Tumor genotype dictates radiosensitization after Atm deletion in primary brainstem glioma models

Katherine Deland; Bryce F. Starr; Joshua S. Mercer; Jovita Byemerwa; Donna M. Crabtree; Nerissa T. Williams; Lixia Luo; Yan Ma; Mark Chen; Oren J. Becher; David G. Kirsch

doi:10.1172/JCI142158

Tumor genotype dictates radiosensitization after Atm deletion in primary brainstem glioma models

Katherine Deland, Bryce F. Starr, Joshua S. Mercer, Jovita Byemerwa, Donna M. Crabtree, Nerissa T. Williams, Lixia Luo, Yan Ma, Mark Chen, Oren J. Becher, David G. Kirsch^*

^*Corresponding author for this work

Pediatrics

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Abstract

Diffuse intrinsic pontine glioma (DIPG) kills more children than any other type of brain tumor. Despite clinical trials testing many chemotherapeutic agents, palliative radiotherapy remains the standard treatment. Here, we utilized Cre/loxP technology to show that deleting Ataxia telangiectasia mutated (Atm) in primary mouse models of DIPG can enhance tumor radiosensitivity. Genetic deletion of Atm improved survival of mice with p53-deficient but not p53 wild-type gliomas after radiotherapy. Similar to patients with DIPG, mice with p53 wild-type tumors had improved survival after radiotherapy independent of Atm deletion. Primary p53 wild-type tumor cell lines induced proapoptotic genes after radiation and repressed the NRF2 target, NAD(P)H quinone dehydrogenase 1 (Nqo1). Tumors lacking p53 and Ink4a/Arf expressed the highest level of Nqo1 and were most resistant to radiation, but deletion of Atm enhanced the radiation response. These results suggest that tumor genotype may determine whether inhibition of ATM during radiotherapy will be an effective clinical approach to treat DIPGs.

Original language	English (US)
Article number	e142158
Journal	Journal of Clinical Investigation
Volume	131
Issue number	1
DOIs	https://doi.org/10.1172/JCI142158
State	Published - Jan 4 2021

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Medicine(all)

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10.1172/JCI142158

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@article{c025a076701c44e083cb13e0502bb074,

title = "Tumor genotype dictates radiosensitization after Atm deletion in primary brainstem glioma models",

abstract = "Diffuse intrinsic pontine glioma (DIPG) kills more children than any other type of brain tumor. Despite clinical trials testing many chemotherapeutic agents, palliative radiotherapy remains the standard treatment. Here, we utilized Cre/loxP technology to show that deleting Ataxia telangiectasia mutated (Atm) in primary mouse models of DIPG can enhance tumor radiosensitivity. Genetic deletion of Atm improved survival of mice with p53-deficient but not p53 wild-type gliomas after radiotherapy. Similar to patients with DIPG, mice with p53 wild-type tumors had improved survival after radiotherapy independent of Atm deletion. Primary p53 wild-type tumor cell lines induced proapoptotic genes after radiation and repressed the NRF2 target, NAD(P)H quinone dehydrogenase 1 (Nqo1). Tumors lacking p53 and Ink4a/Arf expressed the highest level of Nqo1 and were most resistant to radiation, but deletion of Atm enhanced the radiation response. These results suggest that tumor genotype may determine whether inhibition of ATM during radiotherapy will be an effective clinical approach to treat DIPGs.",

author = "Katherine Deland and Starr, {Bryce F.} and Mercer, {Joshua S.} and Jovita Byemerwa and Crabtree, {Donna M.} and Williams, {Nerissa T.} and Lixia Luo and Yan Ma and Mark Chen and Becher, {Oren J.} and Kirsch, {David G.}",

note = "Funding Information: This work is dedicated to the memory of Rose Sugarman, who died from a DIPG. We thank John Nouls from the Duke Center for In Vivo Microscopy for assistance in obtaining the MRI. This work was supported by grants to DGK from the National Cancer Institute (R35 CA197616), Pediatric Brain Tumor Foundation, Hannah{\textquoteright}s Heroes St. Baldrick{\textquoteright}s Research Grant, and The Leon Levine Foundation. DGK and KD were supported by the National Cancer Institute (Duke Brain SPORE P50-CA19099). MC was supported by the National Cancer Institute (F30 CA206424). OJB was supported by Maddox{\textquoteright}s Warriors, the Fly A Kite Foundation, Cristian Rivera Foundation, and the Rory David Deutsch Foundation. Publisher Copyright: {\textcopyright} 2021, American Society for Clinical Investigation.",

year = "2021",

month = jan,

day = "4",

doi = "10.1172/JCI142158",

language = "English (US)",

volume = "131",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

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Tumor genotype dictates radiosensitization after Atm deletion in primary brainstem glioma models. / Deland, Katherine; Starr, Bryce F.; Mercer, Joshua S.; Byemerwa, Jovita; Crabtree, Donna M.; Williams, Nerissa T.; Luo, Lixia; Ma, Yan; Chen, Mark; Becher, Oren J.; Kirsch, David G.

In: Journal of Clinical Investigation, Vol. 131, No. 1, e142158, 04.01.2021.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Tumor genotype dictates radiosensitization after Atm deletion in primary brainstem glioma models

AU - Deland, Katherine

AU - Starr, Bryce F.

AU - Mercer, Joshua S.

AU - Byemerwa, Jovita

AU - Crabtree, Donna M.

AU - Williams, Nerissa T.

AU - Luo, Lixia

AU - Ma, Yan

AU - Chen, Mark

AU - Becher, Oren J.

AU - Kirsch, David G.

N1 - Funding Information: This work is dedicated to the memory of Rose Sugarman, who died from a DIPG. We thank John Nouls from the Duke Center for In Vivo Microscopy for assistance in obtaining the MRI. This work was supported by grants to DGK from the National Cancer Institute (R35 CA197616), Pediatric Brain Tumor Foundation, Hannah’s Heroes St. Baldrick’s Research Grant, and The Leon Levine Foundation. DGK and KD were supported by the National Cancer Institute (Duke Brain SPORE P50-CA19099). MC was supported by the National Cancer Institute (F30 CA206424). OJB was supported by Maddox’s Warriors, the Fly A Kite Foundation, Cristian Rivera Foundation, and the Rory David Deutsch Foundation. Publisher Copyright: © 2021, American Society for Clinical Investigation.

PY - 2021/1/4

Y1 - 2021/1/4

N2 - Diffuse intrinsic pontine glioma (DIPG) kills more children than any other type of brain tumor. Despite clinical trials testing many chemotherapeutic agents, palliative radiotherapy remains the standard treatment. Here, we utilized Cre/loxP technology to show that deleting Ataxia telangiectasia mutated (Atm) in primary mouse models of DIPG can enhance tumor radiosensitivity. Genetic deletion of Atm improved survival of mice with p53-deficient but not p53 wild-type gliomas after radiotherapy. Similar to patients with DIPG, mice with p53 wild-type tumors had improved survival after radiotherapy independent of Atm deletion. Primary p53 wild-type tumor cell lines induced proapoptotic genes after radiation and repressed the NRF2 target, NAD(P)H quinone dehydrogenase 1 (Nqo1). Tumors lacking p53 and Ink4a/Arf expressed the highest level of Nqo1 and were most resistant to radiation, but deletion of Atm enhanced the radiation response. These results suggest that tumor genotype may determine whether inhibition of ATM during radiotherapy will be an effective clinical approach to treat DIPGs.

AB - Diffuse intrinsic pontine glioma (DIPG) kills more children than any other type of brain tumor. Despite clinical trials testing many chemotherapeutic agents, palliative radiotherapy remains the standard treatment. Here, we utilized Cre/loxP technology to show that deleting Ataxia telangiectasia mutated (Atm) in primary mouse models of DIPG can enhance tumor radiosensitivity. Genetic deletion of Atm improved survival of mice with p53-deficient but not p53 wild-type gliomas after radiotherapy. Similar to patients with DIPG, mice with p53 wild-type tumors had improved survival after radiotherapy independent of Atm deletion. Primary p53 wild-type tumor cell lines induced proapoptotic genes after radiation and repressed the NRF2 target, NAD(P)H quinone dehydrogenase 1 (Nqo1). Tumors lacking p53 and Ink4a/Arf expressed the highest level of Nqo1 and were most resistant to radiation, but deletion of Atm enhanced the radiation response. These results suggest that tumor genotype may determine whether inhibition of ATM during radiotherapy will be an effective clinical approach to treat DIPGs.

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SN - 0021-9738

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Tumor genotype dictates radiosensitization after Atm deletion in primary brainstem glioma models

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