Grant: Doctoral: Vanier Canada Graduate Scholarships

Glioblastoma multiforme (GBM) is one of the most common and difficult to treat forms of brain cancer. It is the leading cause of cancer related deaths in children under the age of 15. GBM tumours frequently show increased expression of certain signalling molecules, leading to the suppression of programmed cell death (apoptosis) in these tumours. This phenomenon correlates with adverse outcomes for patients in response to chemo- or radiation therapy. However, the mechanism of apoptotic suppression in these tumours is still not fully understood. Preliminary data from Dr Holcik's group - at the Children's Hospital of Eastern Ontario Apoptosis Research Center - suggest that programmed cell death gene 4 (PDCD4), a known tumour suppressor, acts as a repressor of the protein expression (translation) of at least two anti-apoptotic genes, XIAP and Bcl-xL that, when simultaneously upregulated, virtually suppress all signals leading to apoptosis. Importantly, PDCD4 protein expression itself is frequently repressed in a substantial percentage of human gliomas and its absence is correlated with a poor prognosis in these cancers, thus highlighting the critical role this protein might play in the regulation of levels of antiapoptotic proteins in gliomas. And so for my PhD research project, I propose to work on understanding how PDCD4 regulates the expression of antiapoptotic proteins such as XIAP and Bcl-xL through the IRES translation regulatory mechanism known to be involved in the enhanced translation of these proteins and to determine the functional consequences of this modulation in GBM. Despite advances in treatments for GBM, the median survival time for patients suffering from it is approximately one year, with a five year survival rate of less than 5%. My research will help verify if specific targeting of antiapoptotic proteins such as XIAP and Bcl-xL provides a possible therapeutic benefit to patients with GBM and help improve the survival rate for this type of cancer.