Lorne 2012: Melanoma treatment blasts off

Only a decade ago, being diagnosed with metastatic melanoma was dire news indeed. While around eight out of 10 individuals can be rid of melanoma through surgery, once the cancer spread throughout the body, it is notoriously difficult to treat.

With Australia having the highest incidence of melanoma in the world, this has been of pressing concern particularly to researchers like Richard Kefford, Professor of Medicine at the University of Sydney, Westmead Hospital and Director of the Westmead Institute for Cancer Research, and Co-Director of Research at Melanoma Institute Australia.

Yet in just the last few years there has been something of a revolution in the treatment of metastatic melanoma, says Kefford. He is currently involved in evaluating a suite of new drugs that are making real inroads into treating this recalcitrant disease.

“Until these drugs came alone, less than five per cent of patients survived more than two years,” he says. “We had no effective drug treatment whatsoever. I myself have conducted over 40 clinical trials of agents in metastatic melanoma, and none of them prolonged survival. That’s the dismal landscape we were moving from.”

Breaking BRAF

The breakthrough was the discovery in 2002 of a mutation in a gene called BRAF, which was found in around 50 per cent of metastatic melanomas. It turned out this gene coded for a protein kinase that is involved in a crucial signalling pathway within the cancer cells.

The mutation effectively made BRAF ignore other molecules that would turn down its activity, causing it to overstimulate other kinases further down the pathway, encouraging cell proliferation and survival. This made BRAF a textbook oncogene, and an attractive target for a new range of drugs that inhibit the kinase.

Frustratingly, initial attempts fell flat. One of the first employed sorafenib, marketed by Bayer and Onyx Pharmaceuticals as Nexavar, and approved for sale by the U.S. Food and Drug Administrations in 2005 for treatment of non-melanoma cancers.

Sorafenib inhibits a number of kinases, but is appears to be a relatively poor BRAF inhibitor. It was more potent against others, including BRAF’s cousin CRAF. While hopes were high, trials yielded disappointing results, with the drug having a minimal effect on metastatic melanomas.

Another contender was Roche’s PLX4032, also known as vemurafenib, which showed far more promising results, particularly when given to patients who were screened for the BRAF mutation.

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