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Preparation of Peripheral Blood Mononuclear Cell Pellets and Plasma from a Single Blood Draw at Clinical Trial Sites for Biomarker Analysis
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ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation

Laura Biddlestone-Thorpe1, Muhammad Sajjad, Elizabeth Rosenberg

  • 1Department of Radiation Oncology, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23112, USA.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|April 27, 2013
PubMed
Abstract

Insights

The ATM kinase inhibitor KU-60019 effectively radiosensitizes glioblastoma multiforme (GBM) in vivo, significantly increasing survival in mice. Glioma with mutant p53 showed greater sensitivity to this radiosensitization therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Radiotherapy

Background:

  • Glioblastoma multiforme (GBM) is an aggressive brain cancer with poor prognosis.
  • Current treatments (surgery, chemoradiation) are limited by tumor invasiveness and resistance.
  • Ataxia-telangiectasia mutated (ATM) is crucial for DNA damage response and a potential target for radiosensitization.

Purpose of the Study:

  • To evaluate the in vivo efficacy of the novel ATM kinase inhibitor KU-60019 as a radiosensitizer for glioblastoma.
  • To investigate the differential sensitivity of glioma with wild-type versus mutant p53 to KU-60019-mediated radiosensitization.

Main Methods:

  • Orthotopic xenograft models of GBM were established in mice.
  • KU-60019 was administered intratumorally via convection-enhanced delivery or osmotic pump.
  • Tumor growth, dispersal, and survival were monitored in response to KU-60019 and radiation therapy.

Main Results:

  • Combined KU-60019 and radiation significantly increased mouse survival 2- to 3-fold compared to controls.
  • Glioma with mutant p53 demonstrated markedly higher sensitivity to KU-60019 radiosensitization than wild-type glioma.
  • KU-60019 demonstrated in vitro efficacy in reducing glioma cell migration, invasion, and growth, and potentiating radiosensitivity.

Conclusions:

  • ATM kinase inhibitors like KU-60019 show promise as effective radiosensitizers for GBM.
  • Mutant p53 status may predict patient response to ATM inhibitor-based adjuvant therapies.
  • ATM inhibitors represent a potential therapeutic strategy for mutant p53 brain cancers.

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