Injuries to the bone marrow and gastrointestinal (GI) tract are the prinnary determinants of survival after exposure to ionizing radiation. Progress has been made in the management of hematopoietic radiation injury. In contrast, the management of GI radiation toxicity remains underdeveloped, and countermeasures specifically against intestinal radiation injury are urgently needed. We discovered that a novel somatostatin analog, SOM230, substantially reduces lethality, prolongs survival, and reduces both structural bowel injury and bacterial translocation in mice after total body irradiation (TBI). We also showed that the mechanism involves inhibition of exocrine pancreatic secretion into the gut lumen. Most remarkably, SOM230 retains its lethality-protecting properties even when administration begins 48+ hours after TBI, a realistic time-frame in a mass casualty situation. Thus, SOM230 is an effective radiation mitigator that ameliorates/restores gut structure and function long after the initial damage has occurred. This project will advance SOM230 toward approval by the Food and Drug Administration (FDA) by addressing mechanistic aspects related to its properties as a radiation mitigator and attempting to further enhance logistics and/or efficacy. We proposed to determine 1) the relative significance of GI versus hematopoietic injury;2) the specific requirement for somatostatin type 2 receptor;3) if the number of injections can be reduced by the combination with a longacting somatostatin analog;and 4) whether the mitigating properties can be further enhanced by the combination with gamma-tocotrienol (GT3), a unique vitamin E analog that is currently in advanced development as a radioprophylactic agent. This work has a strong basis in preliminary data and utilizes well established radiation models and physiological assays combined with contemporary molecular techniques. It is highly collaborative with other projects in this program and utilizes several of its cores. These studies will move SOM230 fonward on the drug development path toward FDA approval as a medical countermeasure against radiological emergencies and will have a significant and immediate impact on human health.

Public Health Relevance

This research focuses on developing medical drugs that can be used to protect the public in the event of a radiological emergency situation. The overall goal is to test the efficacy of a particular compound (SOM230), which has the remarkable property that it works well, even if administration begins as late as 2 days after radiation exposure. These studies will have a significant and immediate impact on human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
2U19AI067798-06
Application #
8013117
Study Section
Special Emphasis Panel (ZAI1-KS-I (M1))
Project Start
2010-08-01
Project End
2015-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
6
Fiscal Year
2010
Total Cost
$335,228
Indirect Cost
Name
Duke University
Department
Type
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Cline, John Mark; Dugan, Greg; Bourland, John Daniel et al. (2018) Post-Irradiation Treatment with a Superoxide Dismutase Mimic, MnTnHex-2-PyP5+, Mitigates Radiation Injury in the Lungs of Non-Human Primates after Whole-Thorax Exposure to Ionizing Radiation. Antioxidants (Basel) 7:
Farris, Michael; McTyre, Emory R; Okoukoni, Catherine et al. (2018) Cortical Thinning and Structural Bone Changes in Non-Human Primates after Single-Fraction Whole-Chest Irradiation. Radiat Res 190:63-71
Naqvi, Ibtehaj; Gunaratne, Ruwan; McDade, Jessica E et al. (2018) Polymer-Mediated Inhibition of Pro-invasive Nucleic Acid DAMPs and Microvesicles Limits Pancreatic Cancer Metastasis. Mol Ther 26:1020-1031
Ghandhi, Shanaz A; Turner, Helen C; Shuryak, Igor et al. (2018) Whole thorax irradiation of non-human primates induces persistent nuclear damage and gene expression changes in peripheral blood cells. PLoS One 13:e0191402
Castle, Katherine D; Daniel, Andrea R; Moding, Everett J et al. (2018) Mice Lacking RIP3 Kinase are not Protected from Acute Radiation Syndrome. Radiat Res 189:627-633
Fanning, K M; Pfisterer, B; Davis, A T et al. (2017) Changes in microvascular density differentiate metabolic health outcomes in monkeys with prior radiation exposure and subsequent skeletal muscle ECM remodeling. Am J Physiol Regul Integr Comp Physiol 313:R290-R297
Swanson, Karen V; Junkins, Robert D; Kurkjian, Cathryn J et al. (2017) A noncanonical function of cGAMP in inflammasome priming and activation. J Exp Med 214:3611-3626
Kurkjian, Cathryn J; Guo, Hao; Montgomery, Nathan D et al. (2017) The Toll-Like Receptor 2/6 Agonist, FSL-1 Lipopeptide, Therapeutically Mitigates Acute Radiation Syndrome. Sci Rep 7:17355
Racioppi, Luigi; Lento, William; Huang, Wei et al. (2017) Calcium/calmodulin-dependent kinase kinase 2 regulates hematopoietic stem and progenitor cell regeneration. Cell Death Dis 8:e3076
Himburg, Heather A; Doan, Phuong L; Quarmyne, Mamle et al. (2017) Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms. Nat Med 23:91-99

Showing the most recent 10 out of 197 publications