Malignant glioma drug discovery – targeting protein kinases

Abstract

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.

Keywords::

• glioblastoma
• glioma
• protein kinase
• serine/threonine
• signal transduction
• targeted therapy
• tyrosine

Acknowledgements

Supported in part by funds from the Childhood Brain Tumour Foundation, Accelerate Brain Cancer Cure and the Pediatric Brain Tumour Foundation of the United States. This work was also supported by NIH grants NS047409, NS054276 and CA 116659. JN Rich is a Damon Runyon-Lilly Clinical Investigator supported by the Damon Runyon Cancer Research Foundation and a Sidney Kimmel Cancer Foundation Scholar.