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Melanoma Research Yields Potential Drug Target; 100K Affy Chips Improve Her2-Like Discovery Path


Battling the effects of the summer sun, cancer researchers have identified a possible melanoma drug target and prognostic indicator using an updated version of a microarray-based method. In a research path similar to the Her2 story, any new treatments developed from the research may require diagnostics to identify patient responders.

Melanoma is responsible for more deaths than all other skin cancers, including about 7,700 in the US this year, according to the American Cancer Society. The society expects about 60,000 new diagnoses this year, and that rate is rising. However, if it is identified early, most cases can be cured.

For the research published in the July 7 issue of Nature, the study's first author, Levi Garraway of the Dana-Farber Cancer Institute, and colleagues compared the signals of several SNPs in melanoma DNA to the signal intensity of those SNPs in DNA from normal cells. They then combined these results with expression data to identify genes most likely to have been amplified. After establishing higher expression of the MITF protein in melanoma cells, the researchers found the cells to be dependent on MITF amplification for growth, and a reduction of MITF activity sensitized the cells to chemotherapeutic agents.

"The goal is to really use this kind of technology to redefine cancer on the basis of the genetic alterations."

The technology itself is based on adapted pre-release 100K SNP arrays from Affymetrix, Garraway said. The method is probably not patentable, he said, although the group would likely patent commercially important oncogenes. Other groups, including the UK-based Wellcome Trust Sanger Center, have used lower-resolution, 10K SNP arrays for similar studies.

Asked whether the method might result in the discovery of other possible drug targets, Garraway said, "Absolutely. It certainly can be applied to any cancer class from which you can get enough pure DNA," he said. "The goal is to really use this kind of technology to redefine cancer on the basis of the genetic alterations."

There is potential for the method to produce many drug targets in a manner similar to the Her2 pathway, and at an increasing rate, should the technique gain speed and popularity. "The Her2 gene in breast cancer was found to be amplified, and then they realized that it might make a good target, and then a few years after that, people had therapeutics that targeted the Her2 pathway, in particular Herceptin," said David Rimm, an associate professor at the Department of Pathology of the Yale School of Medicine, and an author of the study. "A few years after that, it was shown that, in the patients [with tumors having amplified Her2], there were responses to the drug. I think this has potential to be an analogous story, although in a much earlier stage," he said.

The group of researchers also found that patients in whose tumors the gene was overexpressed tended to do worse. "They were more likely to die of their disease or have their disease recur than the patients where the gene [and protein] was not amplified," Rimm said.

Indeed, using FISH, the researchers found MITF amplification in two of 19 cutaneous tumors, or about 10 percent, and in 27 of 160 metastatic samples, or about 15 percent. Nine melanocytic nevi controls showed no amplification, mirroring previous PCR results. Tumor samples from patients with metastatic melanoma showed a decreased five-year survival rate with MITF amplification.

The next step for Garraway is to apply the same combined genomic approach to melanomas, which he thinks are most amenable to the technique, due to the ease with which the cells can be grown, manipulated, and tested in the lab.

Currently, the most common approach to identifying gene amplification is comparative genomic hybridization, which involves the hybridization between normal and cancer tissue, Garraway said. "Ours is a much higher resolution approach, and it also gives the opportunity to look for different kinds of mutations," he said.

Rimm and Yale School of Medicine colleagues used HistoRx's Aqua quantitative protein-expression technology to help implicate MITF as a possible drug target. "I think the next natural step is to find an inhibitor or to consider this [protein] as a target," said Rimm. "These might be a good target for a subset of the melanomas."

— Chris Womack ([email protected])

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