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.

TLR-4 Signaling vs. Immune Checkpoints, miRNAs Molecules, Cancer Stem Cells, and Wingless-Signaling Interplay in Glioblastoma Multiforme—Future Perspectives

“…Ibudilast is an agent that is able to diffuse the blood-brain barrier (BBB), developing antitumor activity by inhibiting MIF and phosphodiesterase-4 (PDE-4), also reducing TLR-4 downsignaling with pro-oncogenic properties. Action leads to excessive apoptosis and the limitation of cell proliferation in GBM [196][197][198]. Ibudilast was also observed in trials, including neuroinflammation, amyotrophic lateral sclerosis (ALS), dysphoria, treatment of alcohol-use disorders, and methamphetamine dependence (https://clinicaltrials.gov/ct2/results?cond=ibudilast&term=&cntry=&state=&city=&dist=).…”

Glioblastoma Myeloid-Derived Suppressor Cell Subsets Express Differential Macrophage Migration Inhibitory Factor Receptor Profiles That Can Be Targeted to Reduce Immune Suppression

“…By contrast, MIF signaling through CXCR2 primarily through PI3K/Akt-dependent signaling with Ca transients (41). The pharmacologic targeting of MIF has also been of great interest in a variety of inflammatory conditions including multiple sclerosis, systemic lupus erythrematosus, rheumatoid arthritis, inflammatory bowel disease, and other inflammatory disorders (32,(42)(43)(44)(45)(46)(47)(48)(49). Additionally, clinically approved MIF inhibitors have been developed that could potentially be repurposed for GBM (42).…”

Emerging Role of the Macrophage Migration Inhibitory Factor Family of Cytokines in Neuroblastoma. Pathogenic Effectors and Novel Therapeutic Targets?

“…Furthermore, the anti-MIF monoclonal antibodies were effective in vitro and in vivo in prostate cancer and colon cancer models [15,78]. In addition, add on treatment to temozolomide with the MIF inhibitor ibudilast significantly increased the survival in vivo, in a patient-derived xenograft model of glioblastoma [56].…”

“…Numerous preclinical and clinical studies have demonstrated that MIF is overexpressed and may correlate with tumor aggressiveness in many different types of human cancers such as prostate , bladder, and kidney cancer [30], cervical cancer [20], ovarian cancer [44,45], breast cancer [29], gastric cancer [29], hepatocellular carcinoma [46], colon cancer [47,48], pancreatic cancer [49,50], gallbladder cancer [51], lung cancer [29,52], melanoma [31], head and neck cancer [29], acute myeloid leukemia [53,54], glioblastoma [15,55,56], and NB [57][58][59][60]. Moreover, elevated MIF expression is correlated with a worse patient overall survival in a large variety of cancers such as breast cancer [29], gastric cancer [29], hepatocellular carcinoma [61], pancreatic cancer [49,50], metastatic melanoma [31], head and neck cancer [29], esophageal squamous cell carcinoma [62], acute myeloid leukemia [53], glioblastoma [29,56], and NB [57]. However, conflicting results have also been reported and other studies have shown that, in other types of tumors, endogenous MIF may possess a beneficial anticancer activity.…”