RNAi Inhibition of Olig Genes in Human Gliomas

Santosh Kesari, MD, PhD
Translational Research Grant 2006 - 2007
Dana-Farber Cancer Institute - Boston, Massachusetts
Award: In memory of Theodore Sapper

Gliomas are the most common type of brain tumors, and the most malignant of these is known as glioblastoma (GBM), which is characterized by highly aggressive and infiltrative growth. The lack of durable responses may be due to a small population of resistant tumor stem cells. Our lab has shown that the Olig2 gene is expressed in all diffuse gliomas and in particular the CD133- positive stem cells. In preliminary studies we have shown: i) that 100% of CD133-positive stem cells in fresh surgical isolates of human GBMs express the gliogenic transcription factor Olig2; and ii) that Olig2 is essential for tumor formation in a mouse model of gliomas that emulates human gliomas at a genetic level. The goal of this project is to test the hypothesis that Olig2 is essential for the malignant growth of human CD133-positive GBM stem cells in in vitro and in vivo model systems. We have so far generated lentiviral shRNA vectors to disrupt Olig2 gene expression and show that it does slow the growth of tumor stem cells in vitro and that it does affect tumor growth in vivo. We are characterizing this growth effect in larger sample of fresh GBM tumors and the functional and biological effects on GBM stem cells with loss of Olig2.