Pitt team makes progress against skin cancer
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Merkel cell carcinoma wasn't even identified as a separate skin cancer until 30 years ago. As recent as four years ago, no one knew what caused it or how to treat it.
But, in a quick succession of accomplishments, a University of Pittsburgh Cancer Institute team has not only identified the virus that causes MCC but also found the protein that allows tumor survival.
But the speedy scientific work didn't end there.
The Pitt team, led by Yuan Chang and Patrick S. Moore, also has identified a drug that inhibits that protein, pegging it as a potential treatment for the cancer that kills 40 to 50 percent of patients within three years of diagnosis. The death rate from MCC is "far more grim" than that of melanoma, a more common skin cancer, Dr. Moore said.
In the next six months, multicenter human clinical trials are expected to get under way to test the drug, YM155, made by Astellas of Deerfield, Ill., and not yet approved for general use by the U.S. Food and Drug Administration. Those trials, led by Hussein Tawbi of the University of Pittsburgh School of Medicine and John Kirkwood, co-leader of the UPCI Melanoma Program, involve as many as 26 patients with an initial focus on halting tumor progression.
"I think this will be an exciting new offering for patients who have this cancer and previously only had chemotherapy as a treatment," Dr. Kirkwood said, noting that chemotherapy hasn't proven to be very effective.
In the United States, 1,500 new cases of MCC are diagnosed each year. That number is rising due, in part, to better diagnosis. But that doesn't fully explain the surge in cases.
Drs. Moore and Chang pioneered an approach to identify the MCC virus -- and possibly other cancer-causing viruses. Using the human genome sequence as a road map, they subtracted known human DNA sequences from those of the Merkel cell cancer, eventually identifying one sequence belonging to the foreign virus.
One year later, they announced that the virus, indeed, was responsible for tumor development in most cases of MCC. About 80 percent of adults have the Merkel cell virus in their skin. But cancer occurs only when two genetic mutations make the virus carcinogenic, especially in the elderly or those with suppressed immune systems.
Next, the team identified the biochemical pathway to cancer. A viral protein, or antigen, elevates levels of a cellular protein known as survivin, which prevents cells from dying and supports cell division. Those two functions promote tumor proliferation.
The study also found that survivin in cancer cells was seven times more abundant than in the 20 percent of the Merkel cell cancers not caused by the virus. That established survivin as one of the engines of MCC tumor development, and thus a target for treatment.
When the team analyzed 1,360 drugs, it found two, bortezomib and YM155, that inhibit survivin. Both drugs will be tested in the clinical trials.
Nine cancer-causing viruses already are known, but many others remain unidentified. Dr. Moore says viruses are thought to account for 20 percent of all cancers, but the percentage most likely is higher. For that reason, their method of using tumor genomes to hunt down cancer-causing viruses represents a major burst forward in cancer research.
The MCC study, involving 13 researchers led by Drs. Moore and Chang of UPCI's Cancer Virology Program with Reety Arora and Masahiro Shuda as first authors, was published online Wednesday in Science Translational Medicine.
First Published May 12, 2012 12:00 am