National Infrastructure for experimental radiation oncology
The National Infrastructure for Experimental Radiation Oncology (NIERO) encompasses the facilities for preclinical experimental work employed in other work packages.
This is both access to experimental equipment and setup, the use of a range of relevant biological models for both tumor and normal tissue, and also the possibility for assistance in experimental design and know-how in the area of radiobiological research. NIERO will assist with both help in design and setup of pre-clinical experiments both for in vitro and for in vivo research.
This will support and further develop clinical research.
Detailed infrastructure description
High-quality preclinical research is necessary to secure a continuous foundation for clinical research. The aim of NIERO is to provide the experimental facilities for preclinical studies within Radiation Oncology. NIERO will encompass a large range of facilities to provide state of the art experimental basis.
Description of facilities
The role of NIERO is to function as a toolbox for radiobiological preclinical experiments. The facilities include in vitro and in vivo facilities, as well as a new experimental X-ray facility with a 300 KV horizontal and vertical beam allowing irradiation of all established in vitro and in vivo models. Furthermore, there is access to small animal imaging (PET, MR and CT).
In connection with the Danish Centre for Particle Therapy (DCPT), a state-of-the-art experimental proton radiation facilities will be established, including a dedicated experimental beam room and laboratories for in vivo and in vitro research. The experimental facilities are developed to support national pre-clinical research, and visiting scientists can perform both in vivo and in vitro experiments at the center. The experimental radiotherapy and associated laboratories will be one of the most modern and versatile setups worldwide.
A range of biological models for radiation experiments are established and implemented. These can be used to test different treatment modalities, and the effect on both tumor response as well as on normal tissue damage. The biological models include clinically relevant in vivo normal tissue models for both early effects (acute skin damage) and late effects (radiation-induced fibrosis). Furthermore, a panel of PDX models from head and neck cancer patients with different aetiology (such as HPV status) that respond differently to radiation is established.
NIERO will provide the experimental facilities for studies implemented in the other WPs, eg of immuno-radiotherapy and the molecular background for prediction of normal tissue and tumor radiosensitivity. The activities will partly depend on the needs formulated by our collaborators, and the following activities are examples of currently ongoing projects:
Establishment of relevant RBE factors. The overall estimate of a proton RBE of 1.1 is challenged, and RBE values for a variety of endpoints after clinical relevant fractionation schedules will be established in a panel of experimental assays.
Particle therapy with protons provides a radiation modality that gives a more accurate dose deposition and less dose to the surrounding healthy tissue. However, there is still a range of unresolved radiobiological questions that need to be answered in order to fully exploit the advantages of particle therapy. While the physical characteristics of particle radiation have been the aim of intense research, less focus has been on the actual biological responses of particle irradiation.
This project addresses the biological effect of protons, a key issue in particle therapy, and aims to determine the relative biological effectiveness (RBE) of different normal tissues in a systematic, large scale in vivo setup This will include simulation of clinical treatment. To enlighten the very important issue of increased effects in certain parts of the beam, comparative studies will be performed in different parts of the beam. This effect has been much debated and has been suspected due to in vitro studies and clinical findings. Furthermore, the biological effects of proton radiation on factors as vascular tissue, angiogenesis and inflammation effects will be studied in vitro and in vivo.
This work is initiated and will be further developed when the dedicated experimental beam room at DCPT is ready for use in early 2019.
Clinical simulation studies in PDX tumors.
Central to the development and refinement of image-guided therapy, including combination treatments with biologically targeted treatment, is the development of tumor models that maintain the biological variation and heterogeneous tumor microenvironment (e.g., hypoxia) seen in patients. The current panel of PDX models will be expanded to include other relevant types of cancer, such as anal cancer, sarcomas, and CNS.
The battery of models will be used to identify predictive and early response biomarkers (receptors, metabolism, micro-environment) for treatment with conventional radiotherapy or proton therapy and radiosensitizing drugs, using clinically applicable functional imaging (especially PET). Furthermore, to improve the image-guided target definition to allow possible global or regional dose escalation (or reduction) to overcome inherent and microenvironment-related (hypoxia) resistance factors.
Grid proton therapy
Proton grid therapy is a new idea where the lateral proton beam dose distribution is reshaped to a regular grid pattern of alternating high and low doses, while the beam passes the healthy tissue. Grid therapy with x-rays has in previous studies demonstrated reduced normal tissue complication probability. We expect to see a similar reduction in damage to the healthy tissue for proton beams before the protons reach their target.
When the protons reach the target, the proton grid dose-distribution can be crafted using special collimators so the proton grid pattern will wash out and deliver a homogeneous dose to the tumor, simultaneously with the heterogeneous dose in the normal tissue. This enables us to quantify the potential outcome of this therapy form using an in vivo model. The hypothesis we want to test is that for the same tumor control probability, grid therapy will significantly reduce the normal tissue complication probability, thereby widen the therapeutic window. Grid therapy is technically possible at the new national center for particle therapy (DCPT). The biological validation will be conducted using the in vivo normal tissue models, which will establish the enhancement ratio for normal tissue using proton grid therapy vs. normal proton therapy.
Expected results and Impact
A National Infrastructure for Experimental Radiation Oncology is necessary to support and further develop clinical research.
The expected outcome is to improve our understanding of the radiobiological properties of radiation and enlighten the effect on both the tumor and the normal tissue. Furthermore, to identify validly (quantifiable) and relevant (prognostic/predictive) image-derived biomarkers with clinical applicability for both photon and proton therapy, and additional treatment will ensure a more individualized, adaptive and effective treatment.
This will fully unlock the biological potential of radiation therapy, and provide data for the development of biological models and implementation of these in treatment planning systems. This Infrastructure supports a radiobiological platform in radiation research in Denmark.