Researchers have identified a biochemical signaling pathway that can protect normal tissues from standard and high doses of radiation while delaying tumor growth, according to an article in Science Translational Medicine.
According to senior author David Roberts, MD, from the pathology lab at the Center for Cancer Research, National Cancer Institute, National Institutes of Health in Bethesda, Md., and colleagues, although the use of precise fields and adequate radiation dose planning can limit the damage to tissue surrounding a targeted area, that damage still occurs in most patients and limits the effective dose that can be delivered to a tumor.
In performing experiments on mice, the researchers found that by systemically administering an antisense CD47 morpholino in mice (injected with human tumors) they could block a molecule called thrombodspondin-1 (TSP1) from binding with its CD47 cell receptor and protect normal tissues from damage by ionizing radiation.
"We almost couldn't believe what we were seeing," said lead author Jeff Isenberg, MD, associate professor in the division of pulmonary, allergy and critical care medicine at the University of Pittsburgh School of Medicine. "This dramatic protective effect occurred in skin, muscle and bone marrow cells, which is very encouraging. Cells that might have died of radiation exposure remained viable and functional when pre-treated with agents that interfere with the thrombospondin-1/CD47 pathway."
Any radioprotection strategy creates concerns that it will, in addition to protecting surrounding tissue, also enhance radioresistance in tumors, but the authors determined that in the mice, CD47 suppression did not enhance radioresistance in turmors, but actually increased the time it took for the tumors to grow back.
The authors implanted syngenic B16 melanoma tumors into the thighs of mice, treated them with the CD47-targeting morpholino and followed the tumor growth rates after irradiation. While treatment with the morpholino alone slightly delayed tumor growth, treatment with irradiation alone resulted in the expected growth delay, the authors said.
They also found that “treatment of tumor-bearing limbs with the CD47 morpholino followed by irradiation dramatically delayed tumor regrowth by 89 percent relative to irradiation alone.”
The authors conducted another study in mice implanted with squamous cell carcinoma using the same treatment and radiation schedules. They found that “similar tumor growth delays (71 percent) relative to irradiation alone were seen in those mice treated with the CD47 morpholino.”
The mechanism through which CD47 suppression increases tumor radiosensitivity “is not yet clear,” the authors wrote, but they concluded that the results of their study predict that "therapeutic targeting of the TSP1-CD47 interaction would be an effective means to enhance tumor ablation by radiotherapy while, at the same time, decreasing the harmful effects of radiation treatment on adjacent normal tissues. Our results further show that this selective radioprotection can be achieved by systemic delivery of the CD47 morpholino.”