In a study reported in Clinical Cancer Research, del Alcazar and colleagues assessed the effects of the dual PI3K/mTOR inhibitor NVP-BEZ235 as a radiosensitizer in glioblastoma. No DNA double-strand break repair inhibitors have been successful in treating glioblastoma. However, in prior studies in vitro, these investigators found that NVP-BEZ235 inhibited two central DNA damage response kinases, DNA-PKcs and ATM, suggesting its potential as a radiosensitizer and chemosensitizer.
The studies examined the effects of NVP-BEZ235 in subcutaneous and orthotopic glioblastoma models generated by radioresistant U87-vIII glioma cell line and GBM9 neurospheres in nude mice. The tumors were treated with ionizing radiation, NVP-BEZ235, or both and analyzed for DNA-PKcs and ATM activation, double-strand break repair inhibition, and effect on growth. Tumors exhibited greater levels of DNA double-strand breaks compared with normal brain tissue. NVP-BEZ235 inhibited DNA-PKcs and ATM and the repair of radiation-induced DNA damage in tumors, resulting in remarkable tumor radiosensitization that increased survival of tumor-bearing mice. NVP-BEZ235 also sensitized some subcutaneous tumors to activity of temozolomide, which is routinely used with ionizing radiation in treatment of glioblastoma.
The investigators concluded, “These results demonstrate that it may be possible to significantly improve [glioblastoma] therapy by combining [ionizing radiation] with potent and bioavailable DNA repair inhibitors like NVP-BEZ235.” ■
del Alcazar CG, et al: Clin Cancer Res. December 23, 2013 (early release online).