Skin tumor study leads to topical treatment for seborrheic keratosis

Researchers have identified a potential topical treatment that allows the most common type of benign skin lesion to self-destruct, according to a study published online December 29, 2015, in the Journal of Investigative Dermatology.

The discovery originated from an investigation into the molecular mechanisms that underlie the growth of malignant vs. benign skin tumors—in this case, seborrheic keratoses (SKs).

“Our paper is the first to show that SKs are dependent on an enzyme called Akt for survival,” said the study’s lead author Victor Neel, MD, PhD, Director of Dermatologic Surgery at Massachusetts General Hospital (MGH), in Boston, MA. “Inhibition of this enzyme in SK cells causes rapid cell death while having no effect on normal skin cells. We are confident that this paper heralds the development of an effective, topical treatment for SKs.”

Despite their benign nature, most SKs have at least one oncogene mutation. However, seborrheic keratoses never become malignant. “We still don’t know why SKs resist malignant transformation, but we think studying SKs will help us identify factors that prevent benign lesions from becoming malignant,” Dr. Neel said.

The two genes most frequently mutated in SKs—PI3K and FGFR3—code for proteins that affect the activation of the Akt kinase enzyme, which prevents SK cells from undergoing apoptosis. Previous studies have found that SKs have higher levels of activated Akt than normal skin. But, until now, scientists haven’t been able to keep SK samples alive and healthy long enough to study them in the lab.

In this study, the researchers developed a reliable method of culturing the SKs, which they then tested with a panel of selective kinase inhibitors to evaluate the cells’ survival. One particular Akt inhibitor, A-44, was by far the most efficient at inducing apoptosis in cultured SK cells and in intact SK lesions.

“Within 48 hours of exposure to A-44, the SK lesions from patients completely disintegrated,” said study co-author Anna Mandinova, MD, PhD, of MGH’s Cutaneous Research Biology Center. “This effect was very specific to SK lesions, as A-44 was harmless both to normal skin cells and to malignant squamous cell carcinoma cells.”

This finding indicates an obvious therapeutic solution for SKs, which are not only unsightly but can be a nuisance for patients who have them.

“Understanding why SKs never become malignant, even though they have mutations in classic oncogenes, was the primary question we wanted to address when we started studying this skin lesion,” Dr. Neel explained. “Finding a novel inhibitor of SKs was a serendipitous byproduct of that inquiry.”

“We hope that pinpointing other mutations underlying SK development will help us understand how they resist becoming malignant, which could inform us of new ways of treating more dangerous tumors,” he added. “For example, p53 is commonly mutated both in sun-damaged skin and in cancers like squamous cell carcinoma but is never mutated in SKs.”

For now, the researchers have filed a patent application based on the study findings. They plan to continue to investigate A-44 and other compounds in order to identify the best candidate for clinical trials of a topical treatment for SKs.