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International NETwork for training and innovations in THErapeutic RADiation

Periodic Reporting for period 1 - THERADNET (International NETwork for training and innovations in THErapeutic RADiation)

Reporting period: 2019-09-01 to 2021-08-31

Radiotherapy alone or in multimodality approaches is applied in half of all cancer patients, but despite technical innovations approximately only 50% of the patients receiving radiotherapy are cured. Radiotherapy is limited by resistance mechanisms of the tumor and by adverse reactions in the co-irradiated surrounding normal tissues located in the path of the irradiation beam. Since technical improvements are reaching their limits, substantial improvements are now expected from biological insights on the mechanisms causing tumor cell resistance and normal tissue toxicities to enlarge the therapeutic window.
Altered tumor metabolism, immune responses to the tumor and normal tissue responses are now emerging as novel, highly promising concepts to be integrated into current treatment approaches. Our research program investigates in three scientific work packages the plasticity of an altered tumor metabolism and tumor microenvironment, including the immune system, prior to, and in response to radiotherapy, as well as related dose-limiting adverse effects in normal tissues.
Dedicated precision image-guided small animal radiotherapy platforms, which require excellent imaging- and technology skills will be used to investigate normal tissue- and tumor-oriented biological endpoints. Sparing normal tissue toxicity and the underlying biological mechanisms will be further addressed by a novel type of irradiation applying high dose-rates (FLASH), which only recently pointed towards a completely novel mechanism of ionizing radiation-induced cellular cytotoxicity. These endpoints will be investigated with photon- and in part with proton-radiotherapy, important to future treatment stratification from a biological perspective, and will expose scientists to clinically relevant radiotherapy modalities
The THERADNET network brings together 7 partners from different European academic institutions, and one partner from a non-academic institution, hosting 15 Early Stage Researchers (ESRs). The network also consists of 10 associated partners, including industrial, oncology and patients’ advocacy organizations and publishers.

Scientific objectives: Altered tumor metabolism and immune responses are characterized at the preclinical level in tumor and normal tissue in response to irradiation. New targets are identified and investigated for translation into clinically relevant treatment concepts.
Training objectives: State-of-the-art a) scientific training in applied radiobiology and b) training in transferable skill with a focus on digital communication.
European objectives: The number of researchers focusing on radiation biology is still very small in individual countries, so it is important to collaborate at the European level to achieve a critical mass of scientists with complementary expertise in cancer and radiation biology and to contribute to the formation of a young generation of researchers in this field of applied cancer research.
Our research comprises three scientific work packages (WP) investigating these concepts in the field of applied radiobiology, addressing 1) tumor sensitization, 2) normal tissue protection and 3) adaptation and escape mechanisms. These three WPs are intertwined to reach the overall research goal of THERADNET to identify novel radiotherapy approaches to widen the therapeutic window.
In WP1, clinically relevant in vitro and in vivo tumor models were established to understand the plasticity of an altered tumor metabolism and heterogeneous tumor cell composition prior and in response to radiotherapy and to validate their role as targets for combined treatment modalities with radiotherapy. These models are now used throughout the consortium for the evaluation of metabolic alterations associated with acquired radiotherapy resistance. Imaging sensors to determine metabolic alteration in response to irradiation currently undergo validation to identify respective changes correlating with radiosensitivity.
In WP2, the response of healthy tissues to irradiation was investigated and protocols were probed that reduce treatment toxicity and at the same time increase the potency in the tumor. These protocols include combined treatment modalities with immune-biological normal tissue and tumor-oriented compounds currently developed in industrial companies. Promising preliminary results demonstrate the advantages of using FLASH irradiation, a new mode of delivering irradiation in a very short time that protect normal tissue from radiation injuries.
In WP3, adaptive and escape mechanisms to radiotherapy were investigated to identify potential combined treatment modalities to prevent related treatment failure. Multiple cancer models were used to screen for preselected precise targeting of a given oncogene and for larger screenings involving RNAseq, metabolomics and proteomics. In close association with WP1 metabolic profiling novel links between metabolic changes, DNA repair machineries pro-metastatic behavior and differential radiosensitivities have been uncovered. Furthermore, and next to external beam irradiation, novel radionuclide targeting approaches are developed for precise targeting of specific tumor oncogenes.
Approximately 50% of all cancer patients in Europe have an indication for radiotherapy at least once during the course of their disease, with an absolute number of patients steadily increasing assuming overall cancer rates remain unchanged. Europe therefore needs scientists with a strong background in cancer biology, radiation biology and oncology, as well as in transferable skills capable of advancing cancer research in interdisciplinary research teams and intersectorial approaches. Several workshops already took place during the initial phase of this period, at which the ESRs could present their first results, initiate collaboration and demonstrate their communication skills, also trained during this initial period. Already at this stage of our research project, following the successful recruitment of 15 early-stage research, COVID-19-related delays of the start of the individual research challenges and the successful realization of the initial goals of our objectives, we realize having selected highly ambitious and talented ESRs.
Our research consortium forms a highly attractive European center of excellence in applied radiation biology research and will strengthen Europe's innovation capacity at the forefront of personalized radiotherapy and precision medicine to the benefit of cancer patients. Our consortium will contribute to current and future needs of academic and non-academic employers and will enhance Europe’s power to tackle challenges in cancer. The European community will benefit from the pursuit of innovative hypotheses, training of future leaders in the field and dissemination and communication of knowledge in radiation biology and oncology. By combatting a major death-related disease in Europe, THERADNET will improve health and bring long-term benefit to the European and international community.