Ibudilast sensitizes glioblastoma to temozolomide by targeting Macrophage Migration Inhibitory Factor (MIF)

Wendy Ha; Hatice Sevim-Nalkiran; Ashraf M. Zaman; Kasuko Matsuda; Mustafa Khasraw; Anna K. Nowak; Liping Chung; Robert C. Baxter; Kerrie L. McDonald

doi:10.1038/s41598-019-39427-4

Ibudilast sensitizes glioblastoma to temozolomide by targeting Macrophage Migration Inhibitory Factor (MIF)

Wendy Ha, Hatice Sevim-Nalkiran, Ashraf M. Zaman, Kasuko Matsuda, Mustafa Khasraw, Anna K. Nowak, Liping Chung, Robert C. Baxter, Kerrie L. McDonald

Western Sydney University

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33 Citations (Scopus)

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.

Original language	English
Article number	2905
Number of pages	10
Journal	Scientific Reports
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41598-019-39427-4
Publication status	Published - 2019

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Cite this

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title = "Ibudilast sensitizes glioblastoma to temozolomide by targeting Macrophage Migration Inhibitory Factor (MIF)",

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.",

author = "Wendy Ha and Hatice Sevim-Nalkiran and Zaman, {Ashraf M.} and Kasuko Matsuda and Mustafa Khasraw and Nowak, {Anna K.} and Liping Chung and Baxter, {Robert C.} and McDonald, {Kerrie L.}",

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AU - Sevim-Nalkiran, Hatice

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AU - Matsuda, Kasuko

AU - Khasraw, Mustafa

AU - Nowak, Anna K.

AU - Chung, Liping

AU - Baxter, Robert C.

AU - McDonald, Kerrie L.

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AB - 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.

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Ibudilast sensitizes glioblastoma to temozolomide by targeting Macrophage Migration Inhibitory Factor (MIF)

Abstract

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