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Discovery and Innovation: Unraveling Melanoma

 

by Jim Swyers, M.A.
Used with permission from the University of Maryland Medicine Bulletin, Summer 2010, Volume 95, Number 1

David J. Weber, PhD, with Edward A. Sausville, MD, PhD

David J. Weber, Ph.D., with Edward A. Sausville, M.D., Ph.D.

Melanoma is the deadliest type of skin cancer, and the incidence of cutaneous melanoma is increasing faster than any other common cancer, with an approximate doubling of rates every 10 to 20 years in countries with Caucasian populations. Although melanoma is quite curable in its early stages, once it has metastasized it is extremely difficult to treat.

"Thankfully, most cases of melanoma are caught in the early stages," says Edward A. Sausville, M.D., Ph.D., professor of medicine and associate director for clinical research at Maryland's Marlene & Stewart Greenebaum Cancer Center. "However, if undiagnosed and untreated, the tumor can spread downward into deeper skin layers and to lymph nodes and internal organs. Once that happens, patients' therapeutic options are very limited."

People diagnosed with stage IV melanoma have an average life expectancy of only six to nine months. However, this grim scenario may soon change for some advanced-stage melanoma patients if a clinical trial led by Sausville proves promising. The trial is in a small group of stage IV melanoma patients using a drug called pentamidine. It has previously been approved by the FDA for treating certain types of parasitic infections.

Sausville's main collaborator in the trial is David J. Weber, PhD, professor of biochemistry and molecular biology. Weber's laboratory previously discovered that pentamidine might be effective against melanoma cells using structural biology techniques.

drug pentamidine interferes with S100B’

The two sites where the drug pentamidine interferes with S100B's ability to bind to and inactivate the tumor suppressor protein p53 in melanoma cells

"A few years ago, my laboratory demonstrated that a calcium-binding protein known as S100B, frequently found in high concentrations of melanoma cells, binds and inhibits the function of a well-known tumor suppressor protein, p53. We then hypothesized that if we could interfere with S100B's ability to bind to p53, we might be able to restore p53's normal function and return melanoma cells to their non-cancerous state," explains Weber.

Armed with that knowledge as well as an atomic resolution three-dimensional structure of an S100B-p53 complex, Weber's laboratory began using nuclear magnetic resonance spectroscopy to screen already available chemicals that might be able to disrupt the ability of S100B to tightly bind to p53. After screening a number of candidates, they came upon pentamidine.

"Pentamadine was an extremely exciting candidate," explains Weber. "It is often used to treat infections in AIDS patients. Therefore, it has a demonstrated safety profile. We didn't want to use something that was effective in blocking the S100B-p53 interaction but was toxic to patients."

In subsequent studies, Weber's laboratory demonstrated that pentamidine was both highly effective in interfering with S100B's ability to bind to p53 in melanoma and was able to restore the normal tumor suppression activities of p53. He then contacted Sausville about collaborating on a grant to test pentamidine in a clinical trial for patients with advanced stage melanoma. The grant was funded by the National Cancer Institute late last year.

Sausville and Weber are currently enrolling approximately 16 stage IV melanoma patients for a phase II clinical trial. The only caveat is that the treatment is not for every patient who has melanoma. Patients enrolled in the trial must have the p53 biotype—that is, they must have S100B complexed with wild type p53. Although they are reluctant to predict the outcome of the trial, they suggest it has significant potential to be more effective than previously available therapies.

"Because we are selecting only those patients with a very specific biotype, this is a very personalized approach and is much more targeted therapy than any available to date," Sausville explains.


This page was last updated on: July 30, 2010.