The Effect of Atm Loss on Radiosensitivity of a Primary Mouse Model of Pten-Deleted Brainstem Glioma.

Abstract

Simple SummaryBrainstem gliomas are deadly childhood brain tumors and new treatments are needed. The treatment meeting the standard of care is radiation therapy, but the tumors inevitably progress at some point after this treatment. One treatment strategy under preclinical investigation for brainstem gliomas is to inhibit the function of ataxia–telangiectasia mutated kinase (ATM), a master regulator of the cellular response to radiation therapy. ATM inhibition makes some tumors more sensitive to radiation therapy, but this may depend on the genetic makeup of the tumor. An important subset of brainstem gliomas harbor mutations in the PTEN gene or related genes. Here, we develop a genetically engineered mouse model of Pten-mutated brainstem glioma. We use genetic tools to test if ATM inactivation can enhance the efficacy of radiation therapy in this Pten-mutated brainstem glioma model. We find that ATM inactivation does not enhance the efficacy of radiation therapy for this model of Pten-mutated brainstem glioma. These findings indicate that PTEN mutational status should be considered in the design of inclusion criteria and correlative studies for future clinical trials of ATM inhibitors in brainstem glioma patients.Diffuse midline gliomas arise in the brainstem and other midline brain structures and cause a large proportion of childhood brain tumor deaths. Radiation therapy is the most effective treatment option, but these tumors ultimately progress. Inhibition of the phosphoinositide-3-kinase (PI3K)-like kinase, ataxia–telangiectasia mutated (ATM), which orchestrates the cellular response to radiation-induced DNA damage, may enhance the efficacy of radiation therapy. Diffuse midline gliomas in the brainstem contain loss-of-function mutations in the tumor suppressor PTEN, or functionally similar alterations in the phosphoinositide-3-kinase (PI3K) pathway, at moderate frequency. Here, we sought to determine if ATM inactivation could radiosensitize a primary mouse model of brainstem glioma driven by Pten loss. Using Cre/loxP recombinase technology and the RCAS/TVA retroviral gene delivery system, we established a mouse model of brainstem glioma driven by Pten deletion. We find that Pten-null brainstem gliomas are relatively radiosensitive at baseline. In addition, we show that deletion of Atm in the tumor cells does not extend survival of mice bearing Pten-null brainstem gliomas after focal brain irradiation. These results characterize a novel primary mouse model of PTEN-mutated brainstem glioma and provide insights into the mechanism of radiosensitization by ATM deletion, which may guide the design of future clinical trials.