Glioblastoma
Multiforme (GBM) is the most commonly diagnosed and deadly glioma type yet
remains uncurable despite the advances in understanding the underlying biology
of this disease. Targeted therapies looking to exploit oncogenic pathways
involved in malignancy have reached clinical trials however lack of success in
effecting outcome highlight the inadequacy of current targets and need for
novel approaches. Using the TCGA and Rembrandt databases, we have identified
the cAMP/PKA/CREB pathway as a tumour inhibitory pathway which is activated in
patients which have better overall survival and prognosis. Reactivation of this
pathway selectively induces apoptosis in a subset of GBM cell lines expressing
the mesenchymal marker CD44 through CREB mediated transcription of the
pro-apoptotic factor BIM. Furthermore,
we have found that activation of cAMP/PKA/CREB enhances the cytotoxic effect of
the alkylating agent Temozolomide (TMZ). Finally, we identify a clinically
relevant patient population in which reactivation of the cAMP/PKA/CREB pathway
may be used as a novel target for the treatment of GBM.