BACKGROUND: Promoter methylation of the DNA repair gene, MGMT is associated with improved treatment outcome for newly diagnosed glioblastoma (GBM) treated with standard chemoradiation. Currently, there are no universally effective systemic treatments available for patients with an unmethylated MGMT promoter or treatments for patients whose tumor recurs after primary treatment, irrespective of MGMT methylation status. We used SELDI-TOF MS to identify low molecular weight proteins associated with poor survival. We report a new therapeutic strategy with potential to overcome the drug resistance conferred by MGMT when applied as an adjunct therapy to the standard chemoradiation for patients. METHODS: We screened the low molecular weight proteome of patients' tumors, which were non-responsive to chemoradiotherapy (survival <12 months). Proteins of significant abundance in the non-responsive patients were purified, identified and validated in a larger cohort of GBM (n = 230). Inhibitors were sourced and efficacy of the drug was tested in patient derived tumor models. RESULTS: High expression of the inflammatory related protein Macrophage Inhibitory Factor (MIF) and its receptor, CD74 were found in patients who were non-responsive to chemoradiation. Heightened expression of both MIF and CD74 were identified in 57% of GBM (n = 230) and co-segregated with poor prognosis. CD74 forms a complex with CD44 at the cell surface. After MIF binds to the CD74/44 complex, Src is recruited. Src recruitment then initiates the activation of multiple pathways including Ras/MAPK and Akt resulting in tumor proliferation. Pro-angiogenic effects have also been attributed to this complex. Because of its involvement in tumorigenesis, inhibition of the MIF/CD74/CD44 complex with specific inhibitors in combination with chemoradiotherapy will likely abate the resistance to standard treatment and result in longer survival. Ibudilast (AV411; 3-isobutyryl-2-isopropylpyrazolo-[1,5-a] pyridine) is an anti-inflammatory drug that has been marketed for almost 20 years in Japan for treating asthma. Ibudilast inhibits the catalytic and chemo-functions of MIF. We tested a range of ibudilast concentrations in patient-derived cell lines and orthotopic patient-derived xenografts (PDX) models. When used in combination with TMZ, strong synergistic and inhibitory effects on tumor growth and improved overall survival were observed. CONCLUSIONS: Collectively, these data suggest that MIF/CD74 signaling may be an additional factor that contributes to TMZ resistance. Future studies will confirm whether the testing of GBM patients for increased expression of MIF/CD74 and subsequent treatment with a combination of ibudilast (or other small inhibitors of MIF/CD74) could be effectively used in our armamentarium against GBM. SECONDARY CATEGORY: Neuropathology & Tumor Biomarkers.