Blocking Leptin Receptors Slows Growth of Triple-Negative Breast Cancer

A peptide that inhibits the receptor for the obesity hormone leptin was found to block proliferation of triple-negative breast cancer cells in culture and extend the survival of mice with triple-negative breast-cancer xenografts.

Triple-negative breast cancers, which represent 10% to 20% of all mammary tumors, are characterized by an 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.

The link between this type of cancer and obesity led investigators at Temple University (Philadelphia, PA, USA) to test whether blocking the activity of the obesity hormone leptin would help to control the disease. Although leptin is a circulating signal that reduces appetite, in general, obese people have an unusually high circulating concentration of leptin. These people are resistant to the effects of leptin in much the same way that people with type II diabetes are resistant to the effects of insulin. The high sustained concentrations of leptin from the enlarged stores of fat tissue result in leptin desensitization.

To block leptin activity the investigators prepared a peptide, Allo-aca, which would block the binding of leptin to its receptor, which is expressed in 92% of cases of triple-negative breast cancer.

Results published in the February 23, 2011, online edition of the European Journal of Cancer revealed that in the MDA-MB-231 model triple-negative breast-cancer-cell line the leptin receptor antagonist peptide Allo-aca inhibited leptin-induced proliferation. In an MDA-MB-231 orthotopic mouse xenograft model, Allo-aca administered subcutaneously extended the average survival time by 80%, compared to 21% for chemotherapy. The peptide was found to be nontoxic to normal cells even up to the highest dose administered.

"Obesity increases the risk for triple-negative breast-cancer development,” said senior author Dr. Eva Surmacz, associate professor of biology at Temple University. "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. If this peptide, with its advantageous administration route and safety profile, can be developed as a drug it could be a useful addition to the existing oncology drug repertoire against various forms of cancer, including breast, brain, prostate, and colon cancers.”


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