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Melanoma Cells Grow More Aggressive with Age

Aged tumor cells in melanoma tend to be metastatic and more resistant to treatment compared with younger tumor cells, according to an international team led by researchers out of The Wistar Institute in Philadelphia.

The findings, which appear in the journal Nature, suggest that antioxidants may serve as a better treatment strategy for older patients with melanoma. While multiple factors may contribute, Ashani Weeraratna, PhD, associate professor in the Tumor Microenvironment and Metastasis Program at Wistar, and colleagues, pinpointed age-related changes that occur in the microenvironment of tumor cells. The researchers used dermal fibroblasts from healthy donors 25-35 years of age or from donors 55-65 years of age to understand what factors contribute to the difference in melanoma progression in aging cell populations.

A secreted factor sFRP2 was present in aging cells, the study found. SFRP2 regulates another protein called β-catenin that normally blocks the invasion of melanoma cells. In addition, β-catenin loss has been shown to promote oxidative stress in some cell types. The researchers showed that in an aged microenvironment, there are fewer scavengers of free oxygen radicals, leading to more activity of reactive oxygen species (ROS). At the same time, the age-induced loss of beta-catenin renders melanoma cells less capable of dealing with ROS, resulting in a genetically unstable tumor.

Treatment resistance experienced by older melanoma patients was found with increased activity of ROS and decreased levels of β-catenin, both contribute to increased resistance to treatment with drugs that inhibit BRAF, which is mutated in approximately half of all cases of melanoma. An antioxidant called N-acetylcysteine (NAC) killed melanoma cells in aged dermal fibroblasts, they report.

New Patch Delivers Anti-PD-1 Antibodies Directly to Skin Cancer

A new patch embedded with microneedles may deliver anti-PD-1 antibodies directly to the site of melanoma, according to a study in Nano Letters. In animal studies, the technique more effectively targeted melanoma than other immunotherapy treatments.

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“We need to treat AK because whether you consider it a precancerous lesion or the earliest stage of squamous cell carcinoma, there’s overwhelming evidence that actinic keratosis eventually develops into squamous cell carcinoma in situ and then eventually into squamous cell carcinoma invasive.”

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Recently, cancer immunotherapy research has focused on using anti-PD-1 antibodies to prevent cancer cells from tricking T cells, but this poses several challenges, according to study author Chao Wang, a postdoctoral researcher in the joint biomedical engineering program at North Carolina State University and the University of North Carolina at Chapel Hill. “First, the anti-PD-1 antibodies are usually injected into the bloodstream, so they cannot target the tumor site effectively. Second, the overdose of antibodies can cause side effects such as an autoimmune disorder,” he says.

To address these challenges, the researchers developed a patch that uses microneedles to deliver anti-PD-1 antibodies locally to the skin tumor. The microneedles are made from hyaluronic acid. The anti-PD-1 antibodies are embedded in nanoparticles, along with glucose oxidase. These nanoparticles are then loaded into microneedles, which are arrayed on the surface of a patch. When the patch is applied to a melanoma, blood enters the microneedles. The glucose in the blood makes the glucose oxidase produce acid, which slowly breaks down the nanoparticles. As the nanoparticles degrade, the anti-PD-1 antibodies are released directly into the tumor.

The researchers tested the technique against melanoma in a mouse model. The microneedle patch loaded with anti-PD-1 nanoparticles was compared to treatment by injecting anti-PD-1 antibodies directly into the bloodstream and to injecting anti-PD-1 nanoparticles directly into the tumor. After 40 days, 40 percent of the mice who were treated using the microneedle patch survived and had no detectable remaining melanoma, compared to a zero percent survival rate for the control groups, the study showed.

The researchers also created a drug cocktail, consisting of anti-PD-1 and anti-CTLA-4 antibodies. Using this combination in the microneedle patch, 70 percent of the mice survived and had no detectable melanoma after 40 days.

Can Sunbathing Lead to a Longer Life?

New research, published in the Journal of Internal Medicine, suggests that a decrease in heart disease and noncancer/non-heart disease deaths may explain the paradox why sunbathers tend to live longer than their shade-seeking counterparts.

An analysis of information on 29,518 Swedish women who were followed for 20 years revealed that longer life expectancy among women with active sun exposure habits was related to a decrease in heart disease and noncancer/non-heart disease deaths, causing the relative contribution of death due to cancer to increase. Whether the positive effect of sun exposure demonstrated in this observational study is mediated by vitamin D, another mechanism related to UV radiation, or by unmeasured bias cannot be determined. Additional research is warranted.

FDA Approves PMA Supplement for MelaFind from STRATA Sciences

The FDA recently approved STRATA Skin Sciences, Inc.’s PMA supplement for the MelaFind System. The FDA approved MelaFind’s use of the “classifier score data”, a quantitative result derived by the MelaFind System that can be beneficially used in conjunction with the previously approved binary result (yes/no) from the instrument. The Classifier Score offers dermatologists more complete information to aid in their decision to biopsy an ambiguous skin lesion.

STRATA developed a reader study protocol in conjunction with the FDA and conducted a live study with 160 board-certified dermatologists at the Fall Clinical Dermatology Conference that took place in October 2015. This study measured the impact of the MelaFind binary result plus classifier score information on a dermatologist’s decision to biopsy suspicious pigmented skin lesions.

Results showed average sensitivity (ability to detect disease) increased from 76 percent before the utilization of MelaFind to 92 percent following the use of MelaFind. Average specificity (ability to rule out disease) increased from 52 percent before to 79 percent after MelaFind utilization. These statistically significant results satisfied the requirements for approval of the PMA Supplement. The full results of the study are being prepared for submission to a peer-reviewed publication.

The FDA also agreed that STRATA could terminate the previously required Post Approval Study for MelaFind that had been underway since 2012.

PD-1 Blockers May Not Work for All Melanoma Patients

New research suggests that patterns of gene mutations and expression in a melanoma tumor before starting anti-PD-1 immunotherapy may forecast whether the treatment will work. The study is published online in the journal Cell.

Dermatologist Roger Lo, MD, the study’s lead author and a UCLA Jonsson Comprehensive Cancer Center member, analyzed melanoma tumors from patients before anti-PD-1 therapy. Samples were divided into two groups— patients who responded or failed to respond to treatment. They then sought to assess the “on” or “off” status of a tumor cell’s genes by detecting their mutational rates and/or gene expression levels.

The degree to which genes and groups of genes are turned on or off has a major influence on whether a tumor will respond to or resist a drug, says Dr. Lo. From other computational experiments, the investigators found that tumors with more mutations were associated with longer patient survival after anti-PD-1 therapy. The team also found that another common therapy for advanced melanoma that utilizes small molecules to turn off a specific pathway activated by the BRAF mutation can induce processes inside a tumor similar to those associated with anti-PD-1 resistance.

Despite the potential of BRAF and PD-1 targeted combination therapies to deliver further improvements in patient survival, future development of this approach should consider the altered immune microenvironment brought on by BRAF targeted therapy, the researchers note. n

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