Funded Grants

Investigation of Resistance to the Biological Mediators of Apoptosis Conferred by Expression of the Type III Mutant Epidermal

Despite advances in neurosurgery, radiotherapy and chemotherapy, the vast majority of patients with high grade malignant glial tumours such as glioblastoma multiforme will die within two years of diagnosis. Thus, innovative approaches to the treatment of these diseases are desperately needed.

We and others have demonstrated in pre-clinical models that a number of immune based therapies are effective against brain tumours. We have shown that vaccine strategies using gene modified cells such as cytokine-producing tumour cells, allogeneic gene modified cells or antigen loaded dendritic cells are potent stimulators of immunity against tumours within the CNS in animal (1-3). As well, in another model of immunotherapy we have shown that direct delivery of cytotoxic cytokines, such as TNF a, to the site of CNS tumours can reduce or eliminate tumour growth in mice (2,4). In all of these models the induction of programmed cell death (apoptosis) through biological pathways is pivotal to efficacy.

Thus, it follows that if mechanism exist that render glial tumours resistant to physiological mediators of apoptosis the likelihood of successful immunotherapy is reduced. Such findings would have important implications for the future development of treatment strategies employing immunotherapies.

In this proposal we hypothesise:

i) that the regulation of apoptosis in malignant glioma mediated by the physiological pathways involving factors such as Fas and TNF a are intimately linked to the pathogenesis and behaviour of these diseases.

ii) that a link in the effector pathways exists between the mutant epidermal growth factor receptor (EGFRvIII) expression in approximately 50% of glioblastoma, and the relative resistance observed to Fas and TNF cc related apoptotic events in these tumours.

iii) that any relative resistance to the biological mediators of apoptosis conferred by the expression of the EGFRvIII will in turn lead to a resistance to biological therapies such as active immunotherapy in the form of vaccines or the direct delivery of cytotoxic cytokines.

The overall objectives of this project are to examine the relationship between the physiological pathways controlling programmed cell death and the expression of the EGFRvIII on malignant glioma using a unique species specific syngeneic murine model. Specifically, these studies will explore the significance of interactions between these pathways upon tumourigenesis and resistance to the biological mediators of apoptosis such as TNF a, Fas and perforin/granzyme.

This project also aims to investigate whether EGFRvIII expression mediates inhibition of effective immunotherapies which rely upon the induction of apoptosis via biological pathways. Finally, we will test the hypothesis that the use of agents which specifically inhibit the function of EGFRvIIl will down regulate kinase activity of this receptor and enhance the rate of apoptosis in response to biological therapies.