Drug resistance and new therapeutic targets in adult malignant glioma

Malignant glioma are the most common type of brain tumour in adults and in the UK, about 4500 people each year develop this kind of tumour.

The majority of patients do not respond well to conventional therapeutic regimens of surgical resection, radiation therapy and adjuvant chemotherapy and median survival is less than nine months. Only 5-10% of patients survive 2 years and there are virtually no five-year survivors.

The intrinsic chemoresistance of glioma is primarily due to the failure of tumour cells to undergo activation of apoptosis following exposure to cytotoxic drugs.

We have characterised abnormalities in the gene expression of key components of the apoptotic regulatory network involved in chemoresistance to CCNU, doxorubicin and vincristine in GBM. We are investigating whether inhibition of upregulated genes through siRNA or re-expression of deleted/methylated/mutated genes will increase the propensity of astrocytoma cells to undergo apoptosis and/or to enhance the sensitivity to established cytotoxic agents.

Using high-density genomic arrays, we have identified a number of amplified genes in GBM which have functions primarily associated with DNA damage and repair, cell cycle check-point control, homologous recombination, microtubule formation, migration and energy metabolism regulation, including glucose.

There is substantial evidence to suggest that tumour environment, including oxygen and nutrient availability, regulates gene expression and influences cell behaviour. We are currently investigating how down-regulation of these novel amplified genes through siRNA or pharmacological inhibition and modulation of metabolic pathways reduces tumour cell proliferation and invasion/migration.