Final Report Summary - HORAY (Role of Autophagy and Lysosomal Biogenesis in Hypoxia and Radiation-induced cell death in normal and cancer cells)
The HoRAy (Hypoxia interaction with Radiation and Autophagy) project aimed, for the first time, to investigate the links of autophagy and lysosomal biogenesis in hypoxia and their role in the radiation toxicity of normal and breast cancer cells. Breast cancer has been chosen as a common disease, for which radiotherapy is essential at different stages, and its therapy is the major utilizer of radiotherapy resources. This promising area of cancer research is poorly studied in the literature and there is no data to our knowledge on the radiation interaction with the autophagic/lysosomal machinery of normal tissues.
There were two aims. One was to assess whether autophagy and lysosome biogenesis are involved in the acute and/or late toxicity of radiation in normal cells and tissues, and the eventual radioprotection that could be achieved by modifying the process. Here we developed a liver organoid model to study in radiation toxicity and protection as well to develop new compounds with radiation protection effect. Further, using humanized transgenic reporter mice we aimed to study radiation toxicity and minimize the use of animals. The results of this approach will give us the opportunity for further developing the area of radiation toxicity and protection and to apply for future support.
The second was the role autophagy and lysosomal biogenesis in radiation sensitivity of cancer. Here we found that autophagy and lysosomal biogenesis was regulated by microenviroment stress such as hypoxia, glucose and glutamine deprivation. Also autophagy has a role in breast cancer prognosis as observed from the pathology studies and bioinformatics data sets. Further we found novel targets and future candidates for anticancer therapy as well and synthetic lethality approaches using commercially available drugs and ionizing radiation. Based on the results of this approach we are now in a process of further investigation and applying for future support.
Potential impact and use and any socio-economic impact of the project
A combination strategy that radiosensitizes tumor cells and hypoxic regions in parallel with selective protection of normal tissues would provide an innovative approach for anticancer treatment. Understanding radiosensitivity of normal cells will have important implications in cancer medicine, radioprotection of humans against accidents or acts of terrorism and space radiobiology. New areas of clinical research aiming to protect cancer patients undergoing radiotherapy and chemotherapy will open. This research field is also important in space medicine, where overexposure during space missions is an unresolved problem. New cytoprotection methods will allow the intensification of radiotherapy resulting in increased curability of inoperable and otherwise incurable tumors. Understanding the role of autophagy and lysosomal biogenesis in hypoxia, radiation toxicity and radiation sensitivity, in both normal and cancer cells, will allow the recognition of critical targets for pharmacological or molecular interventions aiming to selective protection of normal cells and enhancement of the efficacy of radiotherapy and/or chemotherapy of tumors. This translates to the subsequent scheduling of clinical trials with molecules targeting autophagy and lysosomal biogenesis in the fields of radiation oncology and chemotherapy, to improve outcome and reduce toxicity.