Genomics used to identify a molecular-based treatment for a viralskin cancer - Sliding Seat

Within a year, they showed it wasresponsible for tumor development in most cases of the disease. Atleast four out of five healthy adults world-wide are infected withMCV, which usually doesn't cause any symptoms. "The virus remains in the skin cells, and in most cases, nodamage is done," Dr. Chang said. "But when mutationsoccur to this virus, it can cause cancer.

Most of the 1,500 new MCCcases per year in the U.S. are caused by MCV infection." In quick succession, the team devised tests to identifyvirus-induced MCC, and began unraveling the biochemical pathwaysthat encourage tumor formation. In their latest project, they"knocked out" a key viral protein called T antigen andfound that MCV directly elevates a cellular protein calledsurvivin. Survivin prevents cells from dying and supports cell division, theresearchers said.

They found that a drug called YM155, which turnsoff the survivin gene again, was an extremely potent killer of MCCcells in test tubes and was able to suppress the growth of humantumors that had been established in experimental mice. Incomparison, 1,360 other drugs -- including most of the commonchemotherapy drugs -- were screened and failed to both kill MCCcells and prevent tumor growth at levels commonly achieved inpatients. One of these drugs was able to kill tumor cells inculture dishes, but made no impact on the MCC tumors in mice. Itremains a promising candidate drug since it may have betteractivity in people and is readily available.

A multicenter clinical trial of YM155, a still-experimentalanti-cancer drug that is made by Deerfield, Ill.-based Astellas, isexpected to begin in the next six months to determine itseffectiveness in MCC patients. The trial will be led locally byPitt School of Medicine assistant professor Hussein Tawbi, M.D.,Ph.D., and professor John Kirkwood, M.D., who also is co-leader ofthe UPCI Melanoma Program, through the Eastern Cooperative OncologyGroup, a multicenter cooperative group supported by the NationalCancer Institute (NCI), part of the National Institutes of Health. Typically, neither the cause of a cancer nor the target for acancer drug is initially known, so most treatments have developedover decades through trial-and-error. Most therapies affect bothhealthy tissues and cancer cells, resulting in side effects thatlimit the drug dose that can safely be given. This study, incontrast, was a "rational" drug study where theunderlying cellular defect caused by the virus was first discoveredthrough genetic studies and then a drug targeting this process wastested.Survivin is needed during fetal development, but not inhealthy adult cells, and YM155 was not toxic to the mice.

"Scientists can now quickly come up with answers to complexproblems, like cancer, using human genetics," Dr. Moore noted."In less than five years, we have gone from knowing verylittle about MCC to knowing its exact cause and are devising new,precisely targeted and less-toxic therapies." Prior to their work on MCV, the Chang and Moore lab team discoveredanother virus, a new human herpesvirus, in 1994 that causesKaposi's sarcoma, the most common cancer among AIDS patients. Co-authors include Reety Arora, Masahiro Shuda, Ph.D., AnnaGuastafierro, Huichen Feng, Ph.D., Tuna Toptan, Ph.D., YanisTolstov, Ph.D., Daniel Normolle, Ph.D., Laura L. Vollmer, AndreasVogt, Ph.D., Alexander Dömling, Ph.D., and Jeffrey L. Brodsky,Ph.D., all of the University of Pittsburgh.

The research was funded by NCI grants CA78039, CA136363, CA120726and P30CA047904, and the American Cancer Society. The authorsdeclare that no funding from Astellas or other companies was usedfor this study.

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