The most common form of malignant glioma in humans is termed """"""""primary glioblastoma"""""""". These tumors are characterized by amplified/mutated EGFR but are generally wild type with respect to P53 status. The genetic integrity of P53 in primary glioma is at odds with the aggressive growth of these tumors and their notorious resistance to radiation and cytotoxic drugs. In preliminary studies, we have found a potential resolution to this paradox. We show I) that essentially 100% of the CD133 positive stem cells that underlie malignant glioma in humans express the bHLH transcription represser OLIG2, ii) that OLIG2 suppresses expression of P21 - a key cell cycle inhibitor gene that is an inducible target gene of P53 and iii) that OLIG2 is essential for growth in a """"""""genetically relevant"""""""" murine model of primary glioma. The objective of our study plan is to test the hypothesis that OLIG2 sustains replication of primary glioma stem cells by opposing the action of P53 and suppressing the expression of P21. This hypothesis makes testable predications that we will address with a series of experiments to be conducted on fresh surgical isolates of malignant glioma. We will complement and validate the work on human tumor stem cells with experiments on murine models of glioma that emulate genetic lesions found in primary glioma and also secondary glioma (wild type EGFR but loss-of-function P53).
Specific aims are as follows:
Aim 1 is to test the prediction that the expression of P21 is precluded in CD133/OLIG2-positive stem cells of primary (P53 positive) gliomas.
Aim 2 is to test the prediction that suppression of OLIG2 will stimulate the expression of P21 in primary glioma stem cells and suppress the malignant phenotype.
Aim 3 is to test the prediction that P21 is epistatic to O/_/G2for maintenance of the malignant phenotype in stem cells for primary glioma.
Aim 4 is to test the prediction that other P53-inducible genes are also suppressed by OLIG2. These additional OLIG2 targets may account for the notorious resistance of primary gliomas to radiotherapy and chemotherapy. In the fullness of time, the work described may lead to new """"""""drugable targets"""""""" for the therapy of malignant glioma in humans. ? ? ?
