Radiosensitizing Glioma by Targeting ATM with Small Molecule Inhibitors

Malignant glioma is a devastating and incurable brain cancer. Current standard treatment of malignant glioma is surgery followed by chemotherapy and radiation. Progress during the past few decades in improving long-term survival has been painfully slow with a median overall survival currently at a little more than 1 year. New strategies targeting the DNA damage response, including the ATM (ataxia telangiectasia mutated) kinase, are currently being pursued. ATM is a master regulator of cell cycle checkpoints, DNA repair, and cell death in response to radiation. Pre-clinical studies using novel small molecule inhibitors of the ATM kinase are in progress and results from these look promising for future testing in humans. In fact, one ATM kinase inhibitor is currently in a Phase I trial in combination with chemotherapy of advanced solid cancers. This chapter focuses on discussing recent advances in developing and testing highly specific inhibitors targeting the ATM kinase for cancer therapy with focus on malignant glioma.