Drugs used to treat the tumors common in people with a disorder called neurofibromatosis 1 (NF1) rarely work, and scientists now know why.
The chemotherapy drugs target a group of related proteins, call RAS proteins, which are thought to be responsible for these tumors.
But University researchers found that the disease affects only one member of the protein family, and it happens to be the one form of RAS that does not respond well to these particular treatments.
The study, which appeared in the Jan. 1 issue of the journal Cancer Research, suggested where researchers should look for more promising approaches to treating NF tumors, and may help scientists understand other cancers related to RAS.
“The downside is our study proves that we may not be using the right therapies for this particular problem,” said principal investigator David H. Gutmann, M.D., Ph.D., the Donald O. Schnuck Family Professor of Neurology and professor of genetics and of pediatrics.
“But we should now be able to explore new, more effective treatment options.”
When scientists learned that RAS proteins become overly active when both copies of the NF1 gene are abnormal, they tried treating tumors with drugs that prevent RAS activity. The results were disappointing.
To understand why, Gutmann’s team examined whether all forms of RAS proteins are overactive in cells lacking both copies of the NF1 gene.
Postdoctoral fellow Biplab Dasgupta, Ph.D., studied support cells in the brain called astrocytes, which are often affected in NF1.
Surprisingly, only one member of the protein family, K-RAS, was significantly affected, suggesting it is an important factor in this disease.
They showed that activated K-RAS in normal astrocytes resulted in many of the same characteristics and activities of cells lacking NF1, and that decreasing K-RAS activity in NF1-deficient astrocytes reversed these abnormalities.
Building on a prior discovery, Gutmann’s team showed that when K-RAS was overly active in astrocytes of mice with two normal copies of NF1, the cells multiplied but did not develop brain tumors.
However, brain tumors did form when K-RAS was activated in astrocytes of mice lacking one copy of NF1 in all cells.
The research team already has made progress toward that goal.
Too much RAS and too little NF1 are both known to result in a cascade of biochemical events.
Gutmann and his colleagues found that this cascade could be mimicked in normal astrocytes by selectively activating K-RAS.
“Collectively, these results suggest that K-RAS activation, specifically, is the biological equivalent of NF1 loss in astrocytes,” Gutmann said.
“If we can understand what K-RAS does that’s unique, we should be able to develop more effective targeted therapies for NF1-associated brain tumors.”