MedicalResearch.com Interview with:
Reeti Behera, Ph.D.
Postdoctoral fellow in the Weeraratna lab
The Wistar Institute
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Malignant melanoma is an aggressive disease and is the cause of the majority of skin cancer deaths. In particular, older individuals have a much poorer prognosis for melanoma and are more resistant to targeted therapy than compared to young individuals. A recently published study from our lab has shown that age-related changes in secreted factors in the microenvironment can drive melanoma progression and therapy resistance.
Klotho is a protein whose expression levels decreases with aging. In this study, we have shown that a decrease in klotho levels in the aged microenvironment drives melanoma aggression and therapy resistance by promoting the oncogenic signaling pathway Wnt5A. We also have shown that reconstituting klotho levels in the aged microenvironment by using rosiglitazone, an FDA-approved drug used to treat diabetes, can reduce tumor burden in aged mice. We also show that Klotho expression is decreased in therapy-resistant melanoma tumors. Reconstituting klotho levels in therapy-resistant melanoma cells by treating with rosiglitazone can inhibit Wnt5A levels and MAPK pathway. We also show that rosiglitazone can significantly decrease therapy-resistant tumor burden in the aged mice, but not in the young.
MedicalResearch.com: What should readers take away from your report?
Response: Understanding the role of the aged microenvironment in melanoma progression and therapy resistance is crucial to be able to design more effective age-specific treatment options. Klotho, a circulating serum factor, is lost during aging and this loss drives melanoma aggression by promoting Wnt5A signaling. Differential treatment option based on age can be beneficial to improve treatment outcomes.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: It is important to understand how changes in young versus aged microenvironments can influence cell fates. In our study, we see rosiglitazone reconstitutes klotho levels in the aged environment and decreases tumor burden, in old but not young mice. In the young mice, in fact, tumors grow faster in the presence of rosiglitazone. Therefore, age should be taken into account when deciding treatment options.
Dr. Weeraratna, the corresponding author, is on the Scientific Advisory Board of Phoremost Technologies
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Reeti Behera, Amanpreet Kaur, Marie R Webster, Suyeon Kim, Abibatou Ndoye, Curtis H Kugel, Gretchen M. Alicea, Joshua X Wang, Kanad Ghosh, Phil F Cheng, Sofia Lisanti, Katie Marchbank, Vanessa Dang, Mitchell Paul Levesque, Reinhard Dummer, Xiaowei Xu, Meenhard Heryn, Andrew E. Aplin, Alexander Roesch, M. Cecilia Caino, Dario C. Altieri and Ashani T Weeraratna. Inhibition of age-related therapy resistance in melanoma by rosiglitazone-mediated induction of Klotho. Clinical Cancer Research, February 2017 DOI: 10.1158/1078-0432.CCR-17-0201
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