Chondrosarcoma response mechanisms in particle beams

Radiotherapy and chemotherapy play limited roles as primary treatment in chondrosarcomas. However, in cases of incomplete resections after surgery they are important treatment options in an adjuvant treatment setting. The safe application of high radiation doses is often limited due to the adjacent radiosensitive organs at risk. Particle therapy with protons and carbon ions (C-ions) has proven to be beneficial in the radiation treatment of chondrosarcomas because their physical and biological characteristics provide the possibility to deliver higher doses to even larger target volumes than photon beams while minimizing doses to normal tissue structures surrounding the tumor. From the biophysical point of view, both protons and C-ions have improved ballistic features, i.e. they travel a fixed distance in tissue that is related to the accelerating energy where they deposit the bulk of their energy (Bragg Peak). In todays radiotherapy treatment planning and computerized treatment plan optimization algorithms it is the macroscopic unit of absorbed dose that is considered, which does not per se represent biological effects. Instead radiobiological effects are considered via the relative biological effectiveness, which varies with tissue type, endpoint, absorbed dose, dose per fraction, particle species etc. and does not factorize in an independent manner with its variables. Although the side effects and sequelae occurring after conventional therapeutic irradiation of chondrosarcomas have been relatively well described, the cellular mechanisms, especially in mesenchyme-derived cells, are still poorly understood. In this project we will thus interconnect the biophysical and the cell biological radiation research for chondrosarcomas. MedAustron offers a unique research infrastructure for particle irradiation in Austria with a horizontal beam line providing proton and C-ions at various clinical energies for research purposes. A reproducible, reliable correlation of spheroid irradiation response and physical parameters will be ensured via a dedicated irradiation setup. Therefore, a new irradiation setup for irradiations with horizontal beams will be developed that are based on existing commercial water phantoms. Extensive dosimetric measurements will be carried out for X-rays, protons as well as C-ions to determine the absorbed dose (in Gy) in the various positions where spheroids are to be positioned for the radiobiological studies. Three more work packages will process the biological efficacy, angiogenesis and migration/invasion behavior, and the signal transduction by the NFkB pathway after proton and C- ion irradiation. For all cell biological experiments we will use 3D spheroid cultures, which mimics donor tissue architecture and enables cell-cell or cell-matrix interactions. The overall aim of this project is to remedy the deficiency of combined biophysical and radiobiological data and to build a base for the further development of particle beam therapy in chondrosarcoma.

While the clinical significance of radiation therapy in chondrosarcoma therapy cannot be overlooked, until recently there were only a limited number of well-established particle therapy related radiobiological studies focusing on this bone tumor entity. In the framework of this FWF funded project we were able to contribute to closing this knowledge gap by respective in-vitro studies. All work packages were completed successfully and numerous high-ranking publications were resulting from this project. The cross-linking of cell biology and radiation physics data in this project was a crucial step towards enhancing the accuracy of medical radiation research and current objective to include microdosimetry aspects in treatment plan optimization in particle therapy. It has been shown that human chondrosarcoma cells have a highly efficient repair program that repairs DNA damage caused by proton and carbon ion irradiation within a very short time. Furthermore, this was accompanied by a reprogramming of the cellular metabolism. Our data clearly demonstrated that cell viability and proliferation were inhibited with increasing ionization density and linear energy transfer. In order to overcome resistance to radiotherapy in chondrosarcomas, additional treatment with various inhibitors was tested. Combined treatment with ATM Inhibitor VE-821 was shown to increase the radiosensitivity of human chondrosarcoma cells in vitro and significantly suppress efficient DNA repair mechanisms, thereby improving the efficiency of radiotherapy. An important aspect of our project was the linking of biological data with radiation physics parameters. In particle therapy, in addition to the macroscopic parameter of the absorbed dose, the microscopic parameter of the released energy per path length plays an important role in the characterization of the radiobiological effects. The absorbed dose can be quantified using standardized procedures and is thus commonly specified in radiobiological and clinical procedures, the released energy per path length cannot be easily determined, which means that this parameter is often neglected. As part of the project, a dedicated set-up for radiobiological experiments was developed and dosimetrically characterized using both macroscopic and microscopic parameters. In framework of this subproject, detectors and methods for microdosimetry were developed in a PhD project. The outcome of this PhD work enables the correlation of biological data with a comprehensive set of radiation physics parameters, which in turn allows to improve radiobiological models. Such model can be applied in the optimization of treatment plans in particle therapy and can contribute to improve outcome.