Title Promoter Affiliations Abstract "Remote controlled miniaturized radiotracer injection device for dynamic PET imaging in free running small animals." "Jeroen Verhaeghe" "Molecular Imaging and Radiology (MIRA)" "In this project, a miniaturized injection device will be developed. The injection device will be carried by a rat and will be operated by remote control to perform an intravenous bolus injection (0.5 ml / min) in the rat via a catheter in the jugular vein. The injection device will be used for the injection of a radio-tracer into the animal while being in the scanner during the dynamic brain imaging of awake, free-running animals. Since access to the scanner is limited due to the small bore size, the injection must be delivered through a miniature injection device that can be carried by the rat. The aim of the project is to be able to extend our previously developed methodology of brain imaging in free-running animals to dynamic scans where the animal is injected while it is in the scanner. Previously, our imaging in awake animals was only performed after the animals were injected outside the scanner. However, these post-injection scans are less useful for quantitative biomedical research in neuroscience. By developing the automated injection device, we will be able to perform the more relevant dynamic PET scans in free-running animals. In this way we can scan free running animals and we can avoid the influence of anesthesia (as used for PET imaging of small animals) on the brain and thus the measurement results. The usability of the injection device will be demonstrated in a dynamic PET test-retest study in rat in which dopamine receptors will be visualized using [11C]raclopride, a D2 receptor antagonist." "Imaging of receptor activator of the nuclear factor κ B ligand (RANKL) tumor microenvironment using immuno-positron emission tomography (PET) in models of head-and-neck and breast cancer." "Tim Van den Wyngaert" "Molecular Imaging and Radiology (MIRA), Molecular Imaging, Pathology, Radiotherapy & Oncology (MIPRO)" "The receptor activator of the nuclear factor κ B ligand (RANKL) is an important component in carcinogenesis, specifically in the maintenance of self-renewal of cancer stem cells and up-regulation of anti-apoptotic pathways. In the tumor microenvironment, RANKL expression by tumor cells is associated with poor prognosis and more aggressive disease, of amongst others head-and-neck and breast cancer; two malignancies with poor outcome and in urgent need of better prognostic biomarkers and treatment options. However, current research on RANKL is hampered by the lack of a non-invasive biomarker of RANKL expression and dynamics in the tumor microenvironment. We propose a novel use of immuno-positron emission tomography (PET) by radiolabeling the anti-RANKL monoclonal antibody denosumab as longitudinal non-invasive imaging biomarker. The current proposal of this innovative approach includes developing and validating the labeling procedure, establishing the preclinical mouse models, evaluating the biodistribution, and biomarker validation in xenograft and metastatic mice models of oral squamous cell cancer (OSCC) and triple-negative breast cancer (TNBC). To this end, tumor models will be created with high and low RANKL expression, as well as modulation of tumor-derived RANKL using pharmacological intervention. Both a long (zirconium-89) and a short (gallium-68) half-life PET emitter will be studied to facilitate translation to human applications. Novel techniques will have to be developed to optimize antibody labeling with specific application to RANKL imaging, to derive unique immuno-PET imaging signatures of RANKL expression, and to establish the predictive value of this new biomarker. This challenging project will contribute to the understanding of the heterogeneity of RANKL expression, the dynamics of RANKL binding, and impact of RANKL-directed treatment on the tumor microenvironment. This can ultimately impact and improve the selection of patients in trials of RANKL-directed cancer treatments in these two frequent and aggressive diseases (i.e. OSCC and TNBC)." "Development of novel cell death PET imaging probes for early treatment response assessment." "Sigrid Stroobants, Leonie Wyffels" "Molecular Imaging and Radiology (MIRA), Medicinal Chemistry (UAMC), Molecular Imaging, Pathology, Radiotherapy & Oncology (MIPRO)" "Apoptosis or programmed cell death plays a major role not only in the pathogenesis but also in the treatment of cancer. In recent years, a variety of novel cell death inducing molecular cancer therapies have entered the clinic. Although many demonstrated their potential as effective treatment options in several types of cancer, costs to patients and the healthcare system are often staggering. Moreover, most anti-cancer treatments are linked to toxicity to healthy tissues. Early objective and accurate evaluation of tumor response to therapy is therefore of great importance. Tumor response assessment based upon the molecular effects of therapies, such as cell death induction, is a promising strategy for early prediction of therapy outcome. The availability of a radiotracer for positron emission tomography (PET) imaging of cell death could offer clinicians a tool to early after onset of treatment predict individualized responses in patients, and aid in personalized and cost-reducing patient care. Activation of caspase-3 and exposure of phosphatidylethanolamine (PE) represent key biomarkers for apoptosis. Currently no caspase-3 selective nor PE targeting PET radiotracers are available. This project therefore aims at developing novel caspase-3 selective and PE targeting radiotracers for PET imaging of cell death. Both cell death targeting strategies will be compared for early in vivo evaluation of response to therapy (immunotherapy and multi-kinase inhibitor treatment in preclinical models of colorectal cancer)." "Imaging synaptic plasticity in therapeutic sleep deprivation for major depression (SleepLess)." "Jeroen Verhaeghe" "Molecular Imaging and Radiology (MIRA), Molecular Imaging, Pathology, Radiotherapy & Oncology (MIPRO)" "Patients with major depression benefit from therapeutic sleep deprivation. The causality of this clinically effective therapeutic measure is unknown; there is particularly only rare information about the underlying molecular mechanisms. We hypothesize that prolonged wakefulness is associated with an increase in synaptic strength, and that the synaptic dysregulation is affecting long term potentiation in patients with major depression. The aim of the project is to examine the synaptic basis of the antidepressant effect of therapeutic sleep deprivation by Positron Emission Tomography (PET) imaging of the synaptic vesicle protein 2A (SV2A) as a measure of synaptic density in patients and healthy subjects as well as animal models of depression. Since both anesthesia and sleep are subject to compromise biologically valid outcomes when studying the synaptic basis of therapeutic sleep deprivation, a fully quantitative PET imaging method for awake animals will be developed. We are convinced that synaptic density determined with PET has the power to become an indicator for the success of therapeutic sleep deprivation and thus providing means for future stratifications of different therapies in major depression. Identifying and understanding the mechanisms that mediate the effects of sleep restriction is necessary to develop effective interventions. This project will test a model that can be used to improve schedule design." "Development of a novel PET-based duramycin probe for cell death imaging in tumors." "Filipe Elvas" "Molecular Imaging and Radiology (MIRA), Molecular Imaging, Pathology, Radiotherapy & Oncology (MIPRO)" "Cell death is a fundamental biological process. As different therapies may result in activation or inhibition of cell death, there is a need for imaging techniques that can identify cell death during patient treatment. The development of molecular probes targeting cell death biomarkers are key. The exposure of phosphatidylethanolamine (PE) in the cell membrane is an important biomarker for cell death. Specific in vivo positron emission tomography (PET) imaging of PE could therefore aid in the assessment of early response to cancer therapy, preventing exposure of patients to needless toxicity. Duramycin is a small peptide that binds to PE with high affinity and selectivity. The aim of the current work is the development of [18F]duramycin as a novel radiotracer for noninvasive PET imaging of cell death. Following optimization of radiochemistry, the tracer will be characterized to assess cell death binding and target selectivity, stability and pharmacokinetic behavior. Clinical applicability of the probe for therapy response assessment will be evaluated in well characterized cancer xenograft models treated with regorafenib, a multi-kinase inhibitor." "Imaging the link between metabotropic and ionotropic signaling in vivo" "Matthias Schönberger" "Radiopharmaceutical Research" "Cellular communication is a prerequisite for the life of multicellular organisms. Evolution has given rise to a variety of messenger systems that differ in speed and range. The communication between the outside and the inside of a cell is a key interface that is largely orchestrated by transmembrane receptors. This family of communication proteins can be roughly divided into two classes: 1) Metabotropic receptors, which trigger intracellular second messenger signaling cascades and 2) ionotropic receptors, which allow ions to cross the cell membrane. G-protein coupled inwardly rectifying potassium (GIRK) channels present a link between these two communication pathways and will be the focus of this thesis." "Unraveling the potential of circular RNAs as novel biomarkers of radiation exposure and- sensitivity and their functional characterization in the radiation response" "Winnok De Vos" "Laboratory of cell biology and histology" "Biomarkers for radiation exposure are important for a number of reasons. With a growing nuclear threat, the identification of efficient biomarkers for radiation exposure that enable fast triage of exposed individuals is becoming increasingly important. Likewise, the identification of robust biomarkers of radiosensitivity should help tuning current tumor radiotherapies to more personalized schemes. Current golden standard methods for biodosimetry such as cytogenetics assays fall short in several aspects related to emergencies, in that their analysis is very laborious, time-consuming and expensive and therefore not amenable for fast screening of large cohorts. In the last decade, gene expression signatures have emerged as potential biomarkers that could be useful for the abovementioned purposes1–6. We have recently taken this research a step further with the identification of exon expression signatures as robust radiation biomarkers7 which are more sensitive than gene signatures, and therefore more suitable in the case of low-dose exposures. One of the main disadvantages of classical mRNA biomarkers is their inherent instability. Circular RNAs (circRNAs) are a recently described class of non-coding RNA molecules9,10, of which the expression varies according to the cell/tissue-type and developmental timing11–16. Due to their covalently closed circular structure, circRNAs are resistant to exonuclease degradation, and therefore remarkably stable17. This, together with observations that circRNAs are highly abundant in blood cells18 and furthermore enriched in exosomes from human serum19 gives them a very high potential as biomarkers in general, and radiation biomarkers in particular. Hence, in this PhD project, we will identify circRNA biomarkers for radiation exposure and radiosensitivity and characterize the functions of the most promising ones." "In vivo imaging and therapy using labeled antibody derivatives" "Guy Bormans" "Radiopharmaceutical Research" "Glycans play a central role in numerous events in cell-cell recognition, cell communication and cell mobility. Errors in glycan architecture and expression level can lead to pathologies such as cancer. Tumor Associated Carbohydrate Antigens (TACA) are specific glycans that can serve as biomarkers for tumor diagnostics as is already the case for carcinoembryogenic antigen (CEA). This project will focus on the xeno-glycan Neu5Gc (N-glycolylneuraminic acid) and the onco-fetal glycan Globo-H (globoside H type 3 trisaccharide) as new targets for in vivo imaging with theranostic potential. Both glycans, detected on the outer cell membrane in breast, ovarian and gastrointestinal cancer, are in clinical studies as antigen for anti-tumor vaccination. We want to investigate the use of fluorine-labeled small biomolecules for visualization of Neu5Gc and Globo-H expression on tumors. Antibodies are suboptimal for in vivo imaging because they require a relatively long waiting time between injection and imaging, necessitating the use of relatively long-lived radionuclides. Depending on the contrast and the pharmacokinetics, the biomolecules will be examined for targeted radionuclide therapy." "Novel preclinical bioluminescence-based combination treatment approaches to improve glioblastoma outcome" "Nuclear Technology Centre" "Glioblastoma multiforme (GBM) is an aggressive malignant brain cancer with a dismal survival with the current standard of care. Although several new therapeutics have been identified, very few clinical successes have been achieved, due to the lack of predictive preclinical models. Using GBM models in the brain of rats mimicking high-grade human gliomas, we will apply a novel approach, namely the downscaling of the clinical concept of human image-guided radiotherapy, to the level of preclinical animal studies, to investigate new therapeutic approached targeting the GBM mechanisms of treatment resistance. These kinds of studies require an integrated irradiation and imaging research platform, of which one of the most advanced in the world is available at UM. To allow non-invasive monitoring of tumor growth and treatment planning, we will apply bioluminescence imaging for which 3D reconstruction algorithms will be developed. These tools will be used to enable radiotherapy treatment planning to establish whether anti-cancer treatment based on hypoxia-targeting prodrugs and immunotherapy in combination with radiotherapy will affect tumor control compared to radiotherapy alone, and if so, if there is synergy between the therapies." "An Open-Label Microdosing Study to investigate the Regional Brain Kinetics of Brain Drug Transporters Using P-glycoprotein and Breast Cancer Resistance Protein Substrates." "Sebastiaan Engelborghs" "Neurochemistry and behaviour" "This is a sequential, open-label, multicenter Phase 1 study and consisting of the following consecutive parts: Part A, in healthy adult male subjects; Part B, in mild AD subjects and healthy age- and gender-matched controls."