Inhibition of DNA double-strand break repair by the dual PI3K/mTOR inhibitor NVP-BEZ235 as a strategy for radiosensitization of glioblastoma

Carlos Rodrigo Gil Del Alcazar, Molly Catherine Hardebeck, Bipasha Mukherjee, Nozomi Tomimatsu, Xiaohuan Gao, Jingsheng Yan, Xian Jin Xie, Robert Bachoo, Li Li, Amyn A. Habib, Sandeep Burma

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Abstract

Purpose: Inhibitors of the DNA damage response (DDR) have great potential for radiosensitization of numerous cancers, including glioblastomas, which are extremely radio- and chemoresistant brain tumors. Currently, there are no DNA double-strand break (DSB) repair inhibitors that have been successful in treating glioblastoma. Our laboratory previously demonstrated that the dual phosphoinositide 3-kinase/mTOR inhibitor NVP-BEZ235 can potently inhibit the two central DDR kinases, DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and ataxia-telangiectasia mutated (ATM), in vitro. Here, we tested whether NVP-BEZ235 could also inhibit ATM and DNA-PKcs in tumors in vivo and assessed its potential as a radio- and chemosensitizer in preclinical mouse glioblastoma models. Experimental Design: The radiosensitizing effect of NVP-BEZ235 was tested by following tumor growth in subcutaneous and orthotopic glioblastoma models. Tumors were generated using the radioresistant U87- vIII glioma cell line and GBM9 neurospheres in nude mice. These tumors were then treated with ionizing radiation and/or NVP-BEZ235 and analyzed for DNA-PKcs and ATM activation, DSB repair inhibition, and attenuation of growth. Results: NVP-BEZ235 potently inhibited both DNA-PKcs and ATM kinases and attenuated the repair of ionizing radiation-induced DNA damage in tumors. This resulted in striking tumor radiosensitization, which extended the survival of brain tumor-bearing mice. Notably, tumors displayed a higher DSB-load when compared with normal brain tissue. NVP-BEZ235 also sensitized a subset of subcutaneous tumors to temozolomide, a drug routinely used concurrently with ionizing radiation for the treatment of glioblastoma. Conclusions: These results demonstrate that it may be possible to significantly improve glioblastoma therapy by combining ionizing radiation with potent and bioavailable DNA repair inhibitors such as NVPBEZ235.

Original languageEnglish (US)
Pages (from-to)1235-1248
Number of pages14
JournalClinical Cancer Research
Volume20
Issue number5
DOIs
StatePublished - 2014

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Double-Stranded DNA Breaks
Glioblastoma
Phosphatidylinositol 3-Kinases
DNA-Activated Protein Kinase
Ataxia Telangiectasia
Ionizing Radiation
Neoplasms
Catalytic Domain
DNA Damage
temozolomide
Radio
Brain Neoplasms
Phosphotransferases
Radiation-Sensitizing Agents
dactolisib
1-Phosphatidylinositol 4-Kinase
Growth
Nude Mice
Glioma
DNA Repair

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Inhibition of DNA double-strand break repair by the dual PI3K/mTOR inhibitor NVP-BEZ235 as a strategy for radiosensitization of glioblastoma. / Gil Del Alcazar, Carlos Rodrigo; Hardebeck, Molly Catherine; Mukherjee, Bipasha; Tomimatsu, Nozomi; Gao, Xiaohuan; Yan, Jingsheng; Xie, Xian Jin; Bachoo, Robert; Li, Li; Habib, Amyn A.; Burma, Sandeep.

In: Clinical Cancer Research, Vol. 20, No. 5, 2014, p. 1235-1248.

Research output: Contribution to journalArticle

Gil Del Alcazar, Carlos Rodrigo ; Hardebeck, Molly Catherine ; Mukherjee, Bipasha ; Tomimatsu, Nozomi ; Gao, Xiaohuan ; Yan, Jingsheng ; Xie, Xian Jin ; Bachoo, Robert ; Li, Li ; Habib, Amyn A. ; Burma, Sandeep. / Inhibition of DNA double-strand break repair by the dual PI3K/mTOR inhibitor NVP-BEZ235 as a strategy for radiosensitization of glioblastoma. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 5. pp. 1235-1248.
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abstract = "Purpose: Inhibitors of the DNA damage response (DDR) have great potential for radiosensitization of numerous cancers, including glioblastomas, which are extremely radio- and chemoresistant brain tumors. Currently, there are no DNA double-strand break (DSB) repair inhibitors that have been successful in treating glioblastoma. Our laboratory previously demonstrated that the dual phosphoinositide 3-kinase/mTOR inhibitor NVP-BEZ235 can potently inhibit the two central DDR kinases, DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and ataxia-telangiectasia mutated (ATM), in vitro. Here, we tested whether NVP-BEZ235 could also inhibit ATM and DNA-PKcs in tumors in vivo and assessed its potential as a radio- and chemosensitizer in preclinical mouse glioblastoma models. Experimental Design: The radiosensitizing effect of NVP-BEZ235 was tested by following tumor growth in subcutaneous and orthotopic glioblastoma models. Tumors were generated using the radioresistant U87- vIII glioma cell line and GBM9 neurospheres in nude mice. These tumors were then treated with ionizing radiation and/or NVP-BEZ235 and analyzed for DNA-PKcs and ATM activation, DSB repair inhibition, and attenuation of growth. Results: NVP-BEZ235 potently inhibited both DNA-PKcs and ATM kinases and attenuated the repair of ionizing radiation-induced DNA damage in tumors. This resulted in striking tumor radiosensitization, which extended the survival of brain tumor-bearing mice. Notably, tumors displayed a higher DSB-load when compared with normal brain tissue. NVP-BEZ235 also sensitized a subset of subcutaneous tumors to temozolomide, a drug routinely used concurrently with ionizing radiation for the treatment of glioblastoma. Conclusions: These results demonstrate that it may be possible to significantly improve glioblastoma therapy by combining ionizing radiation with potent and bioavailable DNA repair inhibitors such as NVPBEZ235.",
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AU - Hardebeck, Molly Catherine

AU - Mukherjee, Bipasha

AU - Tomimatsu, Nozomi

AU - Gao, Xiaohuan

AU - Yan, Jingsheng

AU - Xie, Xian Jin

AU - Bachoo, Robert

AU - Li, Li

AU - Habib, Amyn A.

AU - Burma, Sandeep

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AB - Purpose: Inhibitors of the DNA damage response (DDR) have great potential for radiosensitization of numerous cancers, including glioblastomas, which are extremely radio- and chemoresistant brain tumors. Currently, there are no DNA double-strand break (DSB) repair inhibitors that have been successful in treating glioblastoma. Our laboratory previously demonstrated that the dual phosphoinositide 3-kinase/mTOR inhibitor NVP-BEZ235 can potently inhibit the two central DDR kinases, DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and ataxia-telangiectasia mutated (ATM), in vitro. Here, we tested whether NVP-BEZ235 could also inhibit ATM and DNA-PKcs in tumors in vivo and assessed its potential as a radio- and chemosensitizer in preclinical mouse glioblastoma models. Experimental Design: The radiosensitizing effect of NVP-BEZ235 was tested by following tumor growth in subcutaneous and orthotopic glioblastoma models. Tumors were generated using the radioresistant U87- vIII glioma cell line and GBM9 neurospheres in nude mice. These tumors were then treated with ionizing radiation and/or NVP-BEZ235 and analyzed for DNA-PKcs and ATM activation, DSB repair inhibition, and attenuation of growth. Results: NVP-BEZ235 potently inhibited both DNA-PKcs and ATM kinases and attenuated the repair of ionizing radiation-induced DNA damage in tumors. This resulted in striking tumor radiosensitization, which extended the survival of brain tumor-bearing mice. Notably, tumors displayed a higher DSB-load when compared with normal brain tissue. NVP-BEZ235 also sensitized a subset of subcutaneous tumors to temozolomide, a drug routinely used concurrently with ionizing radiation for the treatment of glioblastoma. Conclusions: These results demonstrate that it may be possible to significantly improve glioblastoma therapy by combining ionizing radiation with potent and bioavailable DNA repair inhibitors such as NVPBEZ235.

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