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Radiation Innovations for Therapy and Education

Periodic Reporting for period 1 - RADIATE (Radiation Innovations for Therapy and Education)

Reporting period: 2015-03-01 to 2017-02-28

45-60% of all cancer patients are treated with radiotherapy. Some patients recover completely, but unfortunately in other cases their illness is not cured. This may result from the outgrowth of distant metastases, but with equal frequency, it results from regrowth of the primary tumour. There is a clear need for further research in this field. This Innovative Training Network (ITN) is built on the premise that advances in understanding radiobiology will open novel routes to improve patient outcomes, and that such progress requires a Europe-wide effort. RADIATE brings together a consortium of radiobiologists, clinicians and scientists, from seven European academic Institutes. These researchers have experience in developing novel strategies to improve radiation therapy for cancer, and in providing training for the next generation of researchers to better the outcome of cancer therapy. Since translation of basic scientific research into the clinic frequently requires commercial participation, this ITN includes industrial partners with expertise in developing novel reagents, biomarkers and drugs that could be used, in combination with radiation, for cancer therapy. This European network will stimulate outstanding science and meet the demand for excellent young academics, thereby enhancing Europe´s competitive capability in this highly relevant but still under-represented and fragmented research area. The Early Stage Researchers (ESRs) and the partners will all benefit from scientific exchange and interactions across the networks’ research and training events.
The failure to eliminate the cancer at its primary site can be placed into two general categories: 1) radioresistance of the tumour and the sensitivity of surrounding normal tissue; 2) the effects of the tumour microenvironment leading to greater overall resistance and altering the immune response to the tumour. Exploration of these two categories form our first two work packages (WP), with translational work designed to identify and implement new therapeutic strategies for use in radiotherapy, being the third.
WP1 addresses the area of cellular radiation resistance and sensitivity. In order to improve therapy, a means for making cancer cells more sensitive to radiotherapy has been sought.
The research by RADIATE ESRs has been focussed in these areas:
• How the DNA repair inhibitor (D-bait) can lead to alterations in the repair of DNA damage.
• Uncovering cell-matrix adhesion targets for radiosensitisation in human pancreatic adenocarcinoma cell lines.
• The differential response to proton versus photon radiotherapy and the biological implications for new indications and combined treatment concepts.
• Characterising the metabolic changes associated with head and neck squamous cell carcinoma (HNSCC) radioresistance.
Results for WP1 show D-bait as a promising drug to maximise the efficiency of tumour treatments through its radiosensitiser property. A 3D high-throughput screen (HTS) with esiRNA has been successfully established to identify cell matrix adhesion targets rapidly. Studies are elucidating the essential repair mechanisms of photon-induced DNA damage. Radioresistant HNSCC cells have been generated and their metabolic profiles compared with wildtype cells.
WP2 is asking how the tumour microenvironment affects the outcome of radiation treatment. The WP brings together projects examining how tumours change their environment to make them more resistant to therapy.
The research by RADIATE ESRs has been focussed in these areas:
• The molecular determinants of the antineoplastic action of membrane-targeted lipid modifying drugs.
• The immune response of tumours to radiotherapy with the emphasis on immunogenic cell death, including an evaluation of photodynamic therapy to further increase the immunostimulatory component of ionising radiations.
• Improving lung cancer treatment by reducing normal lung toxicity via the effects of Notch inhibition and radiotherapy on the cellular differentiation and survival.
• Combining radiotherapy with immunocytokines and immune-checkpoint inhibitors to reduce radiotherapy-related toxicity.
Results for WP2 – Promising experimental data about the mechanisms of action of membrane-targeted lipid modifying drugs has been obtained. The tools and models to probe the induction of immunogenic cell death in response to radiotherapy and photodynamic therapy have been established. It has been demonstrated that Notch signalling has a key role during mucocilliary differentiation in air liquid interface cultures of primary bronchial epithelial cells. The combination of radiotherapy and an immunocytokine resulted in long-lasting protective immunity against colon adenocarcinoma tumours.
WP3 focusses on development of strategies to identify and validate potential targets for increasing tumour sensitivity to radiotherapy.
The research by RADIATE ESRs has been focussed in these areas:
• HTS, in order to identify novel tumour specific radiosensitisation targets. A second HTS project aims to identify proteins involved in DNA damage repair of head and neck cancers.
• Identify the extracellular matrix (ECM) signatures of two different cancer types and identify the ECM proteins that influence irradiation response in these cancers in vivo and in vitro.
• Studying cancer–associated fibroblasts (CAFs), with the aim of developing therapeutic strategies to counteract CAF-induced radiation resistance of cancer cells and tumour regrowth.
• To identify the biological role of active factors secreted in response to ionising radiation.
Results for WP3 – The screening of a lung cancer and a normal lung cell line have been completed. The 3D HTS to study DNA damage repair of head and neck cancers has been developed. A number of key experiments highlighting the influence of CAFs on cancer radiation response have been performed. Genetic targeting has been employed to successfully modulate the endogenous levels of expression and secretion of factors in control and irradiated lung cancer cells.
All the projects
Failure of cancer treatment represents an important socio-economic burden in the European community. Each of the partners brings individual strengths in basic and translational research as well as a track record in taking experimental strategies into the clinic. Students have benefitted from the expertise of the whole, both academic and industrial, including access to unique research technologies that are available throughout the network. These technologies include a variety of screening platforms, methodology for preclinical cancer therapy and novel radiation and imaging technologies. The wider implications of this project are that the European community will benefit from the pursuit of innovative hypotheses, training of new researchers, and dissemination of knowledge. By combating a major death-related disease in Europe this project will improve treatment outcomes and bring long-term benefit to the European and international community.