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Q & A - LOCATION, LOCATION, LOCATION:

When people think of brain tumors, they usually think of cancer. Fortunately, cancerous brain tumors occur relatively rarely, with 20,500 new cases in 2007. But benign, or noncancerous, tumors are more common, and can cause significant p r o b l e m s by pressing on brain regions that control speech, vision, hearing or movement. Andrea McClatchey, PhD, a scientist at Massachusetts General Hospital Cancer Center and associate professor of pathology at Harvard Medical School, concentrates on the benign brain syndrome neurofibromatosis 2 (NF2). These tumors can cause hearing loss, ringing in the ears, mobility and vision problems, and fluid buildup in the brain. Results of McClatchey’s basic research studies indicate a possible new use for two recently FDA-approved drugs.

A CONVERSATION ABOUT BRAIN TUMORS WITH ANDREA MCCLATCHEY, PHD

Q. Why are you studying non-cancerous tumors?
Andrea McClatchey, PhD

A. Neurofibromatosis 2 (NF2) affects about one in 25,000, usually late adolescents or young adults. Unfortunately, we have few treatment options other than surgery to remove the most troublesome tumors, which proliferate throughout life. Standard chemotherapy doesn’t work because it targets rapidly dividing cells, and these divide slowly. Some surgeons use radiation, but others worry it might produce more tumors.

Fifteen years ago, Jim Gusella, PhD, a geneticist who directs the Molecular Neurogenetics Unit and the Center for Human Genetic Research at Massachusetts General Hospital, discovered the gene mutation responsible for NF2 and named it NF2. Genes instruct the formation of proteins, and proteins are vital to all of a cell’s processes. If a gene is mutated, it gives incorrect instructions. These errors can lead to benign and cancerous tumors. Gusella discovered that mutations in NF2 cause the cell to stop producing a protein he called Merlin. I study how Merlin loss leads to tumor growth in hopes of discovering new ways to treat NF2.

Q. What have you learned about these tumors?
A. By comparing cells that lack Merlin with normal cells, we discovered how this protein ordinarily controls cell growth. Numerous cell signals — many of them not yet understood — let a cell know when to reproduce (after an injury, for example) or expire. A tumor forms when these signals don’t function properly and cells over replicate or don’t self destruct. Merlin is one of the proteins that stops cells from reproducing when they are healthy. It works by communicating with other cells, which is interesting because most tumor suppressors work within the cell to regulate growth. This one works at the cell membrane and communicates both inward and outward.
Q. How will these discoveries lead to new brain tumor treatments?

A. This June, we published a study in the Journal of Cancer Biology about how Merlin interacts with a molecule we already know helps accelerate cell growth in cancer, the receptor for the Epidermal Growth Factor (EGF).

In healthy cells, Merlin blocks the EGF receptor so it can’t send out growth signals. If Merlin senses that the tissue needs to grow more cells, it unblocks the EGF receptor, allowing the growth message to be broadcast. Without Merlin, the EGF receptor broadcasts growth signals continuously, leading to multiple NF2 tumors.

This discovery was exciting because many anticancer drugs work by blocking the EGF receptor, and two new “smart” drugs, Iressa and Tarceva, target only this site. We found in culture that those drugs completely block the over-proliferation of cells that lack Merlin, and we’re now seeing if they do so in a preclinical study. If the study is successful, the fact that these drugs are already available might shorten the lag time from bench to bedside. I feel very lucky to be among a collaborative group of NF2 researchers at the Cancer Center and elsewhere seeking to answer this and other questions regarding this poorly understood disease.

Interview by Cathryrn Delude
Advancing the Specialized Care of Individuals with Brain Tumors
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PHYSICIANS' INFO SERVICE

Physicians with
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MGH Brain Tumor Center
 
Harvard Medical School
Mass General Hospital
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