Research Filipe Elvas

Abstract

Fibroblast activation protein (FAP) is a protease biomarker that is selectively expressed on activated fibroblasts. Strongly FAP+ fibroblasts are found in >90% of all tumors, in fibrotic tissue and in tissue remodelling. At UAntwerp, UAMC1110 was earlier discovered: a very potent and selective FAP inhibitor. Radiolabeled derivatives of UAMC1110, called FAPIs, can be used as diagnostics or as therapeutics ('theranostics'). Nowadays, a steeply increasing number of FAPIs is being synthesised. However, there are no good predictions for the in vivo behaviour of novel FAPIs and the understanding of the interactions between FAP and its inhibitors is still limited. Within this FWO-SB application, we will bridge the gap between the present in vitro biochemical evaluation and the in vivo preclinical experiments. In addition, we will provide an expansion of our knowledge about FAP-FAPI interactions. This increase in insights will be realised by: 1) FAPI-PLA, a highly interdisciplinary in vitro platform to accelerate the preclinical development of FAP-targeted theranostics. FAPI-PLA will enable a thorough evaluation of new FAPIs through a combination of biophysical characterization and assessment of their behaviour in a cellular context such that they may eventually be used as theranostics. 2) the elucidation of FAP-FAPI interactions by nanoscale structure determination to expand our knowledge on the interactions.

Researcher(s)

• Promoter: De Meester Ingrid
• Co-promoter: Elvas Filipe
• Co-promoter: Sterckx Yann
• Co-promoter: Van Der Veken Pieter
• Fellow: de Groot Anke

Research team(s)

• Medical Biochemistry

Project type(s)

• Research Project

Abstract

Cancer-associated fibroblasts (CAFs) are a group of tumor stromal cells typically associated with cancer growth and metastasis. These CAFs show high expression of the fibroblast activation protein (FAP) on the cell membrane. Due to the selective FAP expression and cancer-specific distribution, CAFs have emerged as a promising cancer diagnostic marker and an attractive therapeutic target. The recent success of FAP-targeted positron emission tomography (PET) radiotracers, led to more research for radiopharmaceutical therapies to the this protein. Furthermore, a FAP-targeted approach gives the opportunity to use a using the same ligand for both imaging of the expression of FAP and to target it with a radionuclide therapy (theranostics), to enables a personalized cancer treatmentmedicine approach. However, the current FAP ligands show suboptimal tumor-residence time, which is of particular importance for radionuclide therapy. Therefore, in this application we aim to develop novel FAP-targeting radiotheranostics. The radiotracers will be first evaluated in vitro to assess FAP selectivity and activity, followed by in vivo imaging and therapy using a human cancer mouse model.

Researcher(s)

• Promoter: Elvas Filipe
• Co-promoter: Van den Wyngaert Tim
• Co-promoter: Van Der Veken Pieter
• Fellow: Vanermen Maarten

Research team(s)

• Molecular Imaging and Radiology (MIRA)

Project type(s)

• Research Project

Abstract

Radioligand therapy has recently received renewed attention as promising treatment option to improve cancer patient outcome. Compared to conventional cancer treatments, this strategy involves a more specific targeting of therapeutic radionuclides to the tumor, which aims to increase treatment efficacy. Despite recent progress, currently available treatments show insufficient tumor killing and normal tissue toxicity, and we hypothesize that a pretargeted click-to-release (C2R) strategy can bridge this gap. Within this strategy, we propose to explore Fibroblast Activation Protein (FAP) inhibitors as tumor targeting vectors, to deliver a therapeutic radionuclide fragment intracellularly using cell permeable, cleavable transcyclooctene (dcTCO) constructs and compare it with conventional dTCOs. To reinsure intracelular release, after C2R, we designed new structures containing an RGD peptide (with integrin αvβ3 binding specificity). Our molecular constructs also aim to prevent FAP efflux, by using a guanidinium and nicotinoyl residualizing groups. This project will evaluate the reactivity, in vitro stability, logD and radiochemical yield of the new molecules, and the C2R efficiency of the dcTCOs. A FAP inhibitor (dimer) will be weaponized with a tetrazine handle to be the targeting vector and biorthogonal pair of these new constructs, and it's affinity and selectivity will be evaluated in vitro, against other proteases. The dcTCOs and dTCOs with better reaction kinetics and C2R efficiency (dcTCOs) will be selected for the development of 18F- and 125I-radiolabeled probes. The celular uptake and internalization will be evaluated on tumor cells (FAP positive cells, integrin αvβ3 positive cells, both FAP and αvβ3 positive). This project is a innovative strategy to improve the radiation dose delivered to the tumor and improving treatment outcome, while reducing radiotoxicity and achieving better treatment tolerability.

Researcher(s)

• Promoter: Elvas Filipe
• Co-promoter: De Meester Ingrid
• Co-promoter: Van Der Veken Pieter
• Fellow: Da Silva Gustavo

Research team(s)

• Molecular Imaging and Radiology (MIRA)

Project type(s)

• Research Project

Abstract

Nuclear Magnetic Resonance (NMR) is a spectroscopic technique that provides unique insight into the chemical structure and conformational dynamics of molecules. It is indispensable for medicinal and organic chemistry, for natural products research and for all related domains drawing on organic chemistry. For all publications in these fields, journals demand that research data are extensively supported by NMR-analysis: if NMR data are not or only partially delivered, research cannot be accepted for publication. This is because NMR spectroscopy is a sui generis methodology for which no generally applicable alternatives exist. There are currently only two operating NMRs left at UAntwerpen (both 400 MHz): one in the Medicinal Chemistry research group (UAMC) and one in the Organic Synthesis group (ORSY). In both groups, a large number of externally and internationally funded projects entirely rely on these very intensively used machines. Loss or temporary drop-out of a remaining instrument would have ruinous consequences on research. The available spectrometer at UAMC will be 15 years old in 2024 and at the end of its expected life-time. We therefore would like to replace the UAMC NMR. Spectrometers working at 400 MHz are the literature standard for most medicinal, organic and natural products applications and are expected to remain so for the next two decades. This application also fits in a long-term strategy to ensure that NMR-dependent research remains possible at UAntwerp.

Researcher(s)

• Promoter: Augustyns Koen
• Co-promoter: Billen Pieter
• Co-promoter: Elvas Filipe
• Co-promoter: Maes Bert
• Co-promoter: Prothiwa Michaela
• Co-promoter: Tuenter Emmy
• Co-promoter: Van Der Veken Pieter

Research team(s)

• Medicinal Chemistry (UAMC)

Project type(s)

• Research Project

Abstract

Fibroblast activation protein (FAP) is a protease biomarker that is selectively expressed on activated fibroblasts. Strongly FAP-positive fibroblasts are present in > 90% of all tumor types, in fibrotic disease lesions, and in other pathologies that involve tissue remodeling. Researchers at UAntwerpen earlier discovered UAMC1110: to date the most potent and selective FAP-inhibitor described. UAMC1110 is now used widely as the FAP-targeting vector of the so-called FAPIs: radiolabeled derivatives of UAMC1110. These FAPIs can be used as diagnostics or as therapeutics ('theranostics'), depending on the radiolabel. While these FAPIs have shown impressive clinical results in oncodiagnosis, radiotherapy applications are somewhat lagging. This is because the original FAPIs typically have short FAP-residence times, leading to short tissue retention and fast wash-out of radioactivity. To date, mainly optimization strategies that significantly discount on 'druglikeness' have been explored. Examples include the use of 'multi-valency' and the addition of lipophilic, albumin-binding moieties. Remarkably, only a very limited number of papers have focused on optimizing the UAMC1110 pharmacophore. Some of these again have led to very large molecules. Druglikeness is not a critical parameter for most oncology applications, because of the leaky tumor vasculature and loose tissue. In very dense tissue, such as in fibrosis, druglikeness can however be expected to become a key parameter. The host recently discovered several series of druglike, pharmacophore-optimized FAPIs, for which patent applications were submitted. For the last of these applications (submitted in August 2023), we would like to generate additional data that support and exemplify the claims. More specifically, we want to synthesize novel druglike FAPIs that are covered by the patent application's Markush Formula and associated biological data.

Researcher(s)

• Promoter: Van Der Veken Pieter
• Co-promoter: De Meester Ingrid
• Co-promoter: Elvas Filipe

Research team(s)

• Medicinal Chemistry (UAMC)

Project type(s)

• Research Project

Abstract

Ondanks vooruitgang in kankerbehandelingen blijft er een hoge klinische nood bestaan aan nieuwe therapieën om de overleving te verbeteren. Vergeleken met chemotherapie zijn gerichte radiofarmaca gekoppeld aan diagnostische of therapeutische radionucliden veelbelovend om de therapeutische werkzaamheid te verbeteren met minder toxiciteit. De CD70-CD27-as is abnormaal geactiveerd in vele tumoren (vb. niercelcarcinoom) en betrokken bij immuunontwijking en tumorprogressie. De beperkte expressie van CD70 in normale weefsels maakt dit een aantrekkelijk doelwit voor op monoklonale antilichamen (mAb) gebaseerde therapieën. Echter, de huidige beschikbare behandelingen gericht tegen CD70 hebben een onvoldoende tumordodend vermogen laten zien, en wij schuiven de hypothese naar voor dat radioimmunotherapie betere resultaten kan bereiken met behulp van een theranostische benadering. Onder het theranostisch paradigma "wat je ziet is wat je behandelt", zullen wij CD70-gerichte radiofarmaca ontwikkelen met behulp van het krachtige theranostische radionuclide paar 64Cu/67Cu voor diagnose met positron emissie tomografie (PET) en radionuclide therapie. Met dit paar kunnen diagnostische (d.w.z. voor patiëntselectie en behandelingsplanning) en therapeutische (d.w.z. voor kankerbehandeling en dosimetrie na de behandeling) radiofarmaca worden gemaakt die alleen verschillen in het isotoop van hetzelfde element. Hierdoor is er een identiek biochemisch gedrag en farmacokinetiek, in tegenstelling tot vele momenteel gebruikte theranostische middelen. Hiertoe onderzoeken wij een nieuwe intracellulaire pretargeted radioimmunotherapie (PRIT) strategie waarbij gebruik wordt gemaakt van radiogelabelde transcyclooctenen (TCO) en mAb-tetrazine (Tz) conjugaten. Deze strategie is gericht op het verbeteren van CD70 targeting door het creëren van stabiele en reactieve mAb-Tz conjugaten en nieuwe cel-permeabele radiogelabelde TCO structuren met hoge stabiliteit en reactiviteit. Vervolgens zullen we de dosering, het toedieningsschema en de stralingsdosimetrie van de anti-CD70-mAb-Tz en 64Cu/67Cu-NOTA-TCO optimaliseren voor in vivo tumor pretargeting. Ten slotte zullen we een eerste proof-of-concept in vivo preklinische studie uitvoeren om een therapeutisch signaal te detecteren van onze PRIT-benadering.

Researcher(s)

• Promoter: Van den Wyngaert Tim
• Co-promoter: Elvas Filipe
• Fellow: Yu Quanyi

Research team(s)

• Molecular Imaging and Radiology (MIRA)

Project type(s)

• Research Project

Abstract

Multiple myeloma is a rare form of white blood cell cancer of the bone marrow. While there is no cure, multiple myeloma can be managed successfully in many patients for years because of the growing availability of new drugs. Despite these advances, most current treatment strategies follow a one-size-fits-all approach and novel techniques to select patients for specific therapies are needed, especially considering the potential toxicity and cost of emerging immunotherapies (like CAR-based cellular therapies). Moreover, pockets of myeloma cells can exist within a patient with different sensitivity for a specific treatment, and single-site bone marrow biopsy may be less reliable to identify heterogeneous disease. Positron emission tomography (PET) provides a powerful platform to characterize tumors non-invasively by modifying and radio-labeling antibodies to image the tumor phenotype. In this preclinical project, we will develop, validate, and assess the predictive potential of a new antibody-based PET tracer to assess BCMA, a protein that is highly and selectively expressed on myeloma cells, offering our radiopharmaceutical unique specificity. Finally, a mouse model expressing human characteristics will be used to assess our tracer in a clinically relevant setting using CAR-based cell therapy. If successful, our tracer will help physicians select patients who can benefit from CAR therapy and avoid risking the severe side-effects in patients with a low likelihood of response.

Researcher(s)

• Promoter: Anguille Sébastien
• Co-promoter: Elvas Filipe
• Co-promoter: Van den Wyngaert Tim

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Fibroblast activation protein (FAP) is a cell surface marker of Cancer- Associated Fibroblasts (CAFs) in most sarcomas and in > 90% of carcinomas. Together with its negligible expression in most other tissues, this makes FAP a nearly-universal biomarker of tumors. During the past years, diagnostic and therapeutic targeting of FAP with so-called 'FAPIs' has attracted strong attention from nuclear medicine/oncology specialists. Noteworthy, all FAPIs owe their remarkable tumor homing potential to a potent and selective FAP-binding subunit: UAMC1110, reported by the applicants of this proposal. Because FAPIs require further optimization of tumor residence time, we aim to link multiple FAPIs or FAPI subunits to gold nanoparticles (AuNPs). In this way, we hope to obtain FAP-targeting AuNPs with unprecedented FAP affinity and tumor residence, due to the 'multivalency effect'. The nanoparticles will be investigated as cancer theranostics in a mouse model of colorectal cancer and as diagnostics in a lateral flow assay.

Researcher(s)

• Promoter: Van Der Veken Pieter
• Co-promoter: De Meester Ingrid
• Co-promoter: Elvas Filipe
• Co-promoter: Sterckx Yann
• Co-promoter: Stroobants Sigrid

Research team(s)

• Medicinal Chemistry (UAMC)

Project type(s)

• Research Project

Abstract

Fibroblast activation protein (FAP) is a serine protease expressed on stromal cells of > 90% of all epithelial cancers, whereas its expression is almost undetected in normal tissues. In addition, FAP expression is highly restricted and transiently increased in adult tissues during wound healing, inflammation or fibrosis in activated fibroblasts. Among the stromal cells, cancer associated fibroblasts (CAFs) having a FAP-positive phenotype have been associated with poor prognosis in multiple cancers. The highly focal expression and cancer-specific distribution of FAP make this protein a promising cancer diagnostic marker and an attractive therapeutic target. Motivated by the success of FAP-targeted positron emission tomography (PET) radiotracers, FAP-targeted radiopharmaceutical therapies are currently heavily investigated. In addition, FAP-targeted radiopharmaceuticals offer the possibility of imaging diagnostics and targeted radionuclide therapy using the same ligand (theranostics), enabling personalized cancer treatment. However, the relatively rapid washout from the tumor and inadequate pharmacokinetics of current FAP ligands represents a major problem for radioligand therapy. Therefore, the goal of this application is to develop FAP-targeting radiotheranostics. Radiotracers will be evaluated in vitro to assess FAP activity and selectivity. Finally, a human cancer mouse model will be used to assess both imaging and therapeutic potential of our FAP- radiotracers. If successful, our strategy will help physicians select patients who can benefit from FAP-targeted radionuclide therapy.

Researcher(s)

• Promoter: Elvas Filipe
• Co-promoter: Van den Wyngaert Tim
• Co-promoter: Van Der Veken Pieter
• Fellow: Vanermen Maarten

Research team(s)

• Molecular Imaging and Radiology (MIRA)

Project type(s)

• Research Project

Abstract

Europe has a high cancer burden: in 2020, 2.7 million EU citizens were diagnosed with the disease and 1.3 million lost their lives to it. This toll is expected to increase further, mainly because Europe's population is ageing: by 2035, cancer will be the leading cause of death in the EU. In 2021, the EC published its 'Europe's Beating Cancer Plan' (EBCP), calling for a big push in cancer research. Cancer diagnostics and therapeutics should rapidly become more effective and selective, patient-friendly and personalized. All these goals are directly addressed by developing better tumor targeting strategies. Typically, they consist of equipping diagnostics and therapeutics with a vector unit. The vector unit binds to a protein that is overexpressed on cancer cells or in the Tumor Micro-Environment (TME), causing the diagnostic or therapeutic payload to accumulate in the tumor. Over the last decades, huge effort has gone in approaches that use antibodies as vectors, but return-on-investment has overall been rather poor. Exciting, recent innovations rely on small molecule vectors that target TME proteases. Proteases are ideal candidates for tumor targeting: they are often strongly overexpressed in the TME and possess an active site that allows high-affinity anchoring of vectors. Members of this consortium have played a leading role in these developments. OncoProTools wants to force breakthroughs in cancer diagnosis and therapy by: 1) Exploring innovative venues for protease targeting in CAR T cell therapy. 2) Discovering novel vectorsthat bind to other TME proteases: cathepsins S, B, L and granzyme B 3) Personalize applications of protease targeting: deliver innovative diagnostics through deeper understanding of TME biology. At the same time, OncoProTools will deliver a training program that truly captures the MSCA values, to 10 Doctoral Candidates. They will be provided with all capabilities to become leaders of tomorrow's R&I in Europe

Researcher(s)

• Promoter: Van Der Veken Pieter
• Co-promoter: De Meester Ingrid
• Co-promoter: Elvas Filipe
• Fellow: Shikut Nikita
• Fellow: Thanopoulou Magdalini

Research team(s)

• Medicinal Chemistry (UAMC)

Project website

Project type(s)

• Research Project

Abstract

During the past decades, many traditional medical imaging techniques have been established for routine use. These imaging modalities, such as computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US), and radionuclide imaging (PET/SPECT) are widely applicable for both small animal and clinical imaging, diagnosis and treatment. A unique feature of molecular imaging is the use of molecular imaging agents (either endogenous molecules or exogenous tracers) to image particular targets or pathways and to visualize, characterize, and quantify biological processes in vivo. Dedicated high-resolution small animal imaging systems such as microPET/CT scanners have emerged as important new tools for preclinical research. Considerable benefits include the robust and non-invasive nature of these small animal imaging experiments, enabling longitudinal studies with the animal acting as its own control and reducing the number of laboratory animals needed. This approach of "miniaturised" clinical scanners efficiently closes the translational feedback loop to the hospital, ultimately resulting in improved patient care and treatment. By this underlying submission, our consortium aims to renew our 2011 microPET/CT scanners after their ten-year lifetime by a digital up-to-date system in order to continue our preclinical molecular imaging studies in several research fields, including neuroscience, oncology and tracer development.

Researcher(s)

• Promoter: Staelens Steven
• Co-promoter: Augustyns Koen
• Co-promoter: Bertoglio Daniele
• Co-promoter: Elvas Filipe
• Co-promoter: Stroobants Sigrid
• Co-promoter: Van Der Veken Pieter
• Co-promoter: Verhaeghe Jeroen

Research team(s)

• Molecular Imaging and Radiology (MIRA)

Project type(s)

• Research Project

Abstract

The envisaged core facility brings together key preclinical imaging expertise and facilities within UA located in the Uc building on CDE. This joint venture provides preclinical imaging instruments of the highest performance of all Belgian universities. Concretely, the preclinical imaging infrastructure consists of 4 high‐field MRI systems with dedicated RF coils, 2 microPET/CT systems, 1 microSPECT/PET/CT. Using this equipment, virtual sections can be made through a living laboratory animal (which may or may not be a model for a particular pathology) enabling to quantitatively monitor various anatomical, morphological, physiological and molecular processes over time in the same animal. These techniques play a crucial role in basic and applied biomedical and pharmaceutical research and because the same techniques are used in humans/patients (translationally) they are vital for clinical diagnostics and research into early biomarkers of diseases and therapy follow‐up. In addition to the in‐vivo multi‐modal imaging systems, access to Bioluminescence/Fluorescence camera, animal monitoring (pulse oxygenation, temperature, respiration, ECG and EEG), microsurgery, and a radioprotected laboratory animal animalarium (150 laboratory animals single housed) are available.

Researcher(s)

• Promoter: Verhoye Marleen
• Co-promoter: Bertoglio Daniele
• Co-promoter: Elvas Filipe
• Co-promoter: Staelens Steven
• Co-promoter: Verhaeghe Jeroen

Research team(s)

• Bio-Imaging lab

Project type(s)

• Research Project

Abstract

The emerging trend in cancer therapy is to enhance cytotoxic immune response by activating cytotoxic cells to achieve effective killing of malignant cells and to reprogram myeloid cells toward an anti-tumor phenotype, representing the current foundations of cancer immunotherapies. Importantly, immunotherapy has changed the treatment landscape for many cancers, resulting in remarkable tumor responses and improvements in patient survival. But, despite impressive tumor effects and extended patient survival, not all patients respond, and others can develop immune-related adverse events associated with these therapies, which are associated with considerable costs. Therefore, strategies to increase the proportion of patients gaining a benefit from these treatments and/or increasing the durability of immune-mediated tumor response are still urgently needed. I aim to establish a strong Radiopharmacy research group addressing these needs, with a primary interest in developing radiopharmaceuticals for molecular imaging of biomarkers/targets that can contribute to the use of immunotherapy in the most effective way, maximizing the likelihood of response. Currently, measurement of blood or tissue biomarkers has demonstrated sampling limitations due to the intrinsic tumor heterogeneity and the latter are invasive. In addition, conventional imaging modalities have proven challenging to monitor early responses to cancer immunotherapy and fail to provide any biological insight of the immune cells. To overcome some of these issues, the use of a noninvasive, sensitive, and quantitative molecular imaging technique such as positron emission tomography (PET) using specific radiotracers can provide non-invasive and longitudinal whole-body monitoring of immune responses. Hence, I have put three strategies forward. First, the development of radiopharmaceuticals targeting cysteine protease activity. Given the relevance of their immunoregulatory roles, imaging of cysteine protease activity may prove useful for the design of optimized immunotherapies. Second, the use B-cell maturation antigen (BCMA)-targeted immunoPET to monitor tumor burden, interrogate target availability and assess treatment response of patients with multiple myeloma. Third, immunoPET imaging of the co-stimulatory CD27/CD70 pathway is expected to shed light on the heterogeneous target expression observed between patient tumors, thereby increasing the success of cancer immunotherapies with immunomodulatory monoclonal antibodies and paving the way for novel therapeutic approaches. The experimental set-up will be determined in a project-by-project manner but will typically involve the design and (radio-)chemical synthesis of radiopharmaceuticals, as well as in vitro and in vivo validation strategies in relevant tumor cells and mouse models of cancer.

Researcher(s)

• Promoter: Elvas Filipe
• Fellow: Elvas Filipe

Research team(s)

• Molecular Imaging and Radiology (MIRA)

Project type(s)

• Research Project

Abstract

Caspases are well known for their role as executioners of apoptosis. However, recent studies have suggested that these lethal enzymes also have important non-canonical roles in the activation and proliferation of T cells. Effective antitumor immune response is based on the ability of T cells to recognize and destroy cancer cells, for which activation of caspase-3 (c-3) is key. Therefore, the assessment of tumor response based upon the activation of c-3 following immunotherapy, may represent a promising strategy for early prediction of therapy outcome. The current set of c-3-targeted positron emission tomography (PET) radiotracers does not provide adequate resolution and signal-to-noise ratio to precisely visualize c-3 activity during the course of immunotherapy. In addition, monitoring of CAR T-cell trafficking to the tumor site is still not possible in cancer patients. Therefore, the goal of this application is to develop PET radiotracers for selectively imaging c-3 and to investigate their value for prediction and evaluation of responses to immunotherapy. We propose to use novel c-3 specific cell-permeable activity-based probes to visualize dying tumors following immunotherapy, and c-3 specific cleavable metabolic probes for bioorthogonal monitoring of T cell activation and trafficking to tumor cells. Probes will be evaluated in vitro to assess c-3 affinity and selectivity, and in vivo using cancer xenograft models treated with immunotherapy for response evaluation.

Researcher(s)

• Promoter: Elvas Filipe
• Fellow: Lauwerys Louis

Research team(s)

• Molecular Imaging and Radiology (MIRA)

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: De Vos Winnok
• Co-promoter: Baets Jonathan
• Co-promoter: Baggerman Geert
• Co-promoter: Bertoglio Daniele
• Co-promoter: Bogers John-Paul
• Co-promoter: Coppens Violette
• Co-promoter: Elvas Filipe
• Co-promoter: Keliris Georgios A.
• Co-promoter: Kumar-Singh Samir
• Co-promoter: Mertens Inge
• Co-promoter: Morrens Manuel
• Co-promoter: Staelens Steven
• Co-promoter: Stroobants Sigrid
• Co-promoter: Timmerman Vincent
• Co-promoter: Timmermans Jean-Pierre
• Co-promoter: Verhaeghe Jeroen
• Co-promoter: Verhoye Marleen
• Fellow: Lanens Dirk
• Fellow: Prasad Aparna

Research team(s)

• Laboratory of cell biology and histology

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Stroobants Sigrid
• Co-promoter: Elvas Filipe

Research team(s)

• Molecular Imaging and Radiology (MIRA)

Project type(s)

• Research Project

Abstract

Various proteases play an important role in the tumor microenvironment (TME). Hence, tackling tumors by targeting these TME proteases is a very promising approach in the fight against cancer. FAPIs, highly potent and selective probes based on UAMC1110, an inhibitor developed at the UAntwerp, are currently evaluated in clinical studies. In contrast, the targeting of other highly relevant TME proteases is lagging behind. Granzyme B (GRZB) is the most abundant protease present in the granules of cytotoxic immune cells present in the TME and plays a role in the targeted tumor cell destruction. Despite decades of research, many aspects of GRZB immunobiology remain enigmatic. It is currently unknown which percentage of GRZB is active in the TME. To study whether imaging or measuring active GRZB levels has advantages over visualizing total GRZB, there is a need for selective and high affinity GRZB probes. Given the potential of GRZB in cancer diagnosis and treatment, this postdoc challenge aims to reinvigorate the quest for the generation of highly selective GRZB inhibitors starting from a literature-based lead compound. The postdoc will be challenged to determine the high-resolution structure of this inhibitor – GRZB complex to fuel rational ligand design. The labs participating in this call are involved in the recently funded OncoProTools (Protease-guided tumor targeting tools to revolutionize cancer diagnostics and treatment) HE-MSCA-Doctoral Network (granted upon first submission, UAntwerp as the lead applicant). UAntwerp will host two PhD students (PhD1 and PhD2) from January 2023 onwards. Since this international project will be the start of a new GRZB-research line within the 'Tumor Micro-environment Proteases' theme, support by a postdoc is highly desirable. The project will be supported by docking studies for in silico design of new inhibitors (UAMC, Hans De Winter). We will offer in-house access to granzyme activity assays, recombinant protein production and purification infrastructure, protein-ligand interaction assays and a lab fully equipped for structural biology (LMB, Y. Sterckx). The Postdoc candidate is expected to bring own experimental expertise with protein expression and structural biology into the GRZB theme and he/she will benefit from a dynamic international network of academic and industrial partners in the field of oncology.

Researcher(s)

• Promoter: De Meester Ingrid
• Co-promoter: De Winter Hans
• Co-promoter: Elvas Filipe
• Co-promoter: Sterckx Yann
• Co-promoter: Van Der Veken Pieter
• Fellow: Pimenta Fernandes Andreia

Research team(s)

• Medical Biochemistry

Project type(s)

• Research Project

Abstract

Fibroblast activation protein (FAP) is a serine protease expressed on stromal cells of > 90% of all epithelial cancers, whereas its expression is almost undetectable in normal tissues. In addition, FAP expression is highly restricted and transiently increased in adult tissues during wound healing, inflammation, or fibrosis in activated fibroblasts. The highly focal expression makes FAP a promising diagnostic marker and an attractive therapeutic target, not only in cancer, but also in fibrotic and cardiovascular diseases. 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) has received widespread attention as the structural basis for FAP-targeted positron emission tomography (PET) radiotracers and FAP-targeted radiopharmaceutical therapies, which are currently heavily investigated and in high demand by the pharmaceutical industry. Also, at UAntwerp, research is ongoing that aims at producing UAMC1110 derivatives, with main applications in the in vitro diagnostics field. In addition, in the scope of a former IOF-POC project the applicants of this proposal have collaborated on the discovery of 18F-labeled UAMC1110 derivatives that can be used as PET diagnostics in oncology, fibrosis and related domains, and in cardiovascular disease. Recently, we have developed a small library of 18F-labeled probes that show promising stability, pharmacokinetics and tumour-targeting properties in human glioblastoma cancer xenografts. Based on this preliminary data a patent application has been filed. However, there is still room for improvement by reducing the accumulation of these probes in non-targeted organs, which is especially relevant in the context of radionuclide therapy. Through structural optimization (increasing the polarity of the probes), this POC project aims to expand this library and deliver compounds having high metabolic stability and less or no accumulation in liver and gastrointestinal tract. Following the proof-of-concept, these optimized probes will be included in the patent that will be filed in early June 2022, which should strengthen the industrial development of these probes as PET-diagnostics and theranostics.

Researcher(s)

• Promoter: Elvas Filipe
• Co-promoter: De Meester Ingrid
• Co-promoter: Stroobants Sigrid
• Co-promoter: Van Der Veken Pieter

Research team(s)

• Molecular Imaging and Radiology (MIRA)

Project type(s)

• Research Project

Abstract

Caspases are well known for their role as executioners of apoptosis. However, recent studies have suggested that these lethal enzymes also have important non-canonical roles in the activation and proliferation of T cells. Effective antitumor immune response is based on the ability of T cells to recognize and destroy cancer cells, for which activation of caspase-3 (c-3) is key. Therefore, the assessment of tumor response based upon the activation of c-3 following immunotherapy, may represent a promising strategy for early prediction of therapy outcome. The current set of c-3-targeted positron emission tomography (PET) radiotracers does not provide adequate resolution and signal-to-noise ratio to precisely visualize c- 3 activity during the course of immunotherapy. In addition, monitoring of CAR T-cell trafficking to the tumor site is still not possible in cancer patients. Therefore, the goal of this application is to develop PET radiotracers for selectively imaging c-3 and to investigate their value for prediction and evaluation of responses to immunotherapy. We propose to use novel c-3 specific cell-permeable activity-based probes to visualize dying tumors following immunotherapy, and c-3 specific cleavable metabolic probes for bioorthogonal monitoring of Tcell activation and trafficking to tumor cells. Probes will be evaluated in vitro to assess c-3 affinity and selectivity, and in vivo using cancer xenograft models treated with immunotherapy for response evaluation.

Researcher(s)

• Promoter: Stroobants Sigrid
• Co-promoter: Augustyns Koen
• Fellow: Elvas Filipe

Research team(s)

• Molecular Imaging and Radiology (MIRA)

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Van Der Veken Pieter
• Co-promoter: De Meester Ingrid
• Co-promoter: Elvas Filipe
• Co-promoter: Stroobants Sigrid

Research team(s)

• Medicinal Chemistry (UAMC)

Project type(s)

• Research Project

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).

Researcher(s)

• Promoter: Stroobants Sigrid
• Promoter: Wyffels Leonie
• Co-promoter: Elvas Filipe
• Co-promoter: Van Der Veken Pieter
• Fellow: Beroske Lucas

Research team(s)

• Molecular Imaging and Radiology (MIRA)

Project type(s)

• Research Project

Abstract

Radiolabeling of monoclonal antibodies (mAbs) is a powerful preclinical and clinical research tool that finds applications in diagnostic as well as in prognostic and therapeutic settings. Positron Emission Tomography (PET) differs from traditional imaging in that probes known as radiotracers carrying a radioisotope are used to visualize, characterize, and quantify biological processes in vivo. However, despite their attractive properties radiolabeled mAbs have a few important shortcomings. One of the most critical ones is their long circulation time in the body associated with low target to non-target ratios, thus requiring the use of long lived isotopes which yields high radiation dose to the patient. A solution for this problem is offered by pretargeting based on bioorthogonal chemistry. This allows in vivo imaging of the target with superior image contrast and reduced radiation doses. An additional challenge is that many mAbs are internalized upon binding to their target on the cell surface, before the pretargeting reaction. To overcome this issue, this project aims at developing a pretargeted intracellular PET imaging strategy. We will develop novel fluorinated trans-cyclooctene analogues (TCOs) and characterize 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.

Researcher(s)

• Promoter: Augustyns Koen
• Co-promoter: Elvas Filipe
• Co-promoter: Wyffels Leonie
• Fellow: Adhikari Karuna

Research team(s)

• Medicinal Chemistry (UAMC)

Project type(s)

• Research Project

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 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.

Researcher(s)

• Promoter: Elvas Filipe

Research team(s)

• Molecular Imaging and Radiology (MIRA)

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Stroobants Sigrid
• Co-promoter: Augustyns Koen
• Fellow: Elvas Filipe

Research team(s)

• Molecular Imaging and Radiology (MIRA)

Project type(s)

• Research Project