ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation.

Abstract

PURPOSE:

Glioblastoma multiforme (GBM) is the most lethal form of brain cancer with a median survival of only 12 to 15 months. Current standard treatment consists of surgery followed by chemoradiation. The poor survival of patients with GBM is due to aggressive tumor invasiveness, an inability to remove all tumor tissue, and an innate tumor chemo- and radioresistance. Ataxia-telangiectasia mutated (ATM) is an excellent target for radiosensitizing GBM because of its critical role in regulating the DNA damage response and p53, among other cellular processes. As a first step toward this goal, we recently showed that the novel ATM kinase inhibitor KU-60019 reduced migration, invasion, and growth, and potently radiosensitized human glioma cells in vitro.

EXPERIMENTAL DESIGN:

Using orthotopic xenograft models of GBM, we now show that KU-60019 is also an effective radiosensitizer in vivo. Human glioma cells expressing reporter genes for monitoring tumor growth and dispersal were grown intracranially, and KU-60019 was administered intratumorally by convection-enhanced delivery or osmotic pump.

RESULTS:

Our results show that the combined effect of KU-60019 and radiation significantly increased survival of mice 2- to 3-fold over controls. Importantly, we show that glioma with mutant p53 is much more sensitive to KU-60019 radiosensitization than genetically matched wild-type glioma.

CONCLUSIONS:

Taken together, our results suggest that an ATM kinase inhibitor may be an effective radiosensitizer and adjuvant therapy for patients with mutant p53 brain cancers.

• Authors: Laura Biddlestone-Thorpe, Muhammad Sajjad, Elizabeth Rosenberg, Jason M Beckta, Nicholas C K Valerie, Mary Tokarz, Bret R Adams, Alison F Wagner, Ashraf Khalil, Donna Gilfor, Sarah E Golding, Sumitra Deb, David G Temesi, Alan Lau, Mark J O'Connor, Kevin S Choe, Luis F Parada, Sang Kyun Lim, Nitai D Mukhopadhyay, Kristoffer Valerie
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 12 Pg. 3189-200 (Jun 15 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23620409 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(2,6-dimethylmorpholin-4-yl)-N-(5-(6-morpholin-4-yl-4-oxo-4H-pyran-2-yl)-9H-thioxanthen-2-yl)acetamide
• Morpholines
• TP53 protein, human
• Thioxanthenes
• Tumor Suppressor Protein p53
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins

Topics

• Animals
• Ataxia Telangiectasia Mutated Proteins (antagonists & inhibitors, genetics)
• Brain Neoplasms (pathology, therapy)
• Cell Line, Tumor
• Flow Cytometry
• Gene Expression Regulation, Neoplastic (drug effects)
• Glioma (pathology, therapy)
• Humans
• Mice
• Morpholines (administration & dosage)
• Mutation
• Radiation Tolerance (drug effects)
• Radiation, Ionizing
• Thioxanthenes (administration & dosage)
• Tumor Suppressor Protein p53 (genetics)