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Is Age A Primary Determinant Of Melanoma Treatment Resistance?

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Written By Kevin Kerfoot / Reviewed By Ray Spotts

Researchers with Johns Hopkins Kimmel Cancer Center  and Johns Hopkins Bloomberg School of Public Health have learned that age may cause identical cancer cells with the same mutations to behave differently. In animal and laboratory models of melanoma cells, age was a primary factor in treatment response.

The study, published in Cancer Discovery and Clinical Cancer Research, reveals new mechanisms common in aging that contribute to melanoma spread and resistance to treatment. The researchers used newer-generation inhibitors of this pathway, including drugs targeted at two arms of the BRAF pathway, and they assessed the impact of simultaneously depleting FATP2.

The researchers combined fibroblasts - cells that generate connective tissue and allow the skin to recover from injury - from people age 25 to 35 or 55 to 65 with lab-created artificial skin and melanoma cells.

The cells with the aged fibroblasts consistently upregulated a fatty acid transporter known as FATP2 and increased the uptake of fatty acids from the microenvironment in and around the tumor. When exposed to anti-cancer drugs, the melanoma cells cultured with aged fibroblasts resisted cell death, but this rarely occurred in the cells cultured with young fibroblasts.

Melanoma Cells and Response To Treatment

“Taking up a lot of fat protects melanoma cells during therapy,” says study senior author Ashani Weeraratna, Ph.D., the E.V. McCollum Professor and chair of the Department of Biochemistry and Molecular Biology at the Bloomberg School of Public Health, and co-director of the cancer invasion and metastasis program at the Kimmel Cancer Center.

“Because we are using mouse models in which the genetic components are identical, these studies point to the critical involvement of the normal surrounding cells and tell us that it is more than genes that are driving the cancer. Cancer treatment is not one-size-fits-all. Our research shows that younger patients can have very different responses to treatment than older patients. Recognizing that the age of a patient can affect response to treatment is critical to providing the best care for all patients.”

“Age was the clear driver,” added study first author Gretchen Alicea, Ph.D. “In young models, melanoma cells responded to targeted therapy initially, and targeting FATP2 had no further impact. In aged models, melanoma cells did not respond to targeted therapy until we depleted FATP2, and then the response was dramatic. When FATP2 was depleted, in all of the aged models, tumors regressed in size completely, and did not start to grow back for over two months, a significant amount of time in a mouse experiment.”

In older mice, the BRAF-targeted therapy alone worked initially, reducing tumor volume, but tumors came back in 10 to 15 days. However, when they added an FATP2 inhibitor to the targeted therapy, the tumors went away and did not come back during the 60-day period they were monitored.

The next step is development of an FATP2 inhibitor that, once proved to be effective, could be given in combination with targeted therapies to improve treatment responses, particularly for older patients. Although less common, FATP2-related treatment resistance can occur in patients under age 55 too.

Retinoic Acid To Improve Immune Response Against Melanoma

University of Colorado Cancer Center clinical trial results - published in the journal International Immunopharmacology - describe a promising strategy to remove one of melanoma's most powerful defenses.

Immunotherapies use the immune system to fight cancer, but cancers like melanoma have found ways to turn off the immune system, allowing them to resist treatments and often leading to recurrence. By adding retinoic acid to standard-of-care treatment, researchers were able to turn off myeloid-derived suppressor cells (MDSCs) that turn off the immune system, leading to more immune system activity directed at melanoma.

Retinoic acid is a well-known compound derived from the breakdown of vitamin A. It encourages cells to differentiate, transitioning from stem-like cells into the mature cells the body needs for structure and function. Retinoic acid is a common ingredient in topical acne treatments and is also used to treat acute promyelocytic cancer. Work in the McCarter lab and elsewhere showed that the form of retinoic acid known as ATRA could force MDSCs to mature, switching their function from immune suppression to immune support.

Melanoma Patients and Retinoic Acid

MDSCs are immature, undifferentiated cells that are produced in the bone marrow. When healthy, MDSCs quickly mature into cell types that aid immune function, but cancers like melanoma encourage MDSCs to remain immature, and this population of immature MDSCs turns off the immune system.

"The immune response and MDSCs are like yin and yang, balancing each other,” says Martin McCarter, MD, investigator at the CU Cancer Center and surgical oncologist at the UCHealth University of Colorado Hospital. “For example, you want the immune system to fight an infection and then you want MDSCs to shut down the immune system when the infection is gone."

"We started studying our melanoma patients and found a ton of these MDSCs in the circulation and in the tumor itself. Melanoma induces these cells to be around the tumor microenvironment. After identifying that, yes, there are a lot of these cells around, we wanted to find ways to target those MDSCs. If we could render them dysfunctional then in theory a better immune response could go forward."

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Written By:

With over 30 years of writing and editing experience for newspapers, magazines and corporate communications, Kevin Kerfoot writes about natural health, nutrition, skincare and oral hygiene for Trusted Health Products’ natural health blog and newsletters.

Reviewed By:

Founder Ray Spotts has a passion for all things natural and has made a life study of nature as it relates to health and well-being. Ray became a forerunner bringing products to market that are extraordinarily effective and free from potentially harmful chemicals and additives. For this reason Ray formed Trusted Health Products, a company you can trust for clean, effective, and healthy products. Ray is an organic gardener, likes fishing, hiking, and teaching and mentoring people to start new businesses. You can get his book for free, “How To Succeed In Business Based On God’s Word,” at www.rayspotts.com.


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