investigated the ability of PC cells to form tumorspheres when treated with leptin and IONP-LPrA2. The number of colonies was counted and pancreatic cancer stem cells (PCSC) markers (ALDH1, CD44, CD24, ESA) and OB-R expression was assessed. PCSC markers were determined in PC tissue arrays. RESULTS: PCSC markers were expressed in obese PC patients. Leptin induced S phase progression, overexpression of Notch and PCSC markers and increased stemness and tumorigenesis of PC cells. In addition, leptin impaired the efficacy of chemotherapeutic agents on PC cells and derived tumorspheres. The inhibition of leptin signaling via IONP-LPrA2 abrogated PC growth, reduced PCSC markers expression and enhanced chemotherapeutic action by inducing apoptosis. Our data suggests that leptin signaling is essential for PC cells proliferation and survival and reduces chemotherapeutic effects. These findings are of great importance for obese PC patients which show the highest level of leptin, poor prognosis and chemotherapy outcome. LPrA2 has no toxicity and it has been shown that it does not affect health status, appetite, body weight or energy balance in mice. IONP-LPrA2 could be a novel adjuvant for PC treatment, especially for obese PC patients. Acknowledgements: this work was supported by NIH/NCI 5SC1CA138658-05 and the DOD Breast Cancer Idea Award (W81XWH13-1-0382) to RRGP; NIH/2G12RR003034-26 and U54 MSM/UAB Cancer Center Partnership. This research was also supported by facilities and support services at Morehouse School of Medicine (NIH 1C06 RR18386). Citation Format: Adriana Harbuzariu, Robin C. Garrison, Danielle S. Daley-Brown, Derrick J. Beech, Frederick D. Cason, Tia L. Harmon, Lily Yang, Ruben R. Gonzalez-Perez. Identification of a novel adjuvant therapeutic agent for obesity related pancreatic cancer. [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 1205. doi:10.1158/1538-7445.AM2015-1205