Research Tim Van den Wyngaert

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

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 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

Bone health equilibrium can be altered by disease and the use of medication. Antiresorptive drugs are frequently used and highly effective to prevent bone metastasis in patients with cancer. Yet, their use is associated with the occurrence of medication-related osteonecrosis of the jaw (MRONJ), a potentially debilitating side effect characterized by exposed necrotic bone in the oral cavity, infection, and pain Although research on advanced MRONJ lesions have been published, so far little is known on the early disease stages, the initial imaging features and potential preventive measures related to early detection and disease prediction. Likewise, radiological risk factors to identify a successful outcome or therapy resistance have not yet been described. Therefore, the main objective of this project is to build an automated prediction model (radiomics) to allow prediction of MRONJ induction and its response to treatment. This could be reached by the following subobjectives: 1. To identify the radiological and genetically predisposing factors to develop MRONJ 2. To describe risk factors influencing treatment outcome in patients with MRONJ In order to obtain the subobjectives, 2 studies will be carried out: o A prospective cohort study to follow-up patients at risk for MRONJ development enabling to identify risk factors. o A retrospective cohort study in patients MRONJ that underwent surgical or conservative treatment to identify radiological features associated with treatment

Researcher(s)

• Promoter: Van den Wyngaert Tim

Research team(s)

• Molecular Imaging and Radiology (MIRA)

Project type(s)

• Research Project

Abstract

Breast cancer (BC) and cervical cancer (BHK) patients, especially those with advanced disease, are in urgent need of new agents that improve survival and quality of life. One promising strategy is immunotherapy, but the cancer has developed mechanisms that circumvent its effects and benefit only a minority of patients. Recently, the RANK(L) signaling pathway is considered a significant mechanism, as it allows many cancers - including BK and BHK - to disrupt the communication of the immune cells and thus undermine the immune response. Supported by our initial results, we strongly believe that blocking this signal can override the immune system and improve susceptibility to immunotherapy. We therefore seek to reveal the most appropriate anti-RANK(L) immunotherapy to elicit an optimal anti-tumor immune response. Building on the results of our clinical studies, additional laboratory testing will allow us to identify that one, superior combination strategy, which we will further optimize in mouse models. Finally, this project will validate a novel imaging technique to select patients who will benefit from this therapy in order to minimize treatment and financial burden.

Researcher(s)

• Promoter: Van Dam Peter
• Co-promoter: De Waele Jorrit
• Co-promoter: Lardon Filip
• Co-promoter: Prenen Hans
• Co-promoter: Smits Evelien
• Co-promoter: Van den Wyngaert Tim

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

The research activities of the consortium IPPON (Integrated Personalized & Precision Oncology Network) are at the forefront of integrated personalized cancer medicine, with emphasis on 1) developing novel and more effective therapeutic strategies; 2) an improved detection and understanding of mechanisms driving therapeutic resistance; and 3) identifying and validating biomarkers for early detection and personalized therapy, in different cancers in need for improved therapeutic outcomes. In this way, we aim to deliver the right treatment to the right cancer patient at the right time. Novel and emerging anticancer strategies that we investigate include - but are not limited to - locoregional perfusion, targeted therapy, immunotherapy, cold atmospheric plasma therapy as well as novel combination therapies. We are convinced that the interdisciplinary collaboration between basic, translational and clinical researchers, catalyzed through this consortium, will enable us to tackle burning research questions and clinical unmet needs to advance the field of personalized cancer medicine. The members of our consortium bring together unrivaled access to biobank patient samples and to a dedicated clinical phase I/II oncological unit with a unique and complementary set of methods and skills covering the entire spectrum of molecular techniques, 2D and 3D cellular assays (in vitro and ex vivo), small- and large animal studies and clinical studies. IPPON gathers experts with an excellent research track record in fundamental, translational and clinical oncology; surgical techniques; targeted therapy; immunotherapy; (epi)genomics; (epi)transcriptomics; proteomics; imaging; liquid biopsies; pathology and clinical studies.

Researcher(s)

• Promoter: Peeters Marc
• Co-promoter: Dewilde Sylvia
• Co-promoter: Hendriks Jeroen
• Co-promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: Smits Evelien
• Co-promoter: Van Dam Peter
• Co-promoter: Vanden Berghe Wim
• Co-promoter: Van den Wyngaert Tim

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

One of the missions of BELNUC is to promote research and development by young individuals. To that end, BELNUC is calling for applications for one travel award (€10.000) to support a promising young researcher to realize an internship abroad.

Researcher(s)

• Promoter: Van den Wyngaert Tim

Research team(s)

• Molecular Imaging and Radiology (MIRA)

Project type(s)

• Research Project

Abstract

Cervical cancer (CC) patients, especially those with advanced disease, are urgently in need of new treatment options that can increase their survival rate and quality of life. A promising strategy is immunotherapy, however, only a minority of patients responds to it because the cancer has developed mechanisms that evade its effects. In recent years, the RANKL/RANK signaling pathway has been implicated as one such mechanism, as it allows many cancer types - including CC - to circumvent the immune response by disrupting the communication of the immune cells. Supported by our first results, we strongly believe that blocking the RANKL/RANK signal can release the brakes on the immune system and reinvigorate the tumor's susceptibility to immunotherapy. We therefore aim to expose the best possible immunotherapeutic partner(s) for anti-RANK(L) therapy in order to achieve the most optimal anti-tumor immune effects. For this, we have unique access to CC samples retrieved from patients before and after anti-RANKL monotherapy, which we will thoroughly investigate to reveal immune related changes. Thereafter, we will perform additional laboratory tests that will allow us to pinpoint one best-in-class anti-RANKL combination strategy, which we will further optimize in CC mouse models. Finally, this project will validate a novel imaging technique to stratify patients and monitor treatment response for this therapy, thereby minimizing treatment - and economic burden.

Researcher(s)

• Promoter: Van Dam Peter
• Co-promoter: De Waele Jorrit
• Co-promoter: Van den Wyngaert Tim
• Fellow: Verhoeven Yannick

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

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).

Researcher(s)

• Promoter: Van den Wyngaert Tim
• Fellow: Dewulf Jonatan

Research team(s)

• Molecular Imaging and Radiology (MIRA)

Project type(s)

• Research Project