September 7, 2010

Nature

Rare victory in fight against melanoma

Genetically tailored approach could slow disease progress.
 
Patients with advanced melanoma rarely live for more than a year after their diagnosis — a prognosis that has not improved for more than 30 years. But clinical-trial results1 now suggest that a genetically targeted approach could slow the disease's steady march through the body, and separate research2 reveals why the latest drug being tested may succeed where others failed. Patients with advanced melanoma rarely live for more than a year after their diagnosis — a prognosis that has not improved for more than 30 years. But clinical-trial results1 now suggest that a genetically targeted approach could slow the disease's steady march through the body, and separate research2 reveals why the latest drug being tested may succeed where others failed.

The drug could be the first melanoma treatment to join an elite but expanding list of cancer therapies tailored to a patient's genetic make-up (see 'Seek and destroy'). 'It's spectacular,' says Richard Marais, a molecular biologist at the Institute of Cancer Research in London, who was not affiliated with either study. 'There's been a paradigm shift in how you would treat melanoma.'

In 2002, Marais and his colleagues reported3 that more than 60% of patients with melanoma — cancer of the melanin-producing cells typically found in skin — carry mutations in a gene that encodes a protein called B-RAF. The mutations trigger a signalling pathway that accelerates cancerous cell growth.

Drug companies pricked up their ears at the discovery. One of them, a small biotechnology company in Berkeley, California, called Plexxikon, started fishing for compounds that would selectively block mutated B-RAF by filling the unique pocket that the genetic mutation etches into the protein's three-dimensional structure.

At first, the approach was greeted with scepticism, says Plexxikon's chief executive Peter Hirth. Decades of failure had taught drug companies to shy away from testing drugs against advanced melanoma. 'People don't want to do clinical trials in melanoma,' agrees Marais. 'It's sort of the death knell for all cancer therapies.'

Early tests of Plexxikon's drug, called PLX4032, were disappointing. Some patients in the trial were taking dozens of pills a day, to no effect. 'But we just couldn't give the patients any more pills,' says Paul Chapman, a cancer researcher at the Memorial Sloan-Kettering Cancer Center in New York and a co-author on the latest clinical trial1. 'We were starting to think we were going to obstruct their gut with all the cellulose from the capsules.' So Plexxikon, together with its partner, Swiss drug maker Roche, developed a new formulation of the drug that was more easily absorbed by the body.

That reformulation proved crucial. On 26 August, researchers published the first findings from a small clinical trial of the reformulated drug. In one arm of the study1, tumours shrank by at least 30% in 24 out of 32 patients with B-RAF mutations, and disappeared entirely in two other patients.

This week in Nature2, the Plexxikon team reveals why the high doses were necessary: analysis of tumour samples from patients who received different amounts of the drug showed that PLX4032 was effective only at concentrations sufficient to block about 80% of signalling through the B-RAF pathway. This roughly matches early clinical-trial results of a similar drug being developed by London-based GlaxoSmithKline (GSK), says Jeffrey Legos, the company's medicines development leader.

The Plexxikon team also found that PLX4032 was remarkably specific for the mutated form of B-RAF, binding relatively poorly, if at all, to more than 200 other proteins, including unmutated B-RAF. That selectivity, says Hirth, probably explains why patients were able to take PLX4032 at such high doses without severe side effects.

Despite the promising results, PLX4032 has been tested in only a small number of patients and it is too early to declare the drug a success, cautions Chapman. The next stage is a larger trial in 700 patients, which began in January.

And although PLX4032 has clear short-term effects on tumour growth, researchers don't yet know whether the drug will allow patients to live significantly longer. Melanoma tumours quickly become resistant to PLX4032, and researchers estimate that tumour growth typically resurges about seven months after the start of therapy. 'These cancer cells are smart,' says Legos. 'You shut down one specific pathway, and they will find a different way to survive.' Nevertheless, Legos notes that, given the short survival of patients with advanced melanoma, it seems likely that drugs such as PLX4032 will have some effect on lifespan.

 
To overcome resistance, PLX4032 will be tested in combination with other drugs. In addition to the larger trial of PLX4032 alone, Plexxikon is planning a trial that will combine PLX4032 with an experimental drug that blocks MEK, another protein involved in the cell-growth-promoting pathway. Meanwhile, GSK is recruiting patients for a clinical trial combining two of its own experimental drugs, which respectively block mutated B-RAF and MEK.

For now, the promising results from PLX4032 highlight the power of targeting specific genetic mutations in tumours, says Yardena Samuels, a cancer geneticist at the National Human Genome Research Institute in Bethesda, Maryland. 'It's a very important development, not just for melanoma, but for the entire cancer field.'