Ibudilast Plus Temozolomide Shows Preclinical Promise in Glioblastoma

The anti-inflammatory ibudilast shows early preclinical promise against glioblastoma cell lines when combined with temozolomide, according to research presented at the 21st Annual Scientific Meeting of the Society for Neuro-Oncology, held November 17–20 in Scottsdale, Arizona.

“The combination of ibudilast and temozolomide leads to increases in apoptotic cell death in patient-derived cell lines,” said Kerrie Leanne McDonald of the Cure Brain Cancer Neuro-oncology Laboratory at the University of New South Wales in Kensington, Australia. “Ibudilast synergizes with temozolomide, leading to significant decreases in cell proliferation.”

Temozolomide is a first-line treatment for high-grade gliomas. Standard treatment for patients with newly diagnosed glioblastoma is concurrent radiation plus temozolomide, followed by adjuvant temozolomide.

Patients with MGMT promoter methylated glioblastomas have a survival advantage with this regimen, over patients with MGMT promoter unmethylated glioblastomas.

McDonald noted that despite the improvement, relapse occurs. “We are trying to understand those mechanisms of acquired relapse; we don’t understand why, inevitably, all glioblastomas relapse despite initial response to temozolomide.” Candidate mechanisms include MGMT re-expression and increased homologous repair.

McDonald and her team sought to compare proteomic profiles for MGMT promoter methylated glioblastoma samples from patients who survived less than 1 year vs those who survived at least 1 year; they also searched for biomarkers of patient outcome. They found that higher macrophage inhibitory factor (MIF) levels of expression were associated with poorer survival among patients with MGMT promoter methylated glioblastomas; there were high expression levels of MIF and its receptor, CD74, in 57% of glioblastoma samples studied.

MIF is a cytokine associated with inflammation and tumorigenesis, and is highly expressed in stem cells. High expression of MIF and CD74 were associated with poor overall survival (9.5 vs 15.76 months; P = .007), McDonald reported.

Inhibition of MIF using siRNA led to decreased cell line proliferation after 24 hours. It also led to increased glioblastoma cell sensitivity to temozolomide. These findings led the team to search for MIF inhibitors to investigate for possible development for use in this patient population.

“We tried ISO-1 but it is a large-molecular-weight drug and we had to use high doses,” said McDonald. “We went back and found ibudilast, which is actually quite famous in Japan, where it is used to treat chronic asthma and bronchitis.”

Ibudilast is an anti-cytokine small molecule that inhibits the binding of MIF to CD74. Its half-life in animals is not yet known. But because it shows promise in preclinical models of multiple sclerosis, the team knew that it can cross the blood-brain barrier.

“MIF binds to CD74 and forms a complex with CXCR, CD44, and Src kinase,” said McDonald. “This complex activates integrin and genes involved in the promotion of the cell cycle and inhibition of apoptosis.”

Combined ibudilast and temozolomide exposure was associated with an increase in cleaved poly (ADP-ribose) polymerase and significantly decreased levels of p44/42, AKT, and pAKT.

Experiments with an orthotopic mouse model will be completed by the end of 2016, noted McDonald. The team hopes next to conduct phase I clinical trials with patients with recurrent glioblastoma.