Discovery May Lead to Drug Therapy for Skin Cancer
The University of Texas Medical Branch at Galveston
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Galveston, Texas 77555-0144
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FOR RELEASE: July 31, 2001
CONTACT:
Jim Kelly, science writer
(409) 772-8791
jpkelly@utmb.edu
Jingwu Xie, Ph.D, assistant professor of pharmacology jinxie@utmb.edu
For Immediate Release
Discovery May Lead to First Drug Therapy for Skin Cancer
GALVESTON, Texas--A researcher at the University of Texas Medical Branch at Galveston (UTMB) and his colleagues have identified a critical link in the biological pathway leading to skin cancer. Lead author Jingwu Xie believes the discovery could lead to the first drug therapy, perhaps in a cream or sunscreen, to stop the most common form of cancer afflicting human beings.
After two years of research at UTMB and the University of California at San Francisco (UCSF), the scientists published their report on the role of the protein PDGFR-alpha in what is known as the "hedgehog" pathway in the July 31 issue of Proceedings of the National Academy of Sciences. "Hedgehog" -- named for the spiky appearance of skin cells with mutations in the genes that produce it -- is a signaling protein important to the development of organisms as different as humans and fruit flies.
Focusing on the cascade of chemical reactions launched by hedgehog's arrival at the cell surface, Xie and colleagues determined that mutations either in the membrane protein meant to receive hedgehog, which is known to biologists as "patched," or in the protein on which patched acts (dubbed "smoothened"), can cause the hedgehog pathway to be stuck in the "on" position. This causes uncontrolled production of PDGFR-alpha, a substance that tells the cell to reproduce. The result is accelerated cell proliferation, which can lead to tumors and basal cell carcinoma -- skin cancer.
"We knew the important genetic link for this cancer, but we still didn't know the reason
the tumor cells grew so fast," Xie says. "We hypothesized that there was a molecule that made the cells grow faster. We were looking for a drug target, and we think this is the right one."
According to Xie, PDGFR-alpha is generated whenever the hedgehog pathway is activated -- either properly, or improperly, in the case of mutations in the genes that produce the patched and smoothened proteins. In turn, it activates the ras-ERK pathway, which leads to cell growth, and possibly skin cancer. "PDGFR-alpha is the key player, the trigger for the chain reaction," Xie says.
An assistant professor in UTMB's Department of Pharmacology and Toxicology and a scientist with the Sealy Center for Cancer Cell Biology and the Sealy Center for Environmental Health and Medicine, Xie worked on the hedgehog pathway with dermatologist Ervin Epstein and cancer biologist Frank McCormick at UCSF. There, Xie began investigating basal cell nevus syndrome (BCNS), a rare inherited disease whose genetic roots Epstein believed were linked to basal cell carcinoma (BCC), which strikes about one million people annually in the United States, with medical costs of about $1.5 billion yearly. One of Xie's motivations was the prospect of finding a drug therapy for a widespread disease that -- while seldom fatal -- still causes an enormous amount of pain, disfigurement and suffering. "This cancer is extremely common, and currently there's virtually no treatment except surgery," Xie says.
The hunt for the genetic mutation responsible for BCNS and BCC led Xie and Epstein to the gene that produced the membrane protein patched. Then they followed the hedgehog pathway deeper into the cell, examining the chain reaction created by either a defective or missing patched receptor -- the situation that gives rise to both BCNS and BCC.
Working with embryonic mouse cells responsive to the "hedgehog" protein, the researchers determined that PDGFR-alpha was an active link in the chain reaction, and demonstrated that by blocking its action they could prevent runaway cell growth. They also examined tumors on mice that lacked the patched gene, and human BCC tumor cells. In both cases, they found large quantities of PDGFR-alpha, providing additional evidence for its involvement.
The key result, according to Xie, is the discovery that inactivating PDGFR-alpha can prevent tumor formation. Already, he says, there are commercially available substances that should be able to inhibit the key molecule. "Right now, because we believe this is the right target for basal cell carcinoma, we are testing this target in mice and seeing whether pharmaceutical inhibitors for PDGFR-alpha will prevent tumor growth and tumor incidence," Xie says. "It will take time to test these drugs, but once we find one effective in preventing BCC and having the very least side effects, we can discuss the possibility of putting it in some kind of cream -- perhaps even a sunscreen."
Also contributing to this research were UTMB's Xiaoli Zhang and UCSF's Michelle Aszterbaum, Jeanette M. Bonifas, Christopher Zachary and Frank McCormick.
--UTMB--
