Glioblastomas multiforme is the most common primary malignant brain tumor, biologically unique by virtue of their proclivity for local invasion into the adjacent normal brain tissue and the rarity of systemic metastasis. Potential specific therapeutic targets for invasive glioma cells have vet to be identified: however, the successful identification of these targets would be anticipated to catalyze development of novel therapies. We have demonstrated that Fn14 expression is minimal-to-absent in normal brain tissue but increases with increasing tumor grade. Activation of Fn14 signaling by addition of recombinant TWEAK or over-expression of Fn14 enhances glioma cell motility and survival. We HYPOTHESIZE that the activity of Fn14 enhances malignant glioblastoma cell survival and invasion into the normal brain parenchyma. Interfering with the function of Fn14 is likely to specifically target invasive glioblastoma cells and impact the ability of the tumor to recur. This hypothesis will be tested by pursuing the following specific aims: 1. Determine whether the in vitro inhibition of Fn14 signaling sensitizes glioma cells to cytotoxic therapy. Manipulation of the Fn14 signaling cascade by siRNA, small inhibitory molecules, and dominant negative constructs will be performed to assess the effects on apoptosis induction by clinical cytotoxic agents in multiple glioma cell lines and primary low passage cell strains. 2. Determine the function of Fn14 in glioma invasion in vivo. The role of Fn14 in glioma invasion will be assessed using an ex vivo brain slice organotypic substrate and xenografting of human glioma cells orthotopically into the cerebrum of immunocompromised rats. In addition, levels of Fn14 and signaling proteins will be correlated with tumor grade and patterns of invasion using immunohistochemistry on tissue microarrays containing human brain tumors. Understanding Fn14 in the context of glioma migration and cell survival will provide a more thorough insight into malignant progression of glioblastoma and the molecular mechanisms of the invasive phenotype. The results from these studies will profile the suitability and applicability of Fn 14 as a target for therapeutic intervention.
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