Wistar Researchers Target Key Proteins In Neurofibromatosis Type 2

Wistar Researchers Target Key Proteins In Neurofibromatosis Type 2

September 30, 2008

(PHILADELPHIA – October 1, 2008) – There is no effective treatment for neurofibromatosis type 2, a rare cancer that results in devastating nerve cell tumors in children and young adults. Researchers at The Wistar Institute, however, have zeroed in on key molecules activated in the cancer, and have successfully shut them down in laboratory experiments. They say this approach, with further testing, might form the basis of the first targeted treatment of the disease in humans.

In the October 1 issue of the journal Cancer Research, the scientists describe the importance of a family of proteins known as p21-activated kinases to survival of the cancer, which they then “turned off” in a series of experiments. The result was a significant reduction of growth in cancer cells in laboratory cultures, and animals with the disease could not form new tumors.

“This work opens the door to a new approach for treating this tragic disease,” said the study’s lead author, Joseph L. Kissil, Ph.D., an assistant professor in the Molecular and Cellular Oncogenesis Program at The Wistar Institute. “Surgery is the only option today, yet the results are only temporary. The tumors always grow back.”

There are two types of neurofibromatosis, both of which are genetically transmitted. Type 1 is found in 1 out of every 3,000 people, while type 2 affects 1 in 30,000.

In neurofibromatosis type 2 (NF2), cancer forms around Schwann cells, resulting in hearing loss and deafness, and in impaired balance, motor skills, and brain function. The disease is caused by loss of the NF2 gene, which is a tumor suppressor gene – it has the ability to block cancer formation. The protein that the NF2 encodes known as “merlin,” is therefore dysfunctional in this disease and cannot halt development of tumors.

In earlier studies, Kissil and his colleagues at The Wistar Institute and the Massachusetts Institute of Technology had discovered that a normally functioning merlin protein keeps the p21-activated kinases, or Pak proteins, in check; that is, merlin acts like a brake on the Paks. If Pak proteins are active, they allow a cell to grow, Kissil says.

In this study, they found that inhibition of all three Pak proteins successfully reduced tumor growth.

“This is the first definitive demonstration that these Pak proteins are possible targets in treating this cancer,” Kissil says. “No other targets had been identified before this, so we think this is a really promising approach to a new treatment.”

Researchers from the Massachusetts Institute of Technology and Massachusetts General Hospital assisted in the research. The study was funded by grants from The Department of Defense’s Neurofibromatosis Research Program.

The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the country, Wistar has long held the prestigious Cancer Center designation from the National Cancer Institute. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. The Wistar Institute: Today’s Discoveries – Tomorrow’s Cures. On the Web at www.wistar.org.