Le Rhun Emilie, Achenbach Caroline, Lohmann Birthe, Silginer Manuela, Schneider Hannah, Meetze Kristan, Szabo Emese, Weller Michael (2019), Profound, durable and MGMT‐independent sensitivity of glioblastoma cells to cyclin‐dependent kinase inhibition, in International Journal of Cancer
, 145(1), 242-253.
Schneider Hannah, Lohmann Birthe, Wirsching Hans-Georg, Hasenbach Kathy, Rushing Elisabeth J., Frei Karl, Pruschy Martin, Tabatabai Ghazaleh, Weller Michael (2017), Age-associated and therapy-induced alterations in the cellular microenvironment of experimental gliomas, in Oncotarget
, 8(50), 87124-87135.
Silginer Manuela, Nagy Sara, Happold Caroline, Schneider Hannah, Weller Michael, Roth Patrick (2017), Autocrine activation of the IFN signaling pathway may promote immune escape in glioblastoma, in Neuro-Oncology
, 19(10), 1338-1349.
The median survival of patients with glioblastoma, the most malignant subtype of glioma, is still limited to approximately one year, despite multi-modal therapy, in population-based studies. The introduction of the alkylating agent temozolomide (TMZ) has improved the outcome selectively in glioblastoma patients with tumors exhibiting promoter methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene, but even these patients eventually all die from their disease. Anti-angiogenic agents such as bevacizumab or cilengitide did not prolong survival in phase III clinical trials reported in 2014. A population of tumor cells 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 current clinical approaches of radiotherapy (RT), classical cytotoxic chemotherapy, and anti-angiogenesis.We have characterized (i) a type I (alpha/beta) interferon-dependent pathway of sensitization of GIC cultures to TMZ and RT, (ii) a specific inhibitory activity of IFN-beta against sphere formation capacity, a hallmark of stemness in GIC cultures, and (iii) a profound survival prolongation of nude mice carrying orthotopic LN-229 human glioma xenografts in response to systemic pegylated IFN-beta treatment. We have performed transcriptomic and proteomic profiling of IFN-beta-treated GIC in vitro to identify candidate genes mediating these biological responses. Since several immune relevant genes were identified in these analyses, too, we propose to establish syngeneic mouse glioma models to study efficacy, safety and tolerability of GIC-targeted IFN-beta therapy, including analyses not only of intrinsic glioma cell responses, but also of altered immune cell responses and microenvironmental changes. Since IFN-beta 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-beta-based strategies into the clinic.