A NOVEL APPROACH FOR MELANOMA TREATMENT

Drugs that induce a self-inflicted cell-death process called ferroptosis could be used to target de-differentiated melanoma cells, thereby increasing the efficacy of both targeted and immune therapies, researchers suggest.

"Ferroptosis is much more recently discovered and fundamentally different from apoptosis," Dr. Thomas Graeber of the University of California, Los Angeles told Reuters Health by email. "Ferroptosis is mechanistically founded on insufficient anti-oxidant protection of cellular lipid membranes, whereas the death pathway of apoptosis is mechanistically linked to the mitochondria of the cell."

"Ferroptosis is also implicated in neural degeneration diseases," he added.

As reported online April 12 in Cancer Cell, while investigating the mechanisms underlying poor treatment response to existing melanoma therapies, Dr. Graeber and his colleagues identified four melanoma subtypes, each related to a stage in the normal development (or differentiation) of the cells.

The team also found that cell subtypes that de-differentiated - meaning they reverted back to a less mature cell - were sensitive to ferroptosis.

De-differentiation is a resistance "escape pathway" for cells treated by immunotherapy or kinase inhibitors, Dr. Graeber explained. "Thus, drugs that target or prevent de-differentiation have a rational basis for being combined with these new standards of care."

Analyses of screened compounds in a pharmacogenomics database revealed two classes of drugs that induce ferroptosis: drugs that target the system xc- cystine/glutamate antiporter (e.g., erastin), and drugs that target the lipid peroxidase GPX4 (e.g., RSL-3), he said.

"System xc- and GPX4 are two components of the ferroptosis pathway," he continued. "There is active research to improve these drugs (to) make them clinically useful."

Going forward, he said, "We will work to delineate the underlying mechanism of ferroptosis in melanoma cells so that we can better manipulate them with additional drug classes."

"We are putting emphasis on combinations of drugs that work together synergistically to target the susceptibilities of melanoma cells," he concluded.

Melanoma experts commented on the work in emails to Reuters Health.

Dr. Keith Flaherty, Director of Clinical Research, Cancer Center at Massachusetts General Hospital in Boston said, "The work extends our understanding of melanoma's ability to exist in discrete states along the spectrum of primordial precursor cells to melanocyte-like."

"The major discovery relates to the screening of several dozen drugs to identify that those that uniquely target each state," he said. "These findings set the stage for clinical trials aiming to target the de-differentiated cells that underlie resistance to both targeted and immunotherapies in melanoma."

Dr. Philip Friedlander, Director of the Melanoma Medical Oncology Program at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai in New York City, said, "The work presented is very intriguing and hypothesis generating."

"Further investigation is needed to determine in the clinical setting with stage IV melanoma patients if the induction of ferroptosis improves the efficacy of immunotherapy and of anti-BRAF targeted therapy," he said.

"Another question is how to best induce ferroptosis clinically," he added. "Clinical trials are needed to assess the safety and efficacy of such an approach, and designing initial trials to include pharmacodynamic assessments and serial tumor biopsies will be important to better understand mechanisms of action and of resistance development."

Dr. Douglas Johnson, Clinical Director, Melanoma, Vanderbilt-Ingram Cancer Center in Nashville, noted, "It has been well known that tumors become more difficult to treat over time and with each subsequent line of therapy."

"This study provides important insights into the biology of this clinical observation," he said, "(and) suggests a potential treatment approach for these challenging tumors."