Skin Cancer: Potential New Treatment Target Identified For Melanoma

New research from Western University, Canada, has identified a potential new target for the treatment of melanoma, the deadliest of all skin cancers. Silvia Penuela and Dale Laird discovered a new channel-forming protein called Pannexin (Panx1) that is expressed in normal levels on the surface of healthy skin cells. But they found, in melanoma, Panx1 is over-produced to a pathological level. The researchers also discovered that if you reduce it or knock it down, the cell becomes more normal. The research is published in the August 17th issue of the Journal of Biological Chemistry.

Malignant melanoma only accounts for four per cent of all skin cancers and yet, it's responsible for 79% of skin cancer-related deaths. The World Health Organization says there are 200-thousand cases of melanoma diagnosed each year and 65 thousand melanoma-related deaths (2000 statistics).

"We think this over-production of Panx1, enables the melanoma to become very aggressive. The cells have these extra Panx1 channels and they can leave the primary tumor and invade other tissues," explains Laird, a Professor in the Department of Anatomy and Cell Biology, and Canada Research Chair in Gap Junctions and Disease. "And when you find a protein that is highly up-regulated in a disease cell such as a melanoma, the question becomes, is there therapeutic value in targeting a drug to that protein to reduce its production or block its function. Would that be an effective treatment?"

"We now want to correlate our discovery to patient samples using the human melanoma bank through our collaboration with Dr. Muriel Brackstone and other clinicians at the London Health Sciences Centre, to see if this is a cancer marker," says Penuela, a Postdoctoral Fellow working in the Laird lab. "So if a melanoma lesion has a lot of this protein, it might be a tool for prognosis, in saying this is more advanced, or going to be highly metastatic. And because it's on the skin, it would be more accessible for treatment." Penuela suggests potential treatment might be in the form of a topical medication to use on melanoma lesions.

The scientists also worked with David Litchfield and John Lewis and their teams at Schulich Medicine & Dentistry and the London Regional Cancer Program on this research. It was funded through the Canadian Institutes of Health Research. The Laird laboratory recently received a $200,000 Innovation Grant from the Canadian Cancer Society Research Institute to further its studies on Panx1.

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Studying How Elesclomol Works Reveals New Molecular Target For Melanoma Treatment

A laboratory study led by UNC medical oncologist Stergios Moschos, MD, demonstrates how a new targeted drug, Elesclomol, blocks oxidative phosphorylation, which appears to play essential role in melanoma that has not been well-understood. Elesclomol (Synta Pharmaceuticals, Lexington, MA) was previously shown to have clinical benefit only in patients with normal serum lactate dehydrogenase (LDH), a laboratory test routinely used to assess activity of disease.

For more than 60 years, scientists have known that cancer cells undergo glycolysis, or metabolize glucose, at a much higher rate than normal cells. The observation, called the Warburg effect, demonstrated that the normal energy producing processes in the cell are disrupted in cancer cells, preventing them from using metabolic pathways in the cell's mitochondria (often called the cell's "power plants").

Recently, however, increasing evidence suggests that, in addition to glycolysis, other metabolic pathways may also play a role in cancer, with important therapeutic implications. A promising strategy for targeting cancer cells, while sparing normal cells, is to target these altered metabolic processes with drug therapies. Elesclomol has been shown to trigger cell death in metastatic melanoma cells, primarily by suppressing oxidative phosphorylation - the process that cells use to transform nutrients into energy.

Moschos and his team demonstrated in the lab that metastatic melanoma cells exhibit a higher rate of glycolysis compared to their normal counterpart cells, termed melanocytes, which would be expected due to the Warburg effect.

"But we also found, surprisingly, that these cells have higher rates of oxidative phosphorylation - they are producing energy through more than one pathway, which explains a lot about how the drug works," says Dr. Moschos.

He notes that this drug has an interesting history. In a 600-patient phase III clinical trial conducted almost 4 years ago, Elesclomol had clinical benefit in the subgroup of patients with normal serum LDH. However, the FDA discontinued the trial, because the Elesclomol in combination with another chemotherapeutic drug may have negative effects in patients with high serum LDH, which is associated with poorer patient outcomes in metastatic melanoma. At the time, very little was known about Elesclomol's mechanism of action - blocking oxidative phosphorylation.

"Our inability to show how Elesclomol worked through measurement of biomarkers was the major driver to conduct this laboratory study," said Moschos, whose team took the clinical trial results back to the lab to try to figure out why the drug worked.

"Our results suggest that targeting oxidative phosphorylation in melanoma is a promising strategy for early metastatic disease, before melanoma cells switch their primary metabolic source to glycolysis, as Otto Warburg showed 60 years ago" said Dr. Moschos.

"Second, we were able to demonstrate a mechanism of resistance to Elesclomol, where long-term exposure to the drug leads to the selection of melanoma cells with high levels of glycolysis. This suggests that a two-pronged strategy aimed at blocking both metabolic pathways may be called for."

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