Targeting Olig2 Co-regulators for Malignant Glioma Therapy

St. Joseph'S Hospital And Medical Center, Phoenix AZ

Investigators

Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): 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.