The overall goal of this project is to develop two novel agents - NOV-002 and NOV-205 - for the mitigation of radiation-induced pulmonary injury. In the event of a terrorist event or accident involving radiation, it is likely that some individuals will receive substantial radiation exposure to the lungs either from external radiation or inhaled radioisotopes, and the pulmonary injury could be lethal or life threatening. Hence, there is a need to develop efficacious, non-toxic agents as countermeasures to radiation-induced lung damage. Studies to date suggest that NOV-002 and NOV-205 have the potential to be such agents. Specifically, NOV-002 has been shown to increase survival of rodents exposed to lethal doses of radiation when administered after the irradiation, to have a positive impact on hematopoietic damage when given after irradiation or cyclophosphamide in rodents, and to improve hematopoietic parameters, and be well-tolerated, in humans treated with cytotoxic chemotherapy for lung cancer. NOV-205 has been shown to reduce tissue fibrosis, increase survival and normalize plasma levels of pro-inflammatory cytokines in rodent models of hepatotoxicity, and is in Phase I trials in hepatitis patients. Hence, aspects of radiation-induced lung damage that could be mitigated by NOV-002 or NOV-205 are cytokine production, inflammation, immune suppression, fibrosis and mortality. This application proposes a plan for further development of NOV-002 and NOV-205 for mitigation of radiation-induced pulmonary injury. Radiation dose response curves after localized thoracic irradiation in mice will be obtained for several endpoints of lung damage, including lethality, lung function measured by plethysmography, proteins in BAL fluid, and histology without and with each of the agents. The data will allow demonstration of the efficacy and calculation of dose reduction factors for each drug. Additionally, optimization of drug dose schedule will be conducted, with emphasis on determining how soon after radiation exposure the drugs must be administered to be effective and how frequently the agents must be given during the time course until lung damage would normally be seen. It is anticipated that this information will further these promising agents along the path to FDA approval as mitigators of radiation-induced pulmonary injury.
In a terrorist incident involving a radiation-dispersal device or nuclear weapon or in a radiation accident such as at Chernobyl, individuals could receive not only external radiation exposure that might be localized to the thorax, but also internal exposure from inhaled radioisotopes. In such exposures, pulmonary injury could cause decreased survival due to radiation-induced pneumonitis and/or fibrosis. In addition, as treatments for radiation-induced hematopoietic and gastrointestinal damage are developed so that exposed individuals can survive those syndromes, pulmonary damage is likely to be seen at longer times. Clearly, there is a need to develop efficacious, non-toxic agents as countermeasures to radiation-induced lung damage. Studies to date suggest that two novel drugs - NOV-002 and NOV-205 - have the potential to be such agents. The overall goal of this project is to develop these two agents for the mitigation of radiation-induced pulmonary injury.
| Gerweck, Leo E; Wakimoto, Hiroaki (2016) At the Crossroads of Cancer Stem Cells, Radiation Biology, and Radiation Oncology. Cancer Res 76:994-8 |
