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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Stewart, CE; Guerra-García, ME; Luo, L; Williams, NT; Ma, Y; Regal, JA; Ghosh, D; Sansone, P; Oldham, M; Deland, K; Becher, OJ; Kirsch, DG; Reitman, ZJ

Published Date

  • September 17, 2022

Published In

Volume / Issue

  • 14 / 18

PubMed ID

  • 36139666

Pubmed Central ID

  • PMC9496888

International Standard Serial Number (ISSN)

  • 2072-6694

Digital Object Identifier (DOI)

  • 10.3390/cancers14184506

Language

  • eng

Conference Location

  • Switzerland