Abstract
Recurrence in patients with glioblastoma (GBM) is inevitable resulting in short survival times, even in patients with O-6-Methylguanine-DNA Methyltransferase (MGMT) methylation. Other pathways must be activated to escape from temozolomide (TMZ) treatment, however acquired resistance mechanisms to TMZ are not well understood. Herein, frozen tumors from 36 MGMT methylated patients grouped according to overall survival were extracted and proteins were profiled using surface-enhanced laser desorption/ionization (SELDI) with time-of flight (TOF) proteomics to identify low molecular weight proteins that associated with poor survival outcomes. Overexpression of macrophage migration inhibitory factor (MIF) was identified in human GBM specimens that were MGMT methylated but showed poor survival. This correlation was confirmed in an independent cohort of human GBM. MIF overexpression has been reported in several cancer types, including GBM. We repurposed ibudilast, a specific MIF inhibitor, and treated patient derived cell lines. Ibudilast showed modest anti-proliferative activity however, when combined with TMZ, significant synergism was observed, resulting in cell cycle arrest and apoptosis. In vivo, combined ibudilast and TMZ treatment of a patient derived xenograft (PDX) model resulted in significantly longer overall survival. Our findings have significant clinical implications for people with GBM. Since clinical trials involving ibudilast have shown no adverse side effects and the drug readily penetrates the blood brain barrier, treatment of GBM with this combination is clinically achievable.
Highlights
Methylguanine-DNA methyltransferase (MGMT) removes mutagenic alkyl adducts, thereby protecting DNA from the damage induced by TMZ and other alkylating agents
migration inhibitory factor (MIF) expression has been previously associated with poor prognosis and early tumor recurrence in GBM14–16
We found patients who relapsed after TMZ treatment had high levels of MIF expression
Summary
Methylguanine-DNA methyltransferase (MGMT) removes mutagenic alkyl adducts, thereby protecting DNA from the damage induced by TMZ and other alkylating agents. MGMT expression in cells is regulated by hypermethylation of the CpG islands within the promoter and enhancer regions of the gene[4,5,6]. Detection of MGMT promoter methylation correlates strongly with clinical response to TMZ and is a positive prognostic biomarker in TMZ-treated GBM, including in elderly patients[8,9]. Given progression occurs in MGMT promoter methylated tumors[4], this indicates that other pathways must be activated to escape from TMZ treatment, acquired resistance mechanisms to TMZ are not well understood. We took an unbiased approach by selecting human GBM tumors that were MGMT methylated, responded initially to TMZ treatment, and grouped them according to patient survival. Macrophage Migration Inhibitory Factor (MIF) was strongly expressed in tumors from those patients with shorter survival despite MGMT methylation. By targeting MIF with a specific inhibitor, we show that we can sensitize tumors to TMZ treatment in patient derived cell lines and a patient derived xenograft model
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