Kerrie McDonald, PhD
Combination therapy with ibudilast (AV411) and temozolomide for glioblastoma multiforme (GBM) increased apoptosis and prolonged survival by significantly reducing macrophage inhibitory factor (MIF) and receptor CD74 expression, according to in vitro findings presented at the 2016 Society for Neuro-Oncology (SNO) Annual Meeting.
“The MIF pathway is regulated by both the paracrine and endocrine systems,” noted professor Kerrie McDonald, PhD, of the Neuro-Oncology Group at the University of New South Wales in Australia. MIF directly binds to CXCR (the C-X-C motif chemokine receptors), which affects the Src-kinase and thus MAPK/ERK, PI3K/Akt, and p53. Additionally, it is a cytokine associated with inflammation and tumorigenesis. Recurrent GBM tends to have increased expression of MIF and its receptor CD74, which are associated with shorter overall survival.
In previous research, siRNA could be used to inhibit MIF, decreasing cell proliferation, and potentially prolonging life. McDonald explained that her previous research had explored the MIF-antagonist ISO-1, but its high molecular weight meant that very high doses were needed, leading to the exploration of ibudilast, which is an anti-inflammatory agent that blocks MIF.
At this time, ibudilast is mainly used in Japan for chronic asthma and bronchitis, along with multiple sclerosis. In the United States, ibudilast received an orphan drug designation from the FDA in October 2016 as a potential treatment for patients with amyotrophic lateral sclerosis (ALS). McDonald stated that its use for sclerosis indicates that it can cross the blood-brain barrier.
In studies assessing patient-derived cell lines (PDCLs), the combination of ibudilast and temozolomide led to synergies that were apparent by the inhibition of cell growth and by reduced MIF protein. Further, the combination of ibudilast and temozolomide affects the cell cycle, as the G1 phase is decreased and the G2 phase is increased. Apoptosis was induced by the combination.
Synergies between the two therapies were apparent, regardless of the methylation status of MGMT, which can impact the duration of survival for patients with GBM. In a separate study, McDonald’s research team compared patients with GBM who did and did not survive for over 1 year, based on their MGMT methylation status. In general, those with MGMT methylated GBM tend to have a longer overall survival, although most still develop recurrence. “Despite initial responses to temozolomide, all patients with GBM inevitably relapse,” said McDonald.
Together, findings from the PDCLs and MGMT research led to the formation of a study exploring the combination in patient-derived xenograft models of GBM along with PDCLs that are either MGMT-methylated or MGMT-unmethylated. The study has 6 treatment arms: ibudilast at 5 mg/kg, ibudilast at 20 mg/kg, temozolomide at 10 mg/kg, ibudilast at 5 mg/kg and temozolomide at 10 mg/kg, ibudilast at 20 mg/kg and temozolomide at 10 mg/kg, and control.
McDonald did not present data on these mice at SNO, despite having planned to do so. She stated that they were surviving longer than expected and so data were not yet available. However, based on the preclinical research and the longevity already seen in the mice, McDonald believes that a phase I/II trial is warranted for patients with recurrent GBM. At this time, this study has not yet been opened but could soon be on the horizon.
McDonald K, Ha W, Nalkiram HS, et al. Repurposing ibudilast in combination with temozolomide for glioblastoma. Neuro-Oncology. 2016; 18:abstract EXTH-18.<<< View more from the 2016 SNO Annual Meeting