Mechanism of Notch inhibition resistance in glioblastoma stem cells

ABSTRACT The goal of this proposal is to explore the mechanism of Notch inhibition resistance in glioblastoma (GBM) in order to develop novel therapy for this deadly disease. Cancer Stem- like cells (CSCs) are thought to be critical for the engraftment and long-term growth of GBM. They are at least partially spared by traditional chemo- and radiation-therapies, and finding new treatments to target CSCs may be critical for improving patient survival. We recently demonstrated that Notch pathway blockade by gamma-secretase inhibitor (GSI) depleted CSCs, inhibited neurosphere growth in vitro and propagation in vivo, and prolonged the survival of mice bearing the intracranial xenografts. A subsequent Phase I clinical study showed that 24% malignant glioma patients responded well to GSI treatment and have stabilized disease for more than four months. Another Phase I trial showed that GSI indeed cross the blood brain barrier (BBB) and reduce Notch activity in treated GBM CSCs. However, the molecular mechanism of GSI treatment resistant in GBMs are largely unknown. One main possible mechanism of GSI resistance is different genetic background of GBM, such as status of PTEN, may result in different responses to GSI. Our preliminary data showed that GBM with loss of PTEN resistant to GSI treatment. Interestingly, we found that Akt inhibitor can reduce these GSI-resistance GBM neurospheres propagation in vitro and in vivo. We hypothesize that GBM with wild type of PTEN will be sensitive to GSI treatment and that GBM with loss of PTEN will be sensitive to pAkt inhibition. In the present proposal, we will identify GBM patient subsets that will be benefit from Notch pathway inhibition or Akt inhibition in term of targeting CSCs based on individual genetic background. To test our hypothesis, we will pursue the following specific aims: Aim1: Define the mechanism of targeting GBM CSCs by Notch pathway blockade based on tumor's genetic background of PTEN. Aim2: Examine a combination of Notch inhibitor and pAkt inhibitor plus chemo- and radiation-therapy in a pre-clinical GBM intracranial xenograft mouse model. Success in this proposal will enhance our understanding of glioblastoma biology and have significant impact on GBM therapy.