Angewandte Radiobiologie

The major focus of the preclinical research program of the Laboratory for Applied Radiobiology, Department of Radiation Oncology,University Hospital Zurich, is "Combined Treatment Modality". This program includes different aspects of translational research in the field of radiobiology investigating the cellular and tumoral response on the molecular, cellular and in vivo level to ionizing radiation alone and in combination with classical chemotherapeutical and novel pharmacological agents.

Founded in 1995 our laboratory is headed by Prof. Dr. Martin Pruschy, PhD and is completely integrated in both the preclinical research divisions of the head quarters of the University Hospital Zurich and in the clinical premises of the Department of Radiation Oncology.

It is this special environment that contributes to the translational spirit of our laboratory. Several PhD-candidates, MD- and PhD-Post-Doctoral fellows, and a highly motivated lab technician complete our team.

Research Program

The research activities consist of 3 major topics that investigate the cellular response to ionizing radiation alone and in combination with classical chemotherapeutical or novel pharmacological agents. A major goal is to understand treatment resistance on the molecular and cellular level and to translate novel combined treatment modalities into a clinical environment.

1. Ionizing Radiation-Induced Intracellular Signaling: Relevance for Radiation Resistance

DNA double strand breaks are the pivotal cellular damage induced by ionizing radiation. A plethora of molecular and cellular processes are activated as part of the cellular stress response that result in cell cycle arrest and induction of the DNA-repair machinery to restore the damage of DNA or to activate a cell death program. However ionizing radiation also initiates signal transduction cascades that are generated at cellular sites distant from and independent of DNA-damage. These signaling processes are similar to hormone activated growth factor receptor controlled signal transduction cascades and represent interesting targets for anticancer treatment modalities combining ionizing radiation with molecular defined pharmacological compounds. Activation of these signal transduction cascades upon irradiation or upregulation of growth factor mediated pathways due to oncogene-transformation often contribute to an acquired or inherent treatment resistance in malignant cells. Therefore pharmacological compounds inhibiting specific key-entities of these signal transduction cascades potentially sensitize for radiation induced cell death.

In strong collaboration with the pharmaceutical companies, we investigate the radiosensitizing potential of chemotherapeutical compounds that are part of the respective R&D programs of pharmaceutical industries. Both mechanistic and efficacy-oriented endpoints are investigated.

As an important subproject and as part of our longstanding interest in the tumor millieu, we are investigating the combination of radiotherapy with inhibitors of angiogenesis or antisignaling agents affecting the tumor microenvironment. Tumor hypoxia is associated with poor outcome of radiotherapy in terms of locoregional control, disease-free survival and overall survival and is therefore an important factor in the treatment strategy. We are investigating dynamic parameters of the tumor microenvironment in clinically relevant tumor models with regard to mechanistic- and efficacy-oriented endpoints in response to irradiation alone and as part of these promising combined treatment modalities. Integrated into the KFSP Tumor Oxygenation, University of Zürich, we develop bioluminescence-based methodologies to serially determine dynamic changes of tumor hypoxia under treatment.

2. Identification and Targeting of Ionizing Radiation-Activated Treatment Resistances:

The insult on the level of DNA is most important for the cytotoxicity of IR. However IR also affects multiple cellular components that induce a multilayered stress response in the tumor. Para- and autocrine factors are released into the tumor microenvironment in response to radio-and chemotherapy-induced DNA damage and treatment-activated intracellular stress-responses. During the time course of a fractionated radiation regimen they modulate thereby the tumor microenvironment and these processes co-determine the treatment sensitivity of the tumor and eventually treatment outcome. Such IR-activated resistance mechanims and their regulation eventually represent interesting novel targets for combined treatment modalities to sensitize the tumor for IR. We aim to investigate treatment-activated rescue mechanisms of the tumor, which regulate in an auto- or paracrine way the radiation sensitivity of the tumor cell compartment and the tumor microenvironment and thereby co-determine the treatment outcome.

3. Differential Response to Proton Versus Photon Radiotherapy

The generally accepted concept to simply replace the radiation source, i.e. photons with protons, but to otherwise proceed with identical treatment concepts was justifiable and successful in the past, when proton therapy was used largely as the sole treatment without systemic agents and using conventional dose-fractionation schemas. However, this does not permit the conclusion that it is safe to expand this technology without additional preclinical in vitro and in vivo radiobiological data. Of specific concern has to be that there is a widening body of data in-vitro and in-vivo indicating a different RBE in various circumstances and mode of cell death induced by the two radiation sources. In addition, there are, as of yet unexplained occasional severe toxicities in patients. This research project investigates underlying mechanisms for proton radiation-induced cell killing.  The major questions arise from the observed (in absence of systematic molecular and cellular investigations) different biological effectiveness of clinically relevant proton versus clinically relevant photon irradiation. Based on our results we will further investigated the role (and the exploitation) of the Homologous Recombination DNA Repair System for proton-irradiation alone and in combination with pharmaceutical agents.

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