Children with Neurofibromatosis type 1 (NF1) develop optic gliomas which can cause reduced vision. Currently, treatments for these brain tumors involve the use of chemotherapies originally designed to slow the growth of similar cancers in children without NF1. With the identification of the NF1 gene, it is possible to develop treatments specifically targeted to the kinds of brain tumors arising in children with NF1.
Using Nf1 genetically-engineered mice, Dr. Aparna Kaul, a post-doctoral fellow in the laboratory of Dr. David Gutmann, recently showed that two therapies that block the activity of RAS effector proteins are effective treatments for optic glioma. Previous studies performed nearly 20 years ago revealed that the NF1 gene controls cell growth by suppressing the activity of a protein called RAS. RAS, in turn, transmits its growth-promoting signal through two effector molecules, AKT and MEK.
Dr. Kaul demonstrated that drugs that block AKT or MEK activity are effective at reducing optic glioma growth. Importantly, they show that both AKT and MEK work to activate the same protein complex, called the mammalian target of rapamycin (mTOR) complex. This finding builds upon previous work in Dr. Gutmann’s laboratory, which revealed that mTOR inhibition reduced optic glioma growth in mice. Based on this preclinical result, mTOR inhibitors are now being used to treat gliomas in children with NF1.
Moreover, MEK or AKT inhibition in Nf1 genetically-engineered mice also improved the retinal dysfunction that underlies reduced vision. In light of these exciting findings, a clinical trial is now being launched to evaluate MEK inhibitors for NF1 optic glioma.
Kaul A, Toonen JA, Cimino PJ, Gianino SM, Gutmann DH. Akt- or MEK-mediated mTOR inhibition suppresses NF1 optic glioma growth. Neuro Oncol. doi:10.1093/neuonc/nou329, 2014. Epub ahead of print.