Anti-aging gene identified as a promising therapeutic target for older melanoma patients

February 23, 2017, The Wistar Institute

Scientists at The Wistar Institute have shown that an anti-diabetic drug can inhibit the growth of melanoma in older patients by activating an anti-aging gene that in turn inhibits a protein involved in metastatic progression and resistance to targeted therapies for the disease. The study was published online in Clinical Cancer Research.

Even more than other types of cancer, is a disease of aging, with older patients more frequently diagnosed with the disease and having a worse prognosis. Targeted therapies have brought benefits in terms of overall survival compared to chemotherapy but they are limited by intrinsic or acquired resistance. Wistar scientists have previously shown that age-related changes in the —or the surrounding area where tumor cells crosstalk with normal and immune cells—can drive melanoma progression and therapy resistance. They have also discovered that a protein named Wnt5A promotes metastatic progression, resistance to therapy and poorer prognosis, and one of the ways in which it is regulated is by the anti-aging protein Klotho. The new study shows that treating mice with a drug that promotes Klotho expression reduces the levels of Wnt5A and decreases the growth of therapy-resistant melanoma in aged mice but, importantly, not in young mice.

"We have already shown that age-related changes in the tumor microenvironment are accountable for the higher metastatic potential of melanoma in older patients," said Ashani Weeraratna, Ph.D., Ira Brind Associate Professor and program leader of the Tumor Microenvironment and Metastasis Program at Wistar and lead author of the paper. "Our new study indicates that a differential therapeutic approach can be beneficial for in melanoma and suggests that age should be taken into account to design better treatments for certain cohorts of patients."

Weeraratna's team used an artificial skin reconstruct model to recreate the interactions of melanoma cells with either a young or aged tumor microenvironment. They observed an intricate reciprocal regulation between Klotho, Wnt5A, , and the tumor microenvironment. They also showed that they could manipulate Klotho expression pharmacologically using the anti-diabetic drug rosiglitazone, which resulted in decreased levels of Wnt5A. Importantly, while using rosiglitazone in conjunction with targeted therapy reduced in both young and aged pre-clinical models, using rosiglitazone alone accelerated tumor growth in young models, while inhibiting it in aged ones.

"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, Ph.D., a postdoctoral researcher in the Weeraratna lab and first author of the study. "Previous studies had tested the use of rosiglitazone for cancer treatment, but the outcome was not encouraging. I think they may have been missing a piece of the puzzle, by not considering aging and the microenvironment."

This research lays the foundation for the development of promising adjuvant therapy for older melanoma patients. More studies will be needed to confirm the benefits in human subjects. Klotho is a secreted protein that can be measured in the serum of patients and this can help in determining which patients would benefit from rosiglitazone therapy and would be eligible for further studies.

Explore further: Aging impacts therapeutic response of melanoma cells

Related Stories

Aging impacts therapeutic response of melanoma cells

April 4, 2016
Cancer risk increases with one's age as accumulated damage to our cells and chronic inflammation occur over time. Now, an international team of scientists led by The Wistar Institute have shown that aged tumor cells in melanoma ...

Researchers identify how 'phenotype switching' can make melanoma become metastatic and resistant to drugs

October 18, 2013
(Medical Xpress)—One of the challenges of understanding cancer is trying to determine the mechanisms that drive metastasis, or the process by which tumor cells are able to spread throughout the body. In order to investigate ...

Study finds 'sweet spot' where tissue stiffness drives cancer's spread

February 21, 2017
In order for cancer to spread, malignant cells must break away from a tumor and through the tough netting of extracellular matrix, or ECM, that surrounds it. To fit through the holes in this net, those cancerous cells must ...

Immune and targeted therapies with radiation therapy improves outcomes for melanoma brain metastases patients

September 21, 2016
Brain metastases are one of the most common complications of advanced melanoma, requiring multidisciplinary management. Patients who are diagnosed with these metastases have an expected median survival of only 4 to 5 months. ...

Researchers discover mechanism leading to BRAF inhibitor resistance in melanoma

June 19, 2015
The development of targeted therapies has significantly improved the survival of melanoma patients over the last decade; however, patients often relapse because many therapies do not kill all of the tumor cells, and the remaining ...

Estrogen signaling impacted immune response in cancer

October 17, 2016
While the role of estrogen signaling in tumor development is well understood in breast and ovarian cancer, its role in anti-tumor immunity has not been extensively studied. However, new research from The Wistar Institute ...

Recommended for you

Revealing the molecular mystery of human liver cells

October 22, 2018
A map of the cells in the human liver has been created by University Health Network Transplant Program and University of Toronto researchers, revealing for the first time differences between individual cells at the molecular ...

New tool gives deeper understanding of glioblastoma

October 22, 2018
Researchers in the lab of Charles Danko at the Baker Institute for Animal Health have developed a new tool to study genetic "switches" active in glioblastoma tumors that drive growth of the cancer. In a new paper in Nature ...

RNA thought to spread cancer shows ability to suppress breast cancer metastasis

October 22, 2018
Researchers at The University of Texas MD Anderson Cancer Center have discovered that a form of RNA called metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) appears to suppress breast cancer metastasis in mice, ...

Targeting a hunger hormone to treat obesity

October 22, 2018
About 64 per cent of Canadian adults are overweight or obese, according to Health Canada. That's a problem, because obesity promotes the emergence of chronic diseases such as type 2 diabetes, heart disease and some cancers.

New drug combination destroys chemo-resistant blood cancer

October 22, 2018
Researchers from The Ottawa Hospital and the University of Ottawa have developed a promising targeted strategy to treat chemotherapy-resistant acute myeloid leukemia (AML) and a diagnostic test to determine which AML patients ...

Major trial shows targeted drug extends breast cancer survival

October 22, 2018
Combining a targeted drug with hormone therapy substantially extends survival for women with advanced breast cancer, a major clinical trial has found.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.