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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS064593-02
Application #
7903357
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Fountain, Jane W
Project Start
2009-08-01
Project End
2014-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
2
Fiscal Year
2010
Total Cost
$323,762
Indirect Cost
Name
Virginia Commonwealth University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Durant, Stephen T; Zheng, Li; Wang, Yingchun et al. (2018) The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models. Sci Adv 4:eaat1719
Karlin, Jeremy; Allen, Jasmine; Ahmad, Syed F et al. (2018) Orally Bioavailable and Blood-Brain Barrier-Penetrating ATM Inhibitor (AZ32) Radiosensitizes Intracranial Gliomas in Mice. Mol Cancer Ther 17:1637-1647
Beckta, Jason M; Dever, Seth M; Gnawali, Nisha et al. (2015) Mutation of the BRCA1 SQ-cluster results in aberrant mitosis, reduced homologous recombination, and a compensatory increase in non-homologous end joining. Oncotarget 6:27674-87
White, E Railey; Sun, Luxin; Ma, Zhong et al. (2015) Peptide library approach to uncover phosphomimetic inhibitors of the BRCA1 C-terminal domain. ACS Chem Biol 10:1198-208
Zolotarskaya, Olga Yu; Xu, Leyuan; Valerie, Kristoffer et al. (2015) Click synthesis of a polyamidoamine dendrimer-based camptothecin prodrug. RSC Adv 5:58600-58608
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
Khalil, Ashraf A; Jameson, Mark J; Broaddus, William C et al. (2013) Subcutaneous administration of D-luciferin is an effective alternative to intraperitoneal injection in bioluminescence imaging of xenograft tumors in nude mice. ISRN Mol Imaging 2013:
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

Showing the most recent 10 out of 22 publications