Abstract
Abstract Obesity is pandemic and linked to higher incidence and poorer prognosis of several cancers, including pancreatic cancer (PC), triple-negative breast cancer (TNBC), and endometrial cancer type II (EmCa), which do not have targeted therapy. Commonly, patients suffering from these diseases are treated with chemotherapeutics. However, they develop acquired drug resistance, which are additional unmet needs. The specific mechanisms involved in obesity-related cancer are still not completely known. However, chemoresistance is related to the actions of a population of cancer cells with self-renewal capabilities, currently identified as cancer stem cells (CSC). A potential link between obesity and cancer is leptin, the major adipokine secreted by adipose tissue and cancer cells. Leptin levels are increased in obese individuals, which could increase the progression of cancer. Moreover, leptin’s actions could be detrimental to chemotherapeutic efficacy. Leptin induces Notch expression in PC, TNBC, and EmCa, which supports cell proliferation and survival, and is a potent CSC stimulator. It is hypothesized that leptin-Notch signaling is essential for cancer stemness and development of drug resistance. Our data show that leptin induces cancer cell proliferation, the progression of cell cycle, and increases cancer xenograft growth. These leptin effects were found together with a significant stimulation of CSC and reduced response to several chemotherapeutics. Remarkably, the use of a proprietary, very specific, and potent inhibitor of leptin signaling bound to iron-oxide nanoparticles, IONP-LPrA2, significantly reduced leptin-induced effects in cancer cells and xenografts, and increased the effectiveness of chemotherapeutics. LPrA2 has absolute affinity by the leptin receptor, Ob-R, which is expressed higher by cancer cells. IONP-LPrA2 theranostic properties could serve to simultaneously monitor and treat cancer by detecting primary and metastasic tumors via magnetic resonance imagining. A remarkable compelling advantage of this approach is that LPrA2 has no toxicity and does not affect health status, appetite, body weight, or energy balance in mice. Present results suggest that IONP-LPrA2 combined with chemotherapeutics could be an innovative targeted adjuvant therapy for obesity-related cancers. Supported by the National Institute on Minority Health and Health Disparities (NIMHD) of the National Institutes of Health under Award Number 5S21MD000101, and DOD W81XWH-13-1-0382; NIH/NCI 1R41CA183399-01A1; Pilot Project Award from MSM/Tuskegee University/UAB Cancer Center Partnership grant 5U54CA118638; and facilities and support services at MSM (1G12RR026250-03; NIH RR 03034 and 1C06 RR18386). Citation Format: Ruben R. Gonzalez, Adriana Harbuzariu, Danielle Daley-Brown, Tia Harmon, Viola Lanier, Sha'kayla Nunez, Ann Kurian, Crystal Lipsey. A novel adjuvant for the treatment of obesity-related cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B046.
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