title: Efficacy of a leptin receptor antagonist peptide in a mouse model of triple-negative breast cancer.
abstract: Triple-negative breast cancers, which represent 10-20% of all mammary tumours, are characterised by the aggressive phenotype, are often found in younger women and have been associated with poor prognosis. Obesity increases the risk for triple-negative breast cancer development. Because triple-negative breast cancer patients are unresponsive to current targeted therapies and other treatment options are only partially effective, new pharmacological modalities are urgently needed. Here we examined if the leptin (obesity hormone) receptor is a viable target for the treatment of this cancer subtype. In human triple-negative breast cancer tissues, the leptin receptor was expressed in 92% (64/69) and leptin in 86% (59/69) of cases. In a model triple-negative breast cancer cell line MDA-MB-231, the leptin receptor antagonist peptide Allo-aca inhibited leptin-induced proliferation at 50 pM concentration. In an MDA-MB-231 orthotopic mouse xenograft model, Allo-aca administered subcutaneously significantly extended the average survival time from 15.4 days (untreated controls) to 24 and 28.1 days at 0.1 and 1mg/kg/day doses, respectively. In parallel, conventional treatment with 1mg/kg/day intraperitoneal cisplatin prolonged the average survival time to 18.6 days, while administration of 20mg/kg/day oral Tamoxifen (negative control) had no significant survival effects relative to controls. In normal CD-1 mice, Allo-aca produced no systemic toxicity up to the highest studied subcutaneous bolus dose of 50mg/kg, while, as expected, it induced a modest 6-10% body weight increase. Our results indicate that leptin receptor antagonists could become attractive options for triple-negative breast cancer treatment, especially in the obese patient population.
authors.affiliation: Department of Biology, Temple University, Philadelphia, PA 19122, USA. otvos@temple.edu
authors.forename: Laszlo
authors.initials: L
authors.lastname: Otvos
authors.forename: Ilona
authors.initials: I
authors.lastname: Kovalszky
authors.forename: Mirko
authors.initials: M
authors.lastname: Riolfi
authors.forename: Rita
authors.initials: R
authors.lastname: Ferla
authors.forename: Julia
authors.initials: J
authors.lastname: Olah
authors.forename: Andras
authors.initials: A
authors.lastname: Sztodola
authors.forename: Kaushik
authors.initials: K
authors.lastname: Nama
authors.forename: Annamaria
authors.initials: A
authors.lastname: Molino
authors.forename: Quirino
authors.initials: Q
authors.lastname: Piubello
authors.forename: John D
authors.initials: JD
authors.lastname: Wade
authors.forename: Eva
authors.initials: E
authors.lastname: Surmacz
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D055104:Infusions, Subcutaneous; D020738:Leptin / Q000378:metabolism; D051379:Mice; D009368:Neoplasm Transplantation; D009765:Obesity / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry; D054411:Receptors, Leptin / Q000037:antagonists & inhibitors*; D013629:Tamoxifen / Q000494:pharmacology; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D020738:Leptin; D010455:Peptides; D018719:Erb-b2 Receptor Tyrosine Kinases; D054411:Receptors, Leptin; D013629:Tamoxifen