MIF/CD74 guided therapeutic strategy for relapsed glioblastoma patients

Abstract

Abstract Introduction: No universally effective systemic treatments are available for patients whose malignant brain tumor recurs after primary treatment. The treatment for Glioblastoma (GBM) patients consists of surgical removal of the tumor followed by combined treatment with the alkylating agent, temozolomide (TMZ) and radiotherapy (RT) (chemoradiotherapy). Despite this relatively aggressive treatment regime, the overall median survival for patients diagnosed with GBM is less than 15 months. The survival outcome for patients after the tumor recurs is dismal with just 9-16% of patients surviving longer than 6 months after recurrence. The primary objective of this study was to identify new pathways to target in order to improve treatment response and prolong survival.

Methods: We screened the low molecular weight proteome of patients' tumors, which were non-responsive to chemoradiotherapy. 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 treatment. 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.