The antidiabetic drug rosiglitazone has potential as adjuvant therapy for older patients with melanoma who develop resistance to targeted therapies, according to results from a cell culture model. Rosiglitazone can inhibit the growth of melanoma in this patient population by activating the antiaging gene, klotho, which then inhibits a protein involved in resistance to targeted therapies and in metastatic growth.1
Rosiglitazone is a thiazolidinedione and acts as an insulin sensitizer.
Older patients develop melanoma more frequently, and they typically experience worse prognoses. While targeted therapies have improved overall survival compared to chemotherapy, acquired or intrinsic resistance to such treatments limits their usefulness.
Researchers treated mice with rosiglitazone, which increased klotho expression and protein levels. As a result, Wnt5A was inhibited. Wnt5A has been shown to be involved in metastatic progression and in the development of resistance to targeted therapies.
“We have already shown that age-related changes in the tumor microenvironment are accountable for the higher metastatic potential of melanoma in older patients,” explained Ashani Weeraratna, PhD, Ira Brind Associate Professor and program leader of the Tumor Microenvironment and Metastasis Program at Wistar Institute, Philadelphia, Pennsylvania, and senior author of the study.
“Our new study indicates that a differential therapeutic approach can be beneficial for older patients [with] melanoma and suggests that age should be taken into account to design better treatments for certain cohorts of patients.”
Researchers used an artificial skin reconstruction model to recapitulate the interactions of melanoma cells with young or old tumor microenvironments. This revealed reciprocal regulation among klotho, Wnt5A, melanoma cells, and the tumor microenvironment.
When researchers used rosiglitazone to increase klotho, levels of Wnt5A decreased. When researchers used rosiglitazone with targeted therapies, tumor growth decreased in both young and aged tumor microenvironment models. Interestingly, rosiglitazone used alone accelerated tumor growth in young models and inhibited tumor growth in aged models.
“We believe that there is a threshold effect whereby the levels of klotho, dictated mostly by the age of the patients, are crucial in determining whether they will benefit from this treatment or not,” said Reeti Behera, PhD, a postdoctoral researcher in the Weeraratna laboratory, and an author of the study.
Although previous studies investigated the potential of rosiglitazone as a cancer treatment, outcomes were not encouraging. Perhaps because aging and the tumor microenvironment were not considered as part of the puzzle in those studies, noted Behera.
1. Behera R, Kaur A, Webster MR, et al. Inhibition of age-related therapy resistance in melanoma by rosiglitazone-mediated induction of Klotho. Clin Cancer Res. 2017 Feb 23. doi: 10.1158/1078-0432.CCR-17-0201. [Epub ahead of print]