The epidermal growth factor receptor (EGFR) gene is frequently mutated in glioblastoma multiforme (GBM), affecting almost 30% of all GBM patients. Furthermore, a constitutively activated form of the receptor, encoded by EGFRvIII, also occurs in a high proportion of high-grade glioma tumors, especially when the EGFR gene is amplified (Lau, Magill et al. 2014).
Current therapies for GBM are unsatisfactory. Standard therapy, comprising post-resection radiotherapy with alkylating chemotherapy followed by adjuvant chemotherapy, leads to a median survival of 14.6 months with a two-year survival of 26.5% (Stupp, Mason et al. 2005). Patients with favourable MGMT promotor methylation status have a two-year survival of 46%, with a median survival of 21.7 months (Hegi, Diserens et al. 2005).
Currently, some EGFR antagonists and inhibitors, including gefitinib, tarceva, erlotinib, and cetuximab, are approved for use in other human cancers (e.g. colon cancer). Unfortunately these targetted drugs have had a limited benefit in GBM (Lau, Magill et al. 2014).
Purified full-length EGFR will be assembled into discoidal phospholipid bilayer membranes, termed nanodiscs, with the size of the nanodisc determined by the Membrane Structural Protein (MSP) (Nath, Atkins et al. 2007). In this format not only the structure of the EGFR, but the binding and action of selected antibody antagonists and EGFR kinase inhibitors will be investigated. The effects of these agents on the structure of nanodisc-EGFR will be investigated by electron microscopy.
We will present the cytostatic and cytotoxic effects of agents which target the EGFR in a gliosphere model in vitro, with a view to improving the killing of glioma cell in vivo. The effects of pair-wise combinations of antibodies, conjugated-affibodies (e.g.polyethyleneimine-polyethyleneglycol (PEI-PEG)- polyinosine/cytosine (polyIC) congugates (Abourbeh, Shir et al. 2012), kinase inhibitors and/or pro-apoptotic drugs on the survival of human gliospheres in vitro will be compared.