High-grade gliomas are amongst the most aggressive cancers due to their resistance to conventional therapy. Resistance to genotoxic modalities has been attributed to a highly tumorigenic subpopulation of stem-like cells within these tumors. Our previous work has demonstrated that a Central Nervous System-specific transcription factor, OLIG2, is expressed within these `stem-like' cells and is required for glioma formation in orthotopic patient-derived xenografts (PDX) as well as in a genetically defined mouse model of glioma. We have shown that ablation of OLIG2 can suppress tumor growth as well as radiosensitize glioma cells in a p53 dependent manner. Our data suggest that a small molecule inhibitor of OLIG2 could serve as a highly targeted therapy for high grade glioma. However, transcription factors are generally difficult to target. In this study, we propose to target druggale OLIG2 partner proteins (HDAC1 and FYN) as a surrogate means for glioma therapy. In preliminary results, we have identified Histone deacetylase 1(HDAC1) and FYN kinase as novel interactors of OLIG2. We show that knockdown of HDAC1 significantly decreases glioma cell survival, while there is minimal effect on normal neural stem cells. Further, FYN tyrosine kinase interacts with and phosphorylates OLIG2 and its knockdown affects OLIG2 transcriptional functions. We hypothesize that the pro-mitogenic functions of phospho-OLIG2 requires interaction with its partner proteins, HDAC1 and FYN kinase.
In Aim 1, we will test the hypothesis that the pro-mitogenic functions of Olig2 are primarily channeled through HDAC1.
In Aim 2, we will test the hypothesis that the pro-mitogenic functions of OLIG2 in gliomas require interaction with and phosphorylation by Fyn kinase. Lastly, in Aim 3, we will collaborate with Dr. LaBaer's group to test our hypothesis that pOLIG2 interacts with distinct partner proteins under oncogenic conditions. At the conclusion of these experiments we would have identified: a) the molecular mechanism involved in OLIG2-mediated proliferation through HDAC1; b) identified a highly targeted means to inhibit glioma growth, c) shown how the proto-oncogene FYN kinase regulates OLIG2 function and d) mapped novel phospho-Olig2 and glioma specific partner proteins as novel means to target OLIG2 function. In future, these studies will provide the rationale for developing highly targeted (HDAC1/FYN-specific) therapies for glioma.
Malignant gliomas are the most aggressive type of brain tumor with median survival of only 9-14 months after diagnosis. Our studies have shown that targeting Olig2 function can suppress tumor growth and sensitize glioma cells to therapy. Olig2 promotes tumor growth in part by blocking tumor suppressor p53 function. Olig2 is a transcription factor which is typically difficult to drug. The goal of this proposal is to target druggable Olig2 partner proteins (HDAC1 and FYN) that are critical for tumor formation as a surrogate means for glioma therapy. In addition, we will identify tumor-specific co-regulators of Olig2, which might serve as novel drug targets, either stand alone or in conjunction with conventional treatments for high-grade glioma. Successful completion of our studies will pave way for more targeted therapy for this deadly disease.
