Glioblastoma multiforme (GBM) is devastating brain cancer with a mean survival of only 12 months and few therapeutic options. Thus, more effective treatment is urgently needed. Ataxia telangiectasia (A-T) mutated (ATM) is a critical genome surveillance protein that regulates many DNA damage responses including cell cycle checkpoints, DNA repair, and apoptosis. It is believed that ATM also plays additional roles in regulating responses to mitogens and growth factors including insulin, and serves as a master regulator of cellular homeostasis. Because of the extreme radiosensitivity of A-T cells, inhibitors of ATM would be attractive as radiosensitizers for GBM and other types of cancers. Recently, small molecule inhibitors based on the PI3K inhibitor LY294002 were developed by KuDOS Pharmaceuticals, Ltd, that specifically target the ATM kinase. These inhibitors are effective in the nanomolar to micromolar range and radiosensitize various human tumor cell lines in vitro. We recently demonstrated that these inhibitors also suppress DNA double-strand break (DSB) repair. Herein, a second-generation derivative, KU-60019, based on the effective and extensively used predecessor KU-55933, will be tested in vitro and in vivo to determine whether it would be a safe and effective radiosensitizer for GBM. Initial experiments will use brain organotypic slice cultures to characterize the effects of KU-60019 on various radiation responses and whether normal brain with its different types of cells and the tumor cells are affected differently. Specific attention will be given to the possible adverse effects of KU-60019 on neural stem and progenitor cells. Then, the evaluation of KU-60019 as a radiosensitizer of human orthotopic GBM xenografts grown in nude mice will be determined by non-invasive bioluminescence and fluorescence imaging. We expect to determine whether KU-60019 would be a safe and effective radiosensitizer for GBM. We also expect to establish the foundation for an in vivo mouse model system that would allow us to investigate the basic radiobiological properties of neural stem and progenitor cells and assess their behavior and response to KU-60019 therapy.
Glioblastoma multiforme (GBM) is a devastating cancer with a mean survival of only 12 months and few therapeutic options. Standard treatment of GBM is surgery followed by radiotherapy or chemoradiation. Thus, more effective treatment is urgently needed. This proposal will determine whether a highly specific small molecule inhibitor that targets the ataxia telangiectasia mutated (ATM) kinase would be a safe and efficient radiosensitizer of GBM.
|Beckta, Jason M; Ahmad, Syed Farhan; Yang, Hu et al. (2014) Revisiting p53 for cancer-specific chemo- and radiotherapy: ten years after. Cell Cycle 13:710-3|
|Biddlestone-Thorpe, Laura; Sajjad, Muhammad; Rosenberg, Elizabeth et al. (2013) ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation. Clin Cancer Res 19:3189-200|
|Biddlestone-Thorpe, Laura; Marchi, Nicola; Guo, Kathy et al. (2012) Nanomaterial-mediated CNS delivery of diagnostic and therapeutic agents. Adv Drug Deliv Rev 64:605-13|
|Golding, Sarah E; Rosenberg, Elizabeth; Adams, Bret R et al. (2012) Dynamic inhibition of ATM kinase provides a strategy for glioblastoma multiforme radiosensitization and growth control. Cell Cycle 11:1167-73|
|Dever, Seth M; White, E Railey; Hartman, Matthew C T et al. (2012) BRCA1-directed, enhanced and aberrant homologous recombination: mechanism and potential treatment strategies. Cell Cycle 11:687-94|
|Hawkins, Amy J; Golding, Sarah E; Khalil, Ashraf et al. (2011) DNA double-strand break - induced pro-survival signaling. Radiother Oncol 101:13-7|
|Dever, Seth M; Golding, Sarah E; Rosenberg, Elizabeth et al. (2011) Mutations in the BRCT binding site of BRCA1 result in hyper-recombination. Aging (Albany NY) 3:515-32|
|Khalil, Ashraf; Morgan, Rhiannon N; Adams, Bret R et al. (2011) ATM-dependent ERK signaling via AKT in response to DNA double-strand breaks. Cell Cycle 10:481-91|
|Adams, Bret R; Golding, Sarah E; Rao, Raj R et al. (2010) Dynamic dependence on ATR and ATM for double-strand break repair in human embryonic stem cells and neural descendants. PLoS One 5:e10001|
|Golding, Sarah E; Rosenberg, Elizabeth; Valerie, Nicholas et al. (2009) Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion. Mol Cancer Ther 8:2894-902|