The effect of moderate hyperthermia in combination with radiotherapy (HT-RT) was demonstrated in clinical trials and experimentally in vitro and in vivo. A problem of clinical trials is the comparability: Often, different dosimetric concepts have been used and temporal aspects such as time gaps between application of heat and ionizing radiation have not been considered. The recent state of research is not sufficient to support biological treatment planning or optimisation of clinical HT-RT treatments. Clinical trials are faced with the inhomogeneity of treatments due to physiological response (impact of perfusion regulation to temperature during heating) and clinical workflow reasons (time gaps). Therefore, a better understanding of the effects of heating in combination with radiation can lead to adequate thermal dose concepts supporting planning and optimisation of treatments and allowing a comparison of different RT-HT treatment sessions. In this study, it is planned to focus on protein-related aspects interfering with DNA damage formation and repair, cell death mechanisms and immune response (esp. HSP related aspects).
We intend to combine the strengths of advanced dynamical modelling using biophysical dynamic state variables with time resolved biological experiments in vitro and in vivo. As a starting point, the Multi-Hit-Repair (MHR-) model will be used, since this model is able to cover a large variety of radio-biological phenomena and the time-gap dependences of survival data from HT-RT experi-ments in vitro. Time resolved data from Comet- and ?H2AX – assays, western blot analysis and immunofluorescence staining for heat-shock proteins will be used for evaluating the model parameters by an evolutionary optimisation algorithm (in a first step with survival data in vitro as primary training data set and other data as test data). The data in vivo will be gained from biopsy material of animal patients (dogs) treated with heat and radiation at the Veterinary Hospital Zurich. Modifications and extensions of the model with the aim of an adequate description of the relationship between temperature, timing and effect (dynamic dose concept) will be compared systematically to the experimental results. The MHR model uses a simplistic approach for calculating the dynamic state variables??Some recent work in the field of statistical mechanics and protein biophysics will be used to refine the concept of dynamic state variables describing protein damages.
The validation of these dose concepts by clinical trial with human patients is not intended to be a part of this project. But the preparation of methods and tools for this step is envisaged. It is therefore planned to implement promising candidate for dose quantities in a dose calculator allowing the automatic read-in of the temperature output of the treatment units in use. The thermal dose quantities will be compared to the available clinical output of animal treatments.
The planned research can deliver important contributions to theoretical biology and clinical anti-cancer treatment as well. Regarding theoretical aspects of biology and biophysics, the deve-lopment of concepts enabling the coverage of the complex dynamics of biological systems could play a pivotal role in understanding synergistic effects of combined therapies beyond HT-RT. With this project, it is intended to demonstrate the usefulness of dynamic state variables and to elaborate the relation of these quantities to the molecular level by exploiting statistical thermodynamics of life. The approach of using state variables to describe radiation induced protein damage, followed by a subsequent reduction of repair capability of cells is novel. If the extension to data in vivo is successful, this will contribute to a more comprehensive framework for designing new therapeutic approaches for anti-cancer treatments.