P08.34 Targeting glioma stem cells with interferon-β

Abstract

Glioblastoma is the most common malignant primary brain tumor in adults. Despite surgery, radiotherapy and chemotherapy, patients suffering from this tumor have a poor prognosis with a median survival still limited to approximately one year in population-based studies. Current standard of care is only moderately effective and patients eventually all succumb to their disease. Therefore, the main effort in the field consists in finding new and better therapies based on increasing knowledge of the complex tumor microenvironment and the signalling pathways that drive this devastating disease. A population of cells within the tumor with stem cell features, now commonly referred to as “glioma-initiating cells” (GIC), has been attributed a central role in the escape of glioblastomas from the current clinical approaches of radio- and chemotherapy. We have recently demonstrated that long-term glioma cell lines (LTC) as well as GIC cultures express receptors for interferon (IFN)-β, IFNAR1 and IFNAR2, and respond to IFN-β with induction of STAT-3 phosphorylation and MxA protein accumulation. Single exposure to IFN-β inhibits cell cycle progression, induces a minor loss of viability, and strongly interferes with sphere formation in GIC cultures. Modelling acquired IFN-β resistance in GIC in vitro induces a stable resistant phenotype defined by clonogenic survival assays which allows to identify resistance mechanisms in more detail. Transcriptomic and proteomic profiling of IFN-β-treated GIC in vitro already revealed candidate molecules potentially mediating these biological responses. We also examined the anti-glioma activity of type I interferons in clinically relevant orthotopic xenogeneic animal models in vivo. Treatment with the more stable pegylated IFN-β significantly prolongs survival in the LN-229 and ZH-161 mouse models. In vivo, IFN-β induces a significant increase in MxA expression in the tumor cells but does not change vessel density. Since IFN-β is widely used for the treatment of human patients with multiple sclerosis, there is considerable knowledge on its safety in patients with brain disease, allowing for rapid translation of novel IFN-β-based strategies into the clinic.