Obesity is a global pandemic that has been linked to the progression of several different cancers including: breast, pancreatic, and endometrial. The presence of excessive amounts of adipose tissue leads to increased production and circulation of leptin, a 16kDa protein adipokine. Leptin mediates several signaling pathways that are essential to angiogenesis, proliferation, migration, and cancer cell survival. Chronically high levels of circulating leptin have been shown to increase proliferation of cancer cells. Obese African American patients suffering from triple negative breast TNBC or pancreatic cancer have worse clinical outcomes than Caucasian women. Leptin could be a survival factor for these cancers, which lack specific therapies and are treated with chemotherapeutic drugs, which show several undesirable effects. Moreover, these cancers show notable development of chemoresistance and recurrence. We have designed and tested a potent leptin antagonist LPrA2 that inhibits leptin-induced proliferation, invasion, and migration of several cancer cell types. Recently, new LPrA2- like antagonists have been produced. We hypothesize that the new peptide antagonists could be more effective inhibitors of leptin signaling when treating cancer cells in comparison to LPrA2. LPrA2-like antagonists showed no toxicity in non-malignant cells. Minimally invasive and a highly metastatic TNBC and pancreatic cell lines were treated with leptin and antagonists for 24 and 48 hours. Cellometer analysis and MTT assay were used to determine cell cycle staging and cell proliferation, respectively. Additionally, apoptosis rate was determined after combinatory treatments with leptin antagonists and chemotherapeutics were applied to the cancer cells. Our results show that LPrA2-like antagonists were more effective inhibitors of leptin induced S-phase, proliferation and survival than LPrA2. Results from this investigation could lead to the development of new therapeutic regimens for obesity-related cancers, which could help eliminating the gap of cancer health disparity in African American patients.

Citation Format: Crystal C. Lipsey, Adriana Harbuzariu, Courtney Dill, Ruben R. Gonzalez-Perez. Tackling obesity-related cancer health disparity, new inhibitors of leptin signaling. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B96.