Zu den Inhalten springen

Comprehensive Cancer Center Freiburg - CCCF

DKTK-Freiburg: Priority Area 2

Imaging, Biomarker Identification & Radiation Therapy

Imaging, Biomarker Identification & Radiation Therapy are key research areas for the development of strategies in personalized oncology and targeted treatment. Priority area 2 provides valuable data and expertise for multiomic approaches and address major oncological challenges such as tumor heterogeneity and resistance. With Multiparametric and multimodal imaging, information about key processes in cancer development and progression are obtained thereby improving the individual cancer risk stratification, therapy monitoring and precise localization of tumors. Within innovative and established DKTK structures, preclinical research has a strong focus on clinical translation and early clinical trials. The Research Area 2 aims at the identification of novel molecular probes for imaging and therapy in the field of Nuclear Medicine and personalized Radiation Oncology as well as the development of multimodal imaging technologies. Specific topics include, but are not limited to: Discovery of novel imaging probes and targeted radiopharmaceuticals for theranostic approaches, the development of innovative MRI technologies, e. g. hyperpolarization, and personalized radiation therapy approaches covering high-precision, biomarker-based technologies as well as particle therapies.

Chair of the priority area 2:

DKTK Professor for Radiopharmaceutical Development Matthias Eder

Scientific committee members:

DKTK principal investigators and projects in priority area 2:

Magnetic Resonance (MR) spectroscopy allows for non-invasive measurement of metabolic changes at – however – limited spatial, chemical, or temporal resolution. These limitations can be addressed by improving the sensitivity of MR by strongly aligning nuclei of metabolically active molecules in the magnetic field (i.e. spin hyperpolarization, HP). Novel HP contrast agents (CA) have been used to monitor cancer metabolism in vivo in real-time. They have allowed grading of tumors and to observe metabolic response to chemotherapy within a day, non-invasively and without ionizing radiation. Recently, HP has been used to image glioma,
prostate and pancreatic cancer in human, with promising results; more studies are undergoing, e.g. in patients suffering from breast and prostate cancer (our group is contributing imaging methods to these studies).

Head-and-neck squamous cell carcinomas (HNSCC) are common malignancies, and despite advances in diagnosis and treatment, the 5-year survival rate of 40-70% for locally advances tumors is still unsatisfactory. Radiotherapy constitutes a treatment standard for HNSCCs both in the definitive and adjuvant settings. However, the efficacy of radiotherapy depends on the individual tumor biology, and several biological characteristics have been identified that modify radiation effects in HNSCCs. In this context, tumor-associated hypoxia has been most thoroughly studied as a risk factor that impairs radiation response of HNSCC. Functional imaging using hypoxia-specific tracers such as [18F]FMISO allows non-invasive and repeat hypoxia measurements and can deliver a temporal and spatial resolution of the hypoxia distribution. Other biological characteristics that may influence the radiation response of HNSCCs are considerably less well understood.

Our preliminary data strongly suggest that the radiation response of HNSCCs and thereby the outcome of head-and-neck cancer patients undergoing radiotherapy not only depends on the dynamics of tumor-associated hypoxia, but also on other biological factors such as the immune microenvironment. Nevertheless, standard-of-care radiation therapy (RT) planning is based on a binary concept that distinguishes between irradiated target volumes and spared organs-at-risk, and pre-defined homogenous doses are prescribed to treat target volumes irrespective of the individual tumor biology and the well-known tumor heterogeneity. Feeding the increasing knowledge of the tumor biology into the planning process will therefore likely help to improve treatment outcomes for HNSCC patients: Tumor maps that are based on multimodal and molecularly validated bio-imaging and depict the spatially and temporally varying radiobiology will help to devise treatment planning strategies for personalized radiation treatment. This novel approach for adapting and personalizing treatment doses and volumes may help to increase complication-free tumor control probability.

The project deals with multidimensional biomarkers for risk-prediction in prostate cancer and represents a radio-proteomic study for the individualization of salvage radio therapy  concepts based on PSMA PET/CT and biopsy proteomics. It is a collaboration between the Department of Radiation Oncology and the Department of Pathology and involves other DKTK partner sites to identify predictive biomarkers in prostate cancer. It involves quantitative, targeted, and spatially resolved proteomics.

The cellular and molecular composition of the inflammatory microenvironment of tumours is decisive for the invasive and metastatic properties of carcinomas as well as for the pro- or anti-tumour polarization of the immune system. To this end, non-invasive imaging technologies hold great promise for monitoring the microenvironment for diagnosis and subsequent therapy. Nuclear medicine technologies, namely PET (positron emission tomography) imaging, are widely clinically applied and versatile for detecting tumour-biological parameters in vivo. However, there is still a lack of imaging probes that faithfully detect targets characteristic for the tumour-promoting or tumour suppressing states of the microenvironment in the primary tumour and at metastatic sites.

To address this urgent need, this project aims to establish a pipeline for advancing novel microenvironment imaging probes for personalized characterization of the activation state of the stroma in tumours and (pre)metastatic niches

Contrary to previous assumptions, it has recently become clear that local radiation therapy (RT) can be immunogenic. Mouse experiments have demonstrated that RT-induced CD8+ T cells are essential for long-lasting local tumor control and that they can mediate systemic effects on distant nonirradiated tumor lesions (so-called “abscopal effects”). Strong abscopal effects are usually observed only in combination with immunotherapy, e.g., immune checkpoint blockade using anti-PD-1/PD-L1 antibodies. However, clinically, the abscopal effect is still rare and it is still not clear how to intentionally trigger it in patients. Our preclinical work suggests that enhanced abscopal effects can be achieved by triple therapies based on the RT/anti-PD-1 double combination. The long-term goal of our translational research is to understand how suitable RT-based combination therapies activate the patients’ immune systems in order to reject their individual tumors. This requires mutually informing preclinical and clinical trials as well as research in biomarkers.

Radiopharmaceutical science is a highly interdisciplinary field encompassing pharmaceutical sciences, chemistry, biotechnology, medical physics, biology and medicine. Research projects are focused on the identification of novel radiopharmaceuticals in the field of diagnostic and therapeutic medicine. The overall aim is to design and develop novel imaging techniques to study human diseases. The clinically oriented projects include the evaluation of theranostic radiopharmaceuticals for positron emission tomography (PET) and radionuclide therapy as well as optical imaging agents to be used for image-guided surgery.

Using innovative biotechnological and chemical methods, biologically active molecules are identified and labelled with radionuclides or fluorescent dyes in order to visualize in vivo biochemical processes. The resulting radiopharmaceuticals are used for diagnostic imaging or therapy of patients and might help to establish novel treatment regimen for a more precise and sensitive detection of tumors. Novel compounds aiming at different tumor entities will be identified and optimized in respect to their tumor targeting and pharmacokinetic properties. A special interest will be in tumor heterogeneity and the targeting of molecular mechanisms underlying tumor cell invasion and metastasis.