Radiation necrosis is a severe, but late occurring, type of injury to normal tissue that can lead to significant challenges in the management of brain-tumor patients following radiation therapy. Radiation necrosis causes focal neurological sequelae that limit patients'quality of life. Quantitative methods to identify and stage radiation necrosis are of paramount importance in the neuro-oncology community. Additionally, the identification of neuroprotectants that could reduce the incidence or severity of radiation necrosis and therapeutics that could mitigate symptoms would have significant positive impact on patient care. The need for non-invasive, quantitative characterization methods is a particular challenge for diagnosing tissue radiation- damage in the brain. This proposal offers an important advance to meet this critical need. Magnetic resonance imaging (MRI) can provide non-invasive characterization, through measurement of parameters that are sensitive to important physiologic and cellular parameters, including cell density, cerebral blood volume and flow, oxygen utilization, and vascular permeability or leakiness. A detailed understanding of the factors that affect the onset and progression of radiation necrosis requires the development of robust animal models that enable a clear histologic (cellular) description of tissue damage in the irradiated brain. The goals of this application are to develop a well-characterized mouse model of radiation necrosis, to validate non-invasive, translatable MRI tools for identifying necrosis in this model, and subsequently to investigate mechanisms by which this tissue damage can be prevented or mitigated through therapeutic interventions. More specifically, the aims of the grant to: 1) optimize a recently developed mouse model of radiation necrosis in brain;2) develop and validate MRI markers that can uniquely identify radiation necrosis;3) test putative neuroprotectant or therapeutic compounds and monitor their efficacy in reducing radiation damage by non-invasive MR imaging techniques. The project will make use of a number of cutting-edge experimental techniques including high field strength small-animal MRI equipment and advanced imaging sequences. Mice will be irradiated using the Leksell Gamma Knife Perfexion unit, a state-of-the-art unit used for stereotactic irradiation of patients with benign and malignant brain tumors, and following the establishment of radiation necrosis, novel interventional mechanisms will be tested for the prevention and mitigation of tissue damage. This series of experiments will result in a significantly clearer understanding of the brain tissue changes that follow cranial irradiation. The ability to monitor these changes non-invasively, and to prevent and mitigate these changes with therapeutic interventions, will lead to better clinical outcomes and improved quality of life for patients with brain tumors whose treatment paradigms include radiation therapy.

Public Health Relevance

Tissue damage (necrosis) caused by radiation treatment can seriously affect the quality of life of brain-tumor patients. This application describes the development of magnetic resonance imaging (MRI) methods to better characterize and stage radiation necrosis. The ability to monitor radiation necrosis non-invasively, and to prevent and mitigate it with therapeutic interventions, will lead to better clinical outcomes and improved quality of life for patients with brain tumors whose treatment paradigms include radiation therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA155365-02
Application #
8319341
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Prasanna, Pat G
Project Start
2011-08-12
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$315,400
Indirect Cost
$107,900
Name
Washington University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Yang, Ruimeng; Duan, Chong; Yuan, Liya et al. (2018) Inhibitors of HIF-1? and CXCR4 Mitigate the Development of Radiation Necrosis in Mouse Brain. Int J Radiat Oncol Biol Phys 100:1016-1025
Donabedian, Patrick L; Kossatz, Susanne; Engelbach, John A et al. (2018) Discriminating radiation injury from recurrent tumor with [18F]PARPi and amino acid PET in mouse models. EJNMMI Res 8:59
Garbow, Joel R; Tsien, Christina I; Beeman, Scott C (2018) Preclinical MRI: Studies of the irradiated brain. J Magn Reson 292:73-81
Duan, Chong; Perez-Torres, Carlos J; Yuan, Liya et al. (2017) Can anti-vascular endothelial growth factor antibody reverse radiation necrosis? A preclinical investigation. J Neurooncol 133:9-16
Beeman, Scott C; Shui, Ying-Bo; Perez-Torres, Carlos J et al. (2016) O2 -sensitive MRI distinguishes brain tumor versus radiation necrosis in murine models. Magn Reson Med 75:2442-7
Perez-Torres, Carlos J; Yuan, Liya; Schmidt, Robert E et al. (2015) Specificity of vascular endothelial growth factor treatment for radiation necrosis. Radiother Oncol 117:382-5
Jiang, Xiaoyu; Yuan, Liya; Engelbach, John A et al. (2015) A Gamma-Knife-Enabled Mouse Model of Cerebral Single-Hemisphere Delayed Radiation Necrosis. PLoS One 10:e0139596
Perez-Torres, Carlos J; Yuan, Liya; Schmidt, Robert E et al. (2015) Perilesional edema in radiation necrosis reflects axonal degeneration. Radiat Oncol 10:33
Perez-Torres, Carlos J; Engelbach, John A; Cates, Jeremy et al. (2014) Toward distinguishing recurrent tumor from radiation necrosis: DWI and MTC in a Gamma Knife--irradiated mouse glioma model. Int J Radiat Oncol Biol Phys 90:446-53
Jiang, Xiaoyu; Perez-Torres, Carlos J; Thotala, Dinesh et al. (2014) A GSK-3? inhibitor protects against radiation necrosis in mouse brain. Int J Radiat Oncol Biol Phys 89:714-21

Showing the most recent 10 out of 11 publications