Potential clinical relevance of radiation-induced signaling pathways

Radiation therapy is a commonly used treatment modality for cancer. Although in the past decades radiation therapy has shown to be a very successful treatment form, it still can be improved. One problem is that some tumors are particularly resistant to th e cytotoxic effects of radiation and respond poorly to standard treatment protocols. An important task is therefore to elucidate the molecular mechanisms that determine radiosensitivity, in order to find ways to better predict the outcome of clinical radi otherapy, and develop new strategies to specifically sensitize radioresistant tumors. In the past ten years, an enormous progress has been made regarding our understanding of cellular responses to radiation in molecular detail. It is now clear that ionizi ng radiation triggers cascades of signaling events, and it is generally believed that such signaling decides whether cells will survive or die after irradiation, by affecting processes such as DNA repair, cell cycle "checkpoints" and programmed cell death . At present, several such signaling cascades have been elucidated in some detail, however, these pathways are not by any means fully understood. The major goals for the proposed work are 1) to acquire new knowledge about radiation-induced signaling respo nses, with emphasis on the damage-induced checkpoints and 2) to explore potential clinical applications of such knowledge. Particularly, we will elucidate the molecular mechanisms that trigger cell division of cells with unrepaired DNA damage after a prol onged checkpoint arrest, and we will evaluate the strategy of inhibiting a specific signaling protein, human checkpoint kinase 1, to sensitize tumor cells to radiation therapy. Our results will contribute to a better understanding of cellular responses to radiation and may help to identify new potentially clinical relevant approaches for treatment of human cancer.