IMARK. Network for image-based biomarker discovery and evaluation 01/01/2021 - 31/12/2026

Abstract

IMARK capitalizes on the deeply rooted expertise in biomedical imaging at the University of Antwerp to push the boundaries of precision medicine. By resolving molecular and structural patterns in space and time, IMARK aims at expediting biomarker discovery and development. To this end, it unites research groups with complementary knowledge and tools that cover all aspects of imaging-centred fundamental research, preclinical validation and clinical evaluation. IMARK harbours high-end infrastructure for electron and light microscopy, mass spectrometry imaging, magnetic resonance imaging, computed tomography, positron emission tomography and single-photon emission computed tomography. Moreover, IMARK members actively develop correlative approaches that involve multiple imaging modalities to enrich information content, and conceive dedicated image analysis pipelines to obtain robust, quantitative readouts. This unique blend of technologies places IMARK in an excellent position as preferential partner for public-private collaborations and offers strategic advantage for expanding the flourishing IP portfolio. The major application fields of the consortium are neuroscience and oncology. With partners from the Antwerp University Hospital and University Psychiatric Centre Duffel, there is direct access to patient data/samples and potential for translational studies.

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Validation of autophagy induction as a therapeutic strategy: from drug discovery and preclinical evaluation to safety investigation and biomarker research. 01/01/2021 - 31/12/2024

Abstract

Autophagy is a ubiquitous process that removes unnecessary or dysfunctional cellular components from the cytoplasm. Defective autophagy is currently emerging as a hallmark of many diseases. In this framework, there is strong interest in pharmacological agents that stimulate autophagy (so-called 'autophagy inducers'), as a potential treatment for these diseases. The unequivocal validation of autophagy induction as a therapeutic strategy, however, is far from established. Many obstacles persist, including the lack of druglike, selective autophagy inducers and readily translatable preclinical results that are obtained with such compounds. In addition, the availability of reliable biomarkers for autophagy and additional fundamental safety data for the approach, would strongly contribute to its validation. This proposal addresses existing limitations in the state-of-the art in the domain. We have recently carried out a phenotypic High-Throughput Screen (HTS) on a curated compound library. Members in this library were preselected from different providers based on in silico druglikeness scores. One compound family that was identified in the screen and maximally validated prior to this application, will be further optimized chemically for autophagy induction potency and biopharmaceutical properties. The biopharmaceutical profile of the best new representative will be thoroughly characterized in vivo, both involving PET-based pharmacokinetics and phenotypic pharmacodynamics. The compound will subsequently be investigated in two mouse models of diseases characterized by defective autophagy: atherosclerosis and Charcot-Marie-Tooth periferal neuropathy. In addition, we propose to investigate whether autophagy induction is intrinsically sufficiently safe as a therapeutic strategy. Existing hypotheses that autophagy induction could accelerate tumorigenesis and/or tumor growth will be investigated in vivo. In the same framework, metabolomics will be relied on to monitor eventual cellular stress fingerprints that result from chronic or long-term autophagy stimulation. Finally, metabolomics will also be relied on to identify cellular biomarkers of autophagy induction. The latter will be validated in plasma samples of animals that were systemically treated with autophagy inducers. Combined, we expect the knowledge and tools that are generated by this proposal to have strong impact on the field of autophagy research and ongoing endeavors to validate autophagy induction as a therapeutic strategy.

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Multidimensional analysis of the nervous system in health and disease (µNeuro). 01/01/2020 - 31/12/2025

Abstract

Neuropathological research is an interdisciplinary field, in which imaging and image-guided interventions have become indispensable. However, the rapid proliferation of ever-more inquisitive technologies and the different scales at which they operate have created a bottleneck at the level of integration, a) of the diverse image data sets, and b) of multimodal image information with omics-based and clinical repositories. To meet a growing demand for holistic interpretation of multi-scale (molecule, cell, organ(oid), organism) and multi-layered (imaging, omics, chemo-physical) information on (dys)function of the central and peripheral nervous system, we have conceived μNEURO, a consortium comprising eight established teams with complementary expertise in neurology, biomedical and microscopic imaging, electrophysiology, functional genomics and advanced data analysis. The goal of μNEURO is to expedite neuropathological research and identify pathogenic mechanisms in neurodevelopmental and -degenerative disorders (e.g., Alzheimer's Disease, epilepsy, Charcot-Marie-Tooth disease) on a cell-to-organism wide scale. Processing large spatiotemporally resolved image data sets and cross-correlating multimodal images with targeted perturbations takes center stage. Furthermore, inclusion of (pre)clinical teams will accelerate translation to a clinical setting and allow scrutinizing clinical cases with animal and cellular models. As knowledge-hub for neuro-oriented image-omics, μNEURO will foster advances for the University and community including i) novel insights in molecular pathways of nervous system disorders; ii) novel tools and models that facilitate comprehensive experimentation and integrative analysis; iii) improved translational pipeline for discovery and validation of novel biomarkers and therapeutic compounds; iv) improved visibility, collaboration and international weight fueling competitive advantage for large multi-partner research projects.

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High-resolution slide scanner for digital histopathological phenotyping in health and disease. 01/01/2020 - 31/12/2021

Abstract

Digital pathology involves high-speed, high-resolution digital acquisition of images representing entire stained tissue sections from glass slides and allows them to be viewed directly in much the same way as standard microscopy. While this creates a permanent record of histological slide data and facilitates data sharing with collaborators, importantly, it allows analysis, quantification and objective pathological assessment of entire tissue samples, which is now current practice in pre-clinical and clinical research. We propose to acquire a high-resolution whole-slide scanner, notably absent at UA, not only to facilitate research at the promotors' groups, but virtually any research group performing basic, pre-clinical or clinical research at UA involving histopathology. We firmly believe that acquisition of such a digital scanner will help research groups at UA to stay competitive in biomedical research, facilitate and forge scientific and industrial collaborations at UA and beyond, and generate important industrial revenues.

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Development of new TCO-probes and their evaluation for a novel pre-targeted intracellular PET imaging strategy. 01/11/2019 - 31/10/2021

Abstract

Positron emission tomography (PET) imaging of radiolabeled monoclonal antibodies (mAb) is a powerful in vivo research tool with applications in diagnostic as well as in prognostic and therapeutic settings. The molecular precision of antigen-mAb interaction turns radiolabeled mAbs into highly specific radiotracers with a very high affinity. However, the high molecular weight and the long circulation times of mAbs are associated with unsatisfactory target to background ratios, thus requiring the use of long-lived isotopes which yields high radiation burden to the patient. A pretargeting strategy based in biorthogonal chemistry offers a solution to this problem. In this approach, the mAb with biorthogonal tag will be labeled in vivo with a short lived radiotracer through bioorthogonal reaction at the target site. This allows in vivo imaging of the target with superior image contrast and reduced radiation doses. An additional challenge is that many mAbs internalize upon binding to their target on the cell surface, before the pretargeting reaction. To overcome this issue, this project aims to develop a novel pretargeted intracellular PET imaging strategy. We will develop novel cell permeable fluorinated trans-cyclooctene analogues (TCOs) and investigate their potential for pretargeted intracellular imaging using an innovative approach of "turn-on" FluoroBOT labeled mAbs. Finally, following optimization of radiochemistry, the 18F-TCO will be used in an in vivo imaging study.

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Prediction of tumor response to treatment: clinical translation of (99mTc)-Duramycin. 01/02/2019 - 31/01/2023

Abstract

Colorectal cancer (CRC) is one of the major health concerns in the western world and the second leading cause of cancer death in the USA. While the availability of novel active agents has improved the prognosis of patients with CRC, patients with metastatic disease have a 5-year overall survival rate of only 13%. The current treatment paradigm consists of the subsequent use of cytotoxic chemotherapy and/orselected targeted agents. Objective and accurate evaluation of the tumor response to therapy represents one of the biggest challenges in oncology. An early assessment of therapeutic ineffectiveness will avoid treatment related toxicity to the patient and could lead to improved survival by allowing earlier treatment intensification, discontinuation of ineffective therapy, or initiation of second-line therapy. In today's clinical practice treatment response evaluation is primarily based on anatomical imagingand focuses on the volumetric and morphometric assessment of the tumor. Unfortunately, it usually takes a few weeks to months after start of the therapy before morphological changes become apparent. In that time span, non-responding patients are suffering from avoidable side-effects and can possibly be subject to disease progression. Consequently, there is a growing demand for non-invasive molecular imaging biomarkers that allow early monitoring of treatment efficacy. Phosphatidylethanolamine (PE), expressed only on apoptotic and dead cells, provides an attractive molecular biomarker for the detection of cell death. Duramycin, a naturally occurring peptide antibiotic that binds specifically to PE, has been successfully used as a probe for the imaging of cell death in several animal models.The main goals of this project are to conduct Phase 0 and early Phase I clinical studies of the proprietary imaging probe, [99mTc]duramycin, to ascertain its safety and ability to detect cancer therapyinduced cell death. By comparing a [99mTc]duramycin SPECT scan obtained early after onset of the therapy to a pretreatment scan clinicians should be able to distinguish responders versus non-responders sooner than with anatomical methods.

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Flanders BioImaging: towards an integrated, translational and multimodal imaging platform from molecule to man. 01/01/2019 - 31/12/2022

Abstract

Flanders BioImaging (FBI) is an interuniversity consortium dedicated to biomedical imaging and advanced light microscopy, that was set up to integrate, optimize, rationalize and coordinate available imaging infrastructure in Flanders.

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Development of novel cell death PET imaging probes for early treatment response assessment. 01/10/2018 - 30/09/2022

Abstract

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).

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Biopharmaceutical optimization of PET-diagnostic tools targeting fibroblast activation protein (FAP). 01/05/2020 - 30/04/2021

Abstract

Fibroblast activation protein (FAP) is a serine type protease that is expressed on stromal cells of > 90% of all epithelial cancer types, and also in pathological lesions associated with other diseases characterized by tissue remodeling. It is virtually absent in healthy adult tissues. FAP is being studied both as a therapeutic target and a biomarker/diagnostics target: not only in oncology, but also in, e.g., different fibrosis types and cardiovascular disease. UAntwerp has an approved patent for the only highly potent, selective and orally bioavailable small molecule inhibitors of FAP known to date (US9346814 and EP2804859). One of the compounds in this patent (UAMC1110) receives widespread attention as a potential therapeutic and as the structural basis for diagnostic probes. Also at UAntwerp, research is ongoing that aims at producing UAMC1110 derivatives, with main applications in the diagnostics field. A VLAIO-funded O&O project was recently initiated with HistoGeneX, under which fluorescent and colorigenic UAMC1110 derivatives are used to characterize oncology biopsy samples. The applicants of this project now want to apply their expertise in the domain of FAP ligand design for the discovery of new, FAP-targeting PET probes that can be used in diagnostics.

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Preclinical characterization and biopharmaceutical optimization of the autophagy inhibitor UAMC-2526 for oncotherapy. 01/01/2018 - 31/12/2020

Abstract

Three UAntwerp research groups (Medicinal Chemistry, Physiopharmacology, MIPRO) recently joined forces for the discovery and study of autophagy modulators as potential oncology therapeutics. Hitherto, this approach has resulted in a joint patent application and several manuscripts that have either been published or are under preparation. Most attention to date has gone to investigation of UAMC-2526, an Atg4B-targeting autophagy inhibitor that was discovered by the project team. This compound has potent in vivo autophagy blocking properties and significant anti-tumoral potential in an in vivo xenograft mouse model of colorectal cancer. To ensure economical valorization interest for UAMC-2526 and the UAntwerp-patented family of compounds to which it belongs, more basic research is required. The balanced package of medicinal chemistry, in vitro pharmacology and in vivo oncology that is presented here, should provide detailed insight in the potential of UAMC-2526 and its analogues as a potential therapeutic agent. In addition, biopharmaceutically optimized follow-up candidates for UAMC-2526 will be delivered. At the same time, this effort will increase the compounds' attractiveness to external economic valorization partners. Finally, this project will also create critical mass for a preclinical research platform on autophagy research at UAntwerp. This platform will unite chemical and biological capabilities in autophagy research that will be highly instrumental to support research programs, but will also be offered to private partners that require expertise in the domain.

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Development of novel cell death PET imaging probes for early treatment response evaluation 01/10/2017 - 30/09/2020

Abstract

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 the course of patient treatment. The development of molecular probes targeting cell death biomarkers are key. Caspase-3 activation and exposure of phosphatidylethanolamine (PE) in the cell membrane are important biomarkers for cell death. Selective in vivo positron emission tomography (PET) imaging of caspase-3 and PE could therefore aid in the assessment of early response to cancer therapy, preventing exposure of patients to needless toxicity. Recently, the use of unnatural amino acids in the caspase-3 recognition sequence and the modification of prime probe regions were described to be efficient strategies to design caspase-3 selective probes. 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 and 18F-labeled caspase-3 selective probes for noninvasive PET imaging of cell death. Following optimization of radiochemistry, the probes will be characterized to assess cell death binding and target selectivity, stability and pharmacokinetic behavior. Clinical applicability of the different probes will be evaluated in well characterized cancer xenograft models treated with targeted therapy or immunotherapy and compared to the clinical gold standard 18F-FDG for therapy response evaluation.

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Imaging methodology for Huntington's disease. 01/07/2016 - 30/06/2017

Abstract

Huntington's disease (HD) is a dominantly inherited disorder characterized by a progressive neurodegeneration of the striatum that also involves other regions, primarily the cerebral cortex. Patients display progressive motor, cognitive, and psychiatric impairment. Symptoms usually start at midlife. The mutation responsible for this fatal disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin. The pathogenic mechanisms by which mutant huntingtin cause neuronal dysfunction and cell death remain uncertain (Menalled, 2005). It has been established in a HD mouse model that inhibition of PDE10 improves cognition and thus PDE10 might be a good therapeutic target (Giralt et al., 2013). A pilot study of [18F]-MNI-659 PET already showed a markedly reduced binding in HD compared to healthy volunteers (Jennings et al., 2013). Furthermore, the mechanism underlying HD-related suppression of inhibition has been shown to include tonic activity of metabotropic glutamate receptor subtype 5 (mGluR5) as a pathophysiological hallmark (Dvorzhak, Semtner, Faber, & Grantyn, 2013) and inhibition of glutamate neurotransmission via specific interaction with mGluRs might be interesting for both inhibition of disease progression as well as early symptomatic treatment (Scheifer et al., 2004). With the objective to elucidate the role of phosphodiesterase and glutamatergic pathways using small animal PET imaging, this study aims to use [18F]-MNI-659 (2-(2-(3-(4-(2-[18F]fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazo-lin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione), a PET radiotracer with high affinity for PDE 10 and [11C]-ABP-688 (3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-(11)C-methyl-oxime), a noncompetitive and highly selective mGluR5 antagonist, as tracers in a knock-in model of Huntington's disease.

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    Evaluation of the role of phosphodiesterase 7 and 10 in obsessivecompulsive disorders by positron emission tomography. 01/10/2015 - 15/02/2016

    Abstract

    Patients suffering from obsessive-compulsive disorder (OCD) present symptoms as intrusive, unwanted and recurrent thought or images (obsessions) and or repetitive behaviors (compulsions).These symptoms and behaviors become excessive and disturb significantly daily activities and lead to a low quality of life and a high burden for the family of the patient. The use of serotonin reuptake inhibitor is the most efficient strategy of treatment for OCD but 40 to 60% are refractory to this kind of drugs. So there is a need to look for new therapeutic strategies. Phosphodiesterase (PDE) 7 and 10A inhibitors has been recently proposed as potential treatment in OCD. However none study has been perform to prove this hypothesis. In vivo imaging using Positron Emission Tomography (PET) is a powerful tool to monitor the stages of disease, to study human biology, to investigate in vivo the properties of new drugs in clinical trials. This technique is quantitative and very sensitive and it is a non invasive technique which is a major advantage in brain imaging. Radiotracers are investigated to image in vivo biological targets like a receptor, an enzyme or a tumor. The aim of this project is to use PET imaging to determine the role of PDE7 and PDE10A in OCD and also verify if PDE7 and PDE10A inhibitors could be used as treatment.

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      First PET-MR: A Flemish Interuniversity Research Simultaneous Time-of-Flight PET-MR scanner. 14/08/2014 - 14/02/2019

      Abstract

      This project represents a formal research agreement between UA and on the other hand the Flemish Public Service. UA provides the Flemish Public Service research results mentioned in the title of the project under the conditions as stipulated in this contract.

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        Poxylation as next generation Pegylation. 01/02/2013 - 31/01/2014

        Abstract

        The following main challenges and yet unknown biological aspects of Poxylation, that need to be addressed to demonstrate the safety as well as potential of Poxylation over Pegylation, will be the main objectives to establish the poxylation technology. Besides developing the poxylation technology, this initial project aims to develop synthetic strategies for poxylated therapeutics.

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          PET and SPECT imaging of protease activity by activitybased probes. 01/01/2013 - 31/12/2016

          Abstract

          The main objective of this research proposal is the development of a methodology for PET and SPECT imaging of the enzymatic activity of serine and cysteine proteases using a pretargeting approach with specific activity-based probes and bioorthogonal ligation with radiolabels.

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          Biomarker based adaptive development in Alzheimer (BioAdaptAD). 01/01/2013 - 31/12/2016

          Abstract

          The general objectives of this project are to develop a BACE inhibitor for disease modification in Alzheimer's disease and to explore the development in an earlier prodromal Alzheimer's disease population. From a drug development perspective, this will involve multiple adaptation steps and the intensive use of biomarkers.

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          Activity-based probes for PET imaging of protease activity. 01/01/2013 - 31/12/2016

          Abstract

          Proteases are important drug targets and show increasing application as biomarkers for several diseases. Non-invasive imaging of their proteolytic activity status in vivo offers tremendous potential. We will develop activity-based imaging probes targeting proteases with relevance in oncology and inflammation. These probes will be used in a two-step approach in which the pretargeting step is followed by bioorthogonal ligation with a PET label.

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          Molecular imaging for early response assessment of drugs targeting the PI3K/mTOR pathway in an HER-2 amplified breast cancer model. 01/10/2012 - 30/09/2016

          Abstract

          The treatment with Trastuzumab in human epidermal growth factor receptor 2 (HER-2) overexpressing breast cancer is often transient and almost all the cancers eventually progress. One of the mechanisms of resistance has been linked to aberrant activation of PI3K/AKT/mTOR signaling pathway downstream of the receptor. By blocking downstream proteins at select sites resistant cancers may potentially regain sensitivity to HER-2 therapy. Recently, several potential agents for targeting this pathway are allosteric mTORC1 inhibitors (e.g. everolimus) and PI3K inhibitors (e.g. PIK-90) became available. Activation of alternative pathways and/or downregulation of negative feedback loops clearly demonstrates that blockage of one target is not the ultimate solution. The importance of simultaneous development of predictive biomarkers is therefore of utmost importance to select the optimal drug combination for the individual patient. Non-invasive imaging allows for repeated non-destructive assessment of the molecular phenotype and provides spatial and temporal information regarding the whole tumor burden that could complement the information obtained from tissues biopsies. In this project, we want to investigate the potential utility of positron and single photon emission tomography (PET and SPECT) as an early response biomarker for PI3K pathway targeting therapeutics. The PI3K/AKT/mTOR axis regulates different critical cellular functions including metabolism and glycolysis, proliferation and survival. Depending on the tracer used, different aspects of the tumor biology can be assessed. In this project, we will evaluate the use of different tracers in-vitro (uptake studies in 3 different breast cancer cell lines) and in-vivo (serial microPET/SPECT studies in an orthotopic breast cancer mouse-model before and after different treatment strategies). Objectives: 1. The primary aim is to evaluate FDG (tumor glycolysis) and FLT-PET (tumor proliferation) as early response biomarker for drugs targeting the PI3K/Akt/mTOR pathway in HER2 positive breast cancer models. Treatment induced changes of FDG and FLT tumor uptake will be correlated with immunohistochemical (IHC) markers of proliferation and cell death and phosphorylation status of the different key proteins of the signaling pathway using the capillary-based NanoPro immunoassay system, allowing an ultrasensitive chemiluminescence detection. 2. Since some of the investigated drugs also have anti-angiogenic effects, the use of a new RGD SPECT tracer targeting the ανβ3 receptor [Tc99m HYNIC-RGD] will be evaluated as an additional imaging biomarker. 3. Kinetic modeling of dynamic FLT-PET will be performed to derive the optimal quantification method and explore the effect of tumor perfusion on tracer quantification.

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            Design, synthesis and evaluation of new potent radioligands for PDE7 imaging and implication of PDE7 in neurological disorders. 01/10/2012 - 30/09/2015

            Abstract

            The main objective of this project is to develop a PET radiotracer for PDE7 imaging. The PDE7 inhibitors will be used as lead compounds. We selected two families of compounds to increase our chances to discover a suitable PDE7 radiotracer. The structure of the compounds will be modified for labelling with 11C. Precursors for radiolabeling and the 'cold' (non radioactive) standard compounds will be synthesized for radiotracer characterization and in vivo evaluation of PDE7 inhibitory potency and selectivity. The compounds showing the best potency (nanomolar IC50) and selectivity for PDE7 inhibition will be selected for radiolabeling. The next step will be the optimization of the radiosynthesis. The goal will be to obtain the products in a high radiochemical yield and in high radiochemical purity (> 95% for animal studies).

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              VECTor/CT: simultaneous PET/SPECT/CT scanner for small animals. 28/06/2012 - 31/12/2017

              Abstract

              This project represents a formal research agreement between UA and on the other hand the Flemish Public Service. UA provides the Flemish Public Service research results mentioned in the title of the project under the conditions as stipulated in this contract.

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                Transcranial magnetic stimulation for small animals: methods and device. 01/06/2012 - 31/05/2013

                Abstract

                Transcranial Magnetic Stimulation (TMS) is a treatment for various neurological disorders. We have developed a device and methods for the application of TMS in awake and freely moving small experimental animals. The project aims at performing indispensible evaluation tests and to develop a demonstrator, to support patent filing.

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                  Immuno-positron emission tomography as a potential biomarker for diagnosis and treatment in Alzheimer disease. 01/04/2012 - 31/03/2014

                  Abstract

                  This project represents a formal research agreement between UA and on the other hand a private institution. UA provides the private institution research results mentioned in the title of the project under the conditions as stipulated in this contract.

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                    Development of uPA probes as tools for imaging and diagnostic applications. 01/05/2011 - 30/04/2013

                    Abstract

                    The aim of this project is to further develop uPA probes, of which we already showed the efficacy in in vitro studies, to be used in cellular and in vivo. The IP of these innovative probes have recently been submitted to the UA interface for patenting. The first step in the valorisation of the probes is to obtain proof of concept in in vivo disease models. In the subsequent phase these results will permit us to obtain further funding from larger public (Fournier-Majoie, IWT) or private (VC) institutions. Our goal is to proceed with spinning-out this te chnology into a company preferentially within 3 years.

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                    Validation of Urokinase plasminogen activator (uPA) as a therapeutic target and biomarker. 01/01/2011 - 31/12/2014

                    Abstract

                    In a first work package, the combination with other conventional therapies as well as anti-metastatic effects and the influence on the angiogenic pathway will be studied. A second work package will determine the metabolic stability of the inhibitors and the possible presence of toxic metabolites. A third work package is necessary to provide enough material for the different test systems and will transform the uPA inhibitors to imaging probes. In a fourth work package, the effect of the uPA inhibitors will be evaluated in a primary and a metastatic tumour model. This project will determine whether these selective and potent irreversible inhibitors can be used for the development of a new therapy and/or as a chemical tool for biomarker/bio-imaging research.

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