Blocking a Protein that Allows Prostate Cancer to Grow                    


Scientists believe that cancer results from a bunch of tiny hits to the body – damage to the genes that can simultaneously result in accelerated growth, which happens in cancer, and a shutdown of other cells that normally could suppress cancer. Tumor suppressors are genes whose job is to keep cells from turning down a bad road that could lead to cancer. Normally, these genes check cells for signs of abnormal growth and then put a stop to it. But many cancer cells know how to get around this defense: They simply turn off the supply of tumor suppressors. They do this by a process called DNA methylation – basically, structural changes to DNA that keep it from functioning the way it’s supposed to.

This protein does
what soldiers are taught to do:
It secures the perimeter.

Daniel Leahy, Ph.D., The Phyllis and Brian L. Harvey Scholar, is investigating a particular protein involved in methylation. This protein, called MBD2 (for "methyl-CpG Binding Domain Protein"), does what soldiers are taught to do: It secures the perimeter. MBD2 binds to methylated regions of DNA and squelches the ability of nearby genes to fight off cancer. "In mice and in cancer cells studied separately, when MBD2 function is lost, this slows down rampant cell growth," says Leahy, professor of biophysics and biophysical chemistry. "We think this is because it allows the tumor suppressors to come back."

Surprisingly, he adds, "blocking MBD2 in mice does not cause any notable side effects." Could an MBD2-blocking drug help the body fight off prostate cancer? With coinvestigator William G. Nelson, M.D., Ph.D., the Marion I. Knott Director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Leahy is hoping to find out. The Nelson lab has developed a way to screening for MBD2 activity, and "we are beginning to screen more than 300,000 compounds to see whether they inhibit MBD2," at a facility in Florida. The ultra-exact screening process includes using X-ray crystallography to look at the atomic structure of MBD2 as it is bound to methylated DNA . "We have grown crystals of the methyl binding region of MBD2 bound to methylated DNA ," says Leahy. "Having this structure will reveal the precise chemical contacts that MBD2 uses to recognize DNA . Knowing the chemical nature and shape of these regions will guide efforts to design and improve inhibitors of MBD2. We also hope to gain insight into how MBD2 recognizes methylated DNA ," which also should prove very helpful as scientists develop drugs aimed at this new and promising target.

Although Leahy believes the screening process will identify many– maybe even hundreds – of potential MBD2 inhibitors, "these molecules are unlikely to possess optimal drug attributes," and likely will need some pharmacologic tinkering to help produce the most effective drug against prostate cancer.

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