Institution: Johns Hopkins Medical Center
Study Name: Neural Stem Cells and Low Grade Glioma
Principal Investigator: Dr. Eric Raabe
Study date: January 2013
Pediatric low grade glioma (PLGG) is the most common pediatric brain tumor. While many patients do well, others have a more aggressive disease and need chemotherapy, radiation, or repeat surgery. Although there are numerous candidate drugs that could be tried in PLGG, there are no genetically accurate human cell models of pediatric low grade gliomas for testing of new therapeutics, so there is no way to screen these drugs before starting clinical trials in children.
The solution: use human neural stem cells, the cells that we believe give rise to pediatric brain tumors, to create accurate pre-clinical models of PLGG
We have already shown that we can take human neural stem cells and introduce activating mutations in BRAF, the most commonly altered gene in PLGG (Raabe et al, Clinical Cancer Research, 2011). These cells grow well in the beginning, but then stop growing and undergo senescence. This process occurs in non-aggressive PLGG tumors in patients. However, aggressive PLGG do not express senescence markers. We believe that increased expression of stem cell genes prevents senescence and allows aggressive PLGG to tolerate activated BRAF. Examination of aggressive low-grade glioma also shows that activation of the mTOR/AKT pathway defines the highest risk PLGG group (Rodriguez et al, Acta Neuropathol. 2011). mTOR and BMI1 can cooperate in other model systems to prevent senescence. We believe that a combination of mTOR activation and the stem cell factor BMI1 will suppress the senescence caused by BRAF and allow our human neural stem cells to grow indefinitely and form low-grade glioma tumors in mice.