Malignant gliomas are uncommon, but extremely lethal,
cancers. Current standard-of-care includes surgery, radiation and
chemotherapy, but recent research has generated a shift towards targeting the aberrant signal transduction components that underlie the pathogenesis of
malignant gliomas.
Protein kinases are a family of
enzymes that are key elements in signal transduction-regulated cellular homeostasis subdivided based on their catalytic activity into
tyrosine kinases and
serine/threonine kinases.
Protein kinases can be deregulated by several mechanisms, including genomic rearrangement, mutations of oncogenes or loss of tumour suppressor genes and overexpression or mutation of
growth factor receptors to contribute to
cancer initiation and maintenance. In
malignant gliomas, several
protein kinases are commonly over activated and may represent new therapeutic targets. Two main classes of agents targeting
protein kinases are
monoclonal antibodies and small-molecule inhibitors. In clinical trials, these molecularly targeted
therapies have demonstrated limited efficacy as single agents in unselected
malignant glioma patient populations. Several mechanisms of the failure of targeted agent monotherapies have been elucidated as new therapeutic strategies have emerged to overcome the resistance. Multi-targeted
kinase inhibitors and combinations of single-targeted
kinase inhibitors with one another or with traditional cytotoxics may increase treatment efficacy. Identification of
biomarkers of response or resistance will be of paramount importance to enrich patients for specific targeted agents based on their genetic/molecular signature. In this review, the authors discuss the role of
protein kinases in
malignant glioma and how to target aberrant
protein kinases with novel
therapeutics.