ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation

Laura Biddlestone-Thorpe, Muhammad Sajjad, Elizabeth Rosenberg, Jason M. Beckta, Nicholas C K Valerie, Mary Tokarz, Bret R. Adams, Alison F. Wagner, Ashraf Khalil, Donna Gilfor, Sarah E. Golding, Sumitra Deb, David G. Temesi, Alan Lau, Mark J. O'Connor, Kevin S. Choe, Luis F. Parada, Sang Kyun Lim, Nitai D. Mukhopadhyay, Kristoffer Valerie

Research output: Contribution to journalArticle

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Abstract

Purpose: Glioblastoma multiforme (GBM) is the most lethal form of brain cancer with a median survival of only 12 to 15 months. Current standard treatment consists of surgery followed by chemoradiation. The poor survival of patients with GBM is due to aggressive tumor invasiveness, an inability to remove all tumor tissue, and an innate tumor chemo- and radioresistance. Ataxia-telangiectasia mutated (ATM) is an excellent target for radiosensitizing GBM because of its critical role in regulating the DNA damage response and p53, among other cellular processes. As a first step toward this goal, we recently showed that the novel ATM kinase inhibitor KU-60019 reduced migration, invasion, and growth, and potently radiosensitized human glioma cells in vitro. Experimental Design: Using orthotopic xenograft models of GBM, we now show that KU-60019 is also an effective radiosensitizer in vivo. Human glioma cells expressing reporter genes for monitoring tumor growth and dispersal were grown intracranially, and KU-60019 was administered intratumorally by convection-enhanced delivery or osmotic pump. Results: Our results show that the combined effect of KU-60019 and radiation significantly increased survival of mice 2- to 3-fold over controls. Importantly, we show that glioma with mutant p53 is much more sensitive to KU-60019 radiosensitization than genetically matched wild-type glioma. Conclusions: Taken together, our results suggest that an ATM kinase inhibitor may be an effective radiosensitizer and adjuvant therapy for patients with mutant p53 brain cancers.

Original languageEnglish (US)
Pages (from-to)3189-3200
Number of pages12
JournalClinical Cancer Research
Volume19
Issue number12
DOIs
StatePublished - Jun 15 2013

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Ataxia Telangiectasia
Ionizing Radiation
Glioma
Glioblastoma
Phosphotransferases
Brain Neoplasms
Neoplasms
Convection
Survival
Growth
Reporter Genes
Heterografts
DNA Damage
Research Design
2-(2,6-dimethylmorpholin-4-yl)-N-(5-(6-morpholin-4-yl-4-oxo-4H-pyran-2-yl)-9H-thioxanthen-2-yl)acetamide
Radiation
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Biddlestone-Thorpe, L., Sajjad, M., Rosenberg, E., Beckta, J. M., Valerie, N. C. K., Tokarz, M., ... Valerie, K. (2013). ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation. Clinical Cancer Research, 19(12), 3189-3200. https://doi.org/10.1158/1078-0432.CCR-12-3408

ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation. / Biddlestone-Thorpe, Laura; Sajjad, Muhammad; Rosenberg, Elizabeth; Beckta, Jason M.; Valerie, Nicholas C K; Tokarz, Mary; Adams, Bret R.; Wagner, Alison F.; Khalil, Ashraf; Gilfor, Donna; Golding, Sarah E.; Deb, Sumitra; Temesi, David G.; Lau, Alan; O'Connor, Mark J.; Choe, Kevin S.; Parada, Luis F.; Lim, Sang Kyun; Mukhopadhyay, Nitai D.; Valerie, Kristoffer.

In: Clinical Cancer Research, Vol. 19, No. 12, 15.06.2013, p. 3189-3200.

Research output: Contribution to journalArticle

Biddlestone-Thorpe, L, Sajjad, M, Rosenberg, E, Beckta, JM, Valerie, NCK, Tokarz, M, Adams, BR, Wagner, AF, Khalil, A, Gilfor, D, Golding, SE, Deb, S, Temesi, DG, Lau, A, O'Connor, MJ, Choe, KS, Parada, LF, Lim, SK, Mukhopadhyay, ND & Valerie, K 2013, 'ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation', Clinical Cancer Research, vol. 19, no. 12, pp. 3189-3200. https://doi.org/10.1158/1078-0432.CCR-12-3408
Biddlestone-Thorpe L, Sajjad M, Rosenberg E, Beckta JM, Valerie NCK, Tokarz M et al. ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation. Clinical Cancer Research. 2013 Jun 15;19(12):3189-3200. https://doi.org/10.1158/1078-0432.CCR-12-3408
Biddlestone-Thorpe, Laura ; Sajjad, Muhammad ; Rosenberg, Elizabeth ; Beckta, Jason M. ; Valerie, Nicholas C K ; Tokarz, Mary ; Adams, Bret R. ; Wagner, Alison F. ; Khalil, Ashraf ; Gilfor, Donna ; Golding, Sarah E. ; Deb, Sumitra ; Temesi, David G. ; Lau, Alan ; O'Connor, Mark J. ; Choe, Kevin S. ; Parada, Luis F. ; Lim, Sang Kyun ; Mukhopadhyay, Nitai D. ; Valerie, Kristoffer. / ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 12. pp. 3189-3200.
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AU - Deb, Sumitra

AU - Temesi, David G.

AU - Lau, Alan

AU - O'Connor, Mark J.

AU - Choe, Kevin S.

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AU - Lim, Sang Kyun

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