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

doi:10.1158/1078-0432.CCR-13-1607

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

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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, …

Clinical cancer research, Vol.20(5), pp.1235-1248

03/01/2014

DOI: 10.1158/1078-0432.CCR-13-1607

PMCID: PMC3947495

PMID: 24366691

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Abstract

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. 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. 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. 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 NVP-BEZ235.

DNA-Activated Protein Kinase - antagonists & inhibitors

Ataxia Telangiectasia Mutated Proteins - metabolism

Humans

Phosphatidylinositol 3-Kinases - antagonists & inhibitors

Glioblastoma - radiotherapy

Quinolines - pharmacology

DNA-Activated Protein Kinase - chemistry

TOR Serine-Threonine Kinases - antagonists & inhibitors

DNA Breaks, Double-Stranded - drug effects

Glioblastoma - genetics

Dacarbazine - pharmacology

DNA-Activated Protein Kinase - metabolism

Dacarbazine - analogs & derivatives

Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors

Glioblastoma - metabolism

Disease Models, Animal

Catalytic Domain

DNA Repair - drug effects

Protein Interaction Domains and Motifs - drug effects

Radiation-Sensitizing Agents - pharmacology

Mice, Transgenic

Imidazoles - pharmacology

Blood-Brain Barrier - metabolism

Animals

Glioblastoma - pathology

Cell Line, Tumor

Mice

Glioblastoma - drug therapy

Glioblastoma - mortality

Details

Title: Subtitle: Inhibition of DNA double-strand break repair by the dual PI3K/mTOR inhibitor NVP-BEZ235 as a strategy for radiosensitization of glioblastoma
Creators: Carlos Rodrigo Gil del Alcazar - Authors' Affiliations: Departments of Radiation Oncology, Clinical Sciences, and Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center; and VA North Texas Health Care System, Dallas, Texas
Molly Catherine Hardebeck
Bipasha Mukherjee
Nozomi Tomimatsu
Xiaohuan Gao
Jingsheng Yan
Xian-Jin Xie
Robert Bachoo
Li Li - VA North Texas Health Care System
Amyn A Habib
Sandeep Burma
Resource Type: Journal article
Publication Details: Clinical cancer research, Vol.20(5), pp.1235-1248
DOI: 10.1158/1078-0432.CCR-13-1607
PMID: 24366691
PMCID: PMC3947495
NLM abbreviation: Clin Cancer Res
ISSN: 1078-0432
eISSN: 1557-3265
Publisher: United States
Grant note: 5T32GM008203 / NIGMS NIH HHS R01 NS062080 / NINDS NIH HHS P30 CA142543 / NCI NIH HHS T32 GM008203 / NIGMS NIH HHS R01 CA149461 / NCI NIH HHS
Language: English
Date published: 03/01/2014
Academic Unit: Preventive and Community Dentistry; Biostatistics; Dental Research
Record Identifier: 9983917784502771

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