Project Summary Glioblastoma (GBM) is among the most treatment resistant and lethal of all human cancers. Effective GBM treatment is hindered by aggressive tumor cell invasion into surrounding healthy brain tissue that invariably leads to tumor recurrence. Therefore, the development of therapies that target the infiltrative, residual cells are greatly needed in order to improve the survival of GBM patients. We previously reported that the expression of the TNF receptor superfamily member Fn14 is high in infiltrating glioma cells. Increased Fn14 signaling promotes GBM cell migration/invasion and chemoresistance in vitro while Fn14 depletion increases sensitivity to temozolomide (TMZ) and survival in an intracranial xenograft model. Fn14 is an inducible protein that can be activated by constitutively active receptor tyrosine kinases such as amplified EGFR and its active mutant EGFRvIII. EGFRvIII-induced Fn14 upregulation is mainly driven by STAT5 activity to promote glioma invasion and therapeutic resistance. Notably, both Fn14 expression and STAT5 activation are elevated in GBM patient-derived xenograft (PDX) lines selected for temozolomide (TMZ) resistance. Inhibition of JAK1/2 expression/activity in EGFRvIII expressing GBM cells did not affect the phosphorylation of STAT5 (pSTAT5), which is essential for its activation, or Fn14 expression suggesting that STAT5 activation is independent of JAK1/2. Intriguingly, we find that expression of OLIG2, a key cell fate factor important for the tumorigenic potential of glioma stem cells (GSCs), affects STAT5 activation and Fn14 expression. In GSCs, STAT5 interacts with OLIG2 and treatment with the STAT5 inhibitor, pimozide results in decreased Fn14 expression and invasion of GSCs. The upstream molecular mechanisms involved in JAK-independent activation of STAT5 and downstream signaling pathway(s) regulated by OLIG2-STAT5 complex must be identified to ultimately target invasive GSCs. We hypothesize that the STAT5/OLIG2/Fn14 signaling pathway is a node of vulnerability in the invasive, residual GBM cells and targeting this pathway will decrease therapeutic resistance and increase survival in PDX models. In Aim 1, we will determine the mechanism(s) by which STAT5 signaling induces Fn14 expression downstream of EGFRvIII to enhance GBM cell invasion and therapeutic resistance. Aim 2 will identify the molecular mechanism(s) involved in OLIG2-mediated regulation of STAT5-Fn14 expression in GSCs. In Aim 3 we will determine the impact of STAT5 inhibition in combination with TMZ and IR on GBM tumor growth and therapeutic resistance in intracranial xenografts and syngeneic immunocompetent mouse models of GBM. Success of the proposal will identify, validate, and place into a clinically meaningful context the STAT5/OLIG2/Fn14 signaling pathway as a therapeutic target for infiltrating cells that commonly underlie GBM fatality.
|Effective start/end date||9/30/20 → 8/31/21|
- National Institute of Neurological Disorders and Stroke: $580,194.00
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