Q & A - LOCATION, LOCATION, LOCATION:

A CONVERSATION ABOUT BRAIN TUMORS WITH ANDREA MCCLATCHEY, PHD

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.

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.