Wednesday, 04 May, 13:00

Presentation Title, “Curing mice with Glioblastoma”

Speaker Profile

B.Sc. in Chemistry at Stockholm University 1988 followed by PhD in Quantum Chemistry at Uppsala University 1992 and a year as postdoc with Russ Boyd at Dalhousie University, Canada. Following positions at Stockholm, Uppsala and Örebro University (Sweden), he came to NUI Galway in 2009 as professor of theoretical biophysical chemistry, and in 2011 moved to his current position at University of Gothenburg.

With over 300 research publications, ~10000 citations and 3 patents, Eriksson is one of the leading Swedish computational chemists. Early work on computational modeling of radical reactions and properties progressed into studies of bio-radicals, radical enzymes and effect of radiation damage to biomolecules. During the last 15 years, Eriksson has focused on modeling of protein structures, protein-protein and protein-ligand interactions, and computational drug development mainly in the area of cancer. Recent work also focuses on development of a novel state-of-the-art Machine Learning tool in drug discovery.

 

Abstract 

From computer to bedside: Curing mice with glioblastoma

Glioblastoma multiforme (GB) is one of the most common forms of brain tumors, with 2-3 individuals per 100 000 developing the disease in any given year.  It is also the most aggressive type, with frequent recurrence after treatment, and with a life expectancy of only 1-2 years post diagnosis. Current standard-of-care (SOC) includes surgical removal, radiation therapy and chemotherapy with temozolomide (TMZ).

New treatment modalities are of utmost need. In our work, we have focused on the high activity of the unfolded protein response (UPR) pathways in GB cells, caused by the upregulated protein synthesis in these. The UPR is the cellular mechanism to cope with a high burden of un/mis-folded proteins in the endoplasmic reticulum (ER), and restore cellular homeostasis. As high or prolonged load of ER-stress instead leads to the cells switching over to apoptosis, our aim is thus to block the main UPR-triggering pathway mediated by the Inositol Requiring Enzyme 1a (IRE1a).

Here we report the discovery of a set of novel and highly potent IRE1a inhibitors. These were developed using a range of advanced computational approaches and verified in in vitro assays, in primary GB cell lines, and in in vivo experiments on mice with orthotopically implanted human GB tumors. In short, our experiments show that these new IRE1 inhibitors pass the blood-brain-barrier and sensitize GB tumor cells to TMZ treatment, leading to full eradication of the tumor and no recurrence noted thus far. These constitute first-in-class compounds and may alter current SOC.