IDENTIFICATION OF NOVEL TARGETS FOR RADIOSENSITIZATION
Radiotherapy-induced processes at the secretome level represent a promising source for the identification of novel targets for combined treatment modalities with ionizing radiation and for monitoring treatment responses (biomarkers). With a strong research interest in the identification of specific molecular entities and signal transduction cascades that regulate the cellular and tumor pathophysiological response to radiotherapy, we investigate the radiotherapy-induced secretome and related resistance mechanisms. We have identified the sheddase ADAM17, which co-determines the radiation response in lung adenocarcinoma, and which can now be targeted and investigated on the translational level. Furthermore, we integrate our experience in the analysis of the secretome into translational parts of ongoing clinical studies in our Dept. of Radiation Oncology.
These studies are performed as part of Swiss National Foundation (SNF) and Swiss Cancer League-supported basic and translational research projects; in strong collaboration with the Dept. of Pathology at the University Hospital Zurich (USZ) and the Depts. of Radiation Oncology at the USZ and the CHUV (Lausanne). These studies are also funded by our Horizon2020 Marie-Curie ITN.
Radioimmunotherapy: The current strong interest of research at the interface of radiation oncology and tumor immunology is accounted by collaborations with the Inst. of Experimental Immunology, UZH, Dept. of Immunology, USZ and national experts (CHUV) in tumor immunology. In collaboration with the Dept. of Immunology, USZ (Prof. Onur Boyman), and funded by CRC funding program of the University Zurich, we investigate alternative combined radioimmunotherapies to overcome treatment-related resistances. We here investigate the combined treatment modality of radiotherapy with hIL-2/NARA1 complexes in preclinical lung and melanoma tumor models. Initial experiments will be performed to identify an optimal treatment regimen for this combined treatment modality, followed by efficacy- and mechanistic-oriented experiments in orthotopic tumor models.
Collaboration with international pharmaceutical companies: We investigate novel clinically-relevant anti-cancer agents in vitro and in vivo for their potential as a combined treatment modality with ionizing radiation. We focus on novel combined treatment modalities of radiotherapy with a) hypoxia-modulating agents and b) novel microtubule targeting agents. We have substantially contributed to the launch of clinical phase I/II studies of Basilea Pharmaceutica with their MTA BAL101553, and will continue our strong collaboration on the preclinical level with Basilea Pharmaceutica. With our clinical colleagues from our Dept. of Radiation Oncology and from Basilea Pharmaceutica, we currently discuss the design of an in-house clinical study of radiotherapy with BAL101553.
DIFFERENTIAL BIOLOGICAL RESPONSES TO PROTON AND PHOTON IRRADIATION
Patient stratification in radiation oncology for photon- versus proton-irradiation is today primarily based on clinical parameters. However, little attention has been given to the fact that different modalities of ionizing radiation with slight differences in their energy profile and route of application may induce differential biological processes relevant for tumor cell killing and/or normal tissue damage that may be critically relevant for cancer patient management. In close collaboration with the Center for Proton Therapy at the Paul Scherrer Institute (PSI-Villigen) and at MedAustron (Wiener Neustadt, Austria) we investigate differential requirements of the two major DNA double strand break repair pathways in response to clinically-relevant low LET proton- versus photon-irradiation. The long term goal is to gain knowledge on the differential “biologies” induced by the different sources of ionizing radiation.
Optimization and combination of the different sources of ionizing radiation for an individual patient situation might thereby lead to a more personalized approach of radiotherapy, taking also biological parameters into consideration. These studies are currently funded by our Horizon2020 Marie-Curie ITN.
IMPLEMENTATION OF PRECLINICAL TUMOR MODELS AND RADIOTHERAPY APPROACHES
A small animal image-guided radiotherapy platform was acquired and installed in 2016. This small animal radiotherapy platform renders it possible to implement more relevant small animal tumor models into our research projects and to address clinical challenges with the appropriate state-of-the art preclinical approaches.
This catalyzes a strong exchange between the different research subdisciplines (medicine, physics, biology) in our Dept. of Radiation Oncology and could already initiate several research collaborations on the local (USZ, UZH, ETHZ) and national level (CHUV) and also outside of the field of radiotherapy (e.g. collaboration with Prof. Bruno Weber, Neuroscience Center Zürich). We have now integrated more advanced tumor models into our ongoing and planned projects (orthotopic liver, brain, lung, mammary tumor models in immunocompetent murine background).
We thereby take also the current interest in immunological endpoints into consideration and provide preclinical relevant tumor models for experimental endpoints of the physics and clinical research units of our department (e.g. mechanistic studies in the promising field of radiomics).