Vol 9. Issue 30 / October 12, 2009
Scientists Make Advance Against Melanoma
By Jason Bardi
A team of researchers at The Scripps Research Institute and the Genomics Institute of the Novartis Research Foundation (GNF) has identified a potential new drug target for malignant melanoma, a deadly type of skin cancer that kills thousands of people in the United States every year.
This new target is a protein called TYRO3, and its discovery may lead to new treatments for melanoma. In an upcoming issue of the journal Proceedings of the National Academy of Sciences, the scientists describe how the gene works and show how blocking it affects cancer cells.
"Knocking down this gene [altering it to decrease its expression] inhibits tumor formation in mice," explains the paper's first author Shoutian Zhu, who conducted the research with Heiko Wurdak, and their colleagues at Scripps Research and GNF. The work was led by Peter G. Schultz, who is the Scripps Family Chair Professor of Chemistry and director of GNF, and Xu Wu, adjunct assistant professor at Scripps Research and associate director of biological chemistry at GNF.
Melanoma is by far the most serious type of skin cancer, accounting for some 75 percent of all skin-cancer-related deaths. According to the National Institutes of Health, its occurrence rate has doubled in the last 30 years.
When diagnosed early, melanoma is very treatable through routine surgery. Some 80 percent of people whose melanoma is detected early can be successfully treated by surgical resection. If the disease progresses undetected, however, cancerous cells can metastasize and migrate elsewhere in the body, making the disease harder to address surgically — especially since melanoma often resists standard chemotherapy treatments. The five-year survival rate for people first diagnosed with later-stage melanoma is only 16 percent.
Hoping to find a new way to combat malignant melanoma, the Scripps Research and GNF team focused on a protein called MITF, which is a "master regulator" that controls many different genes necessary for melanoma cell growth and survival.
MITF has been linked to melanoma in studies of cancer tissues that have shown it is often found at higher-than-normal concentrations in melanoma cells. Similar studies in other laboratories have also shown that MITF can help cancer cells to survive longer and to resist chemotherapy.
However, targeting MITF itself is not feasible, due to the fact that it is a transcription factor whose function cannot easily be modulated by drugs. Aware of this problem, the scientists at Scripps Research and GNF went searching for "druggable" proteins that act as regulators of MITF itself — but only in melanoma cells. The scientists reasoned that if they could identify such a protein, they might have found a potential new way to fight the cancer.
The researchers screened thousands of genes and identified 15 candidates that regulated MITF. When these were subjected to expression profiling among different types of cells, one gene – called TYRO3 – showed higher levels in melanoma cells. Through expression analysis of tissue samples taken from 43 patients with melanoma, the researchers found that the expression levels of TYRO3 are higher than normal skin tissues in more than half of the samples tested.
That's how the researchers identified the potential new drug target, and could then go on to design experiments to see what would happen if they reduced the levels of TYRO3 in melanoma cells. The team found that knocking down the gene's expression inhibited the growth of cancer cells in culture dishes. They also observed that knocking down TYRO3 prevented the formation of the tumors in mice with one of the most aggressive types of melanomas.
Since TYRO3 is a kinase (enzyme that regulates cell signaling) expressed on the cell surface, the next step, the researchers say, is to identify compounds or antibodies that inhibit the action of TYRO3 and to use these compounds or antibodies as starting points for designing new drugs. Different types of melanoma have different TYRO3 expression levels, and it is possible that targeting this protein would be more effective at combating some types of cancer than others.
Even if lead drug candidates can be identified, it will likely take years to develop them into actual formulations, and their safety and effectiveness will need to be established in clinical trials before they are approved by the U.S. Food and Drug Administration.
The article, "A genomic screen identifies TYRO3 as a MITF regulator in melanoma" is authored by Shoutian Zhu, Heiko Wurdak, Yan Wang, Anna Galkin, Haiyan Tao, Jie Li, Costas A. Lyssiotis, Feng Yan, Buu P. Tu, Loren Miraglia, John Walker, Fanxiang Sun, Anthony Orth, Peter G. Schultz, and Xu Wu. It was published online by the journal Proceedings of the National Academy of Sciences on September 23, 2009. See: http://www.pnas.org/content/early/2009/09/23/0909292106.
This work was supported by the Novartis Research Foundation.
For more information on melanoma, see:
Send comments to: mikaono[at]scripps.edu