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.