Abstract 3540: Targeting obesity-related cancer progression with novel leptin receptor antagonists

Abstract

Abstract Obesity is a global health issue that has been identified as a risk factor for several types of cancer. High levels of body fat and circulating leptin are typical identifiers of obesity in humans and animals. Leptin is a 16kD protein hormone which is secreted by adipocytes, and maybe secreted from cancer cells, that functions to control satiation via leptin receptor binding. However, obese individuals often develop “leptin resistance”, which is a mechanism that leads to the accumulation of excess leptin. Increased binding of leptin to its receptor (OB-R) due to leptin resistance has been associated with disease progression and poor prognosis in human cancers. Our group has previously shown that leptin-mediated cancer cell proliferation is inhibited by the LPrA2 (leptin peptide receptor antagonist 2). We have prepared novel leptin antagonists and tested their ability to block leptin-induced survival and chemoresistance to Paclitaxel (TAX) and Gemcitabine (GEM) in cancer cells and derived tumorspheres (pancreatic: PANC-1, MiaPaca2 and triple negative breast cancer: MDA-MB231 and MDA-MB468). Western blot protein analyses showed the ability of the antagonists to specifically inhibit leptin-induced phosphorylation of STAT3, and expression of cyclin D, and Notch1 in cancer cells. Additionally, potential toxicity of antagonists was tested using MTT assay with concentrations up to 100X higher than the effective dose in non-malignant breast cells (MCF-10A). Data generated show no toxicity of the novel antagonists in vitro. Leptin-induced proliferation of breast cancer and pancreatic cancer cells (120-160%) was significantly inhibited by the novel antagonists. In addition, leptin-mediated progression of S-phase was also reduced by the antagonists. Leptin increased TAX and GEM chemoresistance in cells and tumorspheres that were efficiently inhibited by the antagonists. These data suggest that the new antagonists could be equally or more effective than LPrA2 for adjuvant treatment of cancer. Acknowledgements: This work has been supported by Pilot Project Award from MSM/Tuskegee University/UAB Cancer Center partnership grant 5U54CA118638; PC SPORE Grant from UAB to RRGP, and facilities and support services at Morehouse School of Medicine (1G12RR026250-03; NIH RR 03034 and 1C06 RR18386). Citation Format: Crystal C. Lipsey, Adriana Harbuzariu, Ruben R. Gonzalez-Perez. Targeting obesity-related cancer progression with novel leptin receptor antagonists [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3540. doi:10.1158/1538-7445.AM2017-3540