Glioblastoma remains a uniformly lethal disease. Both the alkylating agent temozolomide and oncolytic viruses (engineered to preferentially infect and kill cancer cells) hold promise in treatment of glioblastoma. The effects of combining the two and the mechanisms of their interaction on cancer stem cells were recently investigated by Kanai and colleagues from Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, Transgene, Strasbourg, France, and Fujita Health University, Toyoake, Japan.
In their study, athymic mice with glioblastoma stem cell–derived glioblastoma tumors were treated with the oncolytic herpes simplex virus (HSV) G47Δ and temozolomide. The combination showed synergistic effects in killing glioblastoma stem cells, but not neurons, in association with robust induction of DNA damage.
Mediator of Synergy
Studies with pharmacologic inhibitors and short-hairpin RNA (shRNA)–mediated knockdown of DNA repair pathways showed that activated ataxia telangiectasia mutated (ATM), a kinase that normally repairs DNA breaks, was a crucial mediator of synergy. Activated ATM was relocalized to HSV DNA replication compartments, where it appeared to enhance oncogenic HSV replication and to be prevented from participating in repair of temozolomide-induced DNA damage. The combination of G47Δ and temozolomide prolonged survival of mice with glioblastoma stem cell–derived intracranial tumors, achieving long-term remission in four of eight mice at temozolomide doses attainable in patients.
The investigators summarized their findings by stating “The combination of G47Δ and temozolomide acts synergistically in killing [glioblastoma stem cells] through oncogenic HSV-mediated manipulation of DNA damage responses. This strategy is highly efficacious in representative preclinical models and warrants clinical translation.” ■
Kanai R, et al: J Natl Cancer Inst 104:42-55, 2012.