Research team

Center for Oncological Research (CORE)

Expertise

The Center for Oncological Research (CORE) has research expertise in 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 personalized therapy, in different cancers in need for improved therapeutic outcomes. Novel and emerging anticancer strategies that we investigate are targeted therapy, immunotherapy, radiotherapy, cold atmospheric plasma therapy as well as novel combination therapies. In CORE, there is a strong interdisciplinary collaboration between basic, translational and clinical researchers. The members of our consortium bring together unrivaled access to biobank patient samples and to a dedicated oncological clinical phase I/II 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), animal studies and clinical studies. CORE gathers experts with an excellent research track record in targeted therapy, immunotherapy, radiotherapy, combination therapies, genomics, transcriptomics, proteomics, bioinformatics, liquid biopsies, pathology and clinical studies.

Unraveling of the role and the regulation of hypoxia-inducible factors in natural killer cell functioning in hypoxic and stimulating environments. 01/01/2020 - 31/12/2023

Abstract

Natural killer (NK) cells are potent cytotoxic cells from the hematopoietic system, playing an important role in the control of infection and malignancy. NK cells often operate under harsh conditions, such as in deprived oxygen or hypoxia. Hypoxia stabilizes its primary regulators hypoxia-inducible factors (HIF), more specifically HIF-1? and HIF-2?. While hypoxia reduces NK cell-mediated cytotoxicity, data on other NK cell features is conflicting. In addition, the role of HIF in NK cells has been neglected, as only one mouse study demonstrated that HIF-1? ablation in NK cells indirectly reduces tumor load via angiogenic rather than cytotoxic effects. However, murine NK cells show quite some disparities to human NK cells. In addition to hypoxia, also stimuli such as cytokines can stabilize HIF. Hence, HIF could play a pivotal role in NK cells. Therefore, this project aims to gain fundamental insights in the role and regulation of HIF in human NK cells via combining omics with functional assays. First, we will unravel the effect of hypoxia on (stimulated) NK cells. Next, we will dissect the divergent roles of HIF-1? and HIF-2? in the functioning of NK cells in response to hypoxic and stimulatory conditions. HIF isoform-specific knockout NK cells will be created using CRISPR-Cas9. Finally, we will elucidate how HIF isoforms regulate their effects in NK cells. The obtained knowledge could prove extremely valuable in rational guidance of rising novel NK-cell based immunotherapies.

Researcher(s)

Research team(s)

Novel, rationally designed combination strategies, based on genomic and proteomic analyses, to enhance the response to cetuximab therapy in head and neck cancer. 01/01/2020 - 31/12/2020

Abstract

Development of therapeutic resistance poses a challenging problem and limits the success of cancer therapies in the clinic. Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), is currently used for the treatment of locally advanced head and neck squamous cell carcinoma (HNSCC) as well as recurrent/metastatic HNSCC. However, 5-year survival rates remain low. In this project, we will focus on the identification of novel combination therapies to overcome cetuximab resistance. Targets for the combination will be identified through genetic and proteomic analysis of the molecular profile of the tumour. We hypothesize that inhibiting oncogenic bypass pathways responsible for cetuximab resistance, by a novel treatment strategy combining (i) cetuximab with (ii) radiotherapy and (iii) an additional molecularly targeted agent, can lead to elimination of HNSCC cells that are resistant to treatment with cetuximab alone. We will investigate the role of human papilloma virus (HPV) in this response, as HPV positive HNSCC patients represent a biologically distinct group. The potential of these combination therapies will be investigated in vitro on a well-established, comprehensive panel of HNSCC cell lines with different sensitivities to cetuximab. Synergistic combinations will be validated under hypoxia and in 3D spheroids. Next, the most promising combination strategy will be investigated in vivo in HNSCC patient-derived xenograft (PDX) mouse models. The biological and therapeutic implications of our study hold great promise for clinical translation in patients with HNSCC.

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Research team(s)

Development of a novel immunometabolic combination strategy for glioblastoma. 01/10/2019 - 30/09/2023

Abstract

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumour, however it remains a rare disease (incidence: 3.20/100,000). Tumour progression is fast and recurrence inevitable. The added value of the current standard of care (SOC: surgical resection, radiation and chemotherapy) is only limited, leading to a median survival of less than 15 months and a five-year survival of less than 5%. In addition, undesired side effects impact on the quality of life. Hence, new effective treatment modalities represent a highly unmet need. While scientific advances have generated clinical breakthroughs in other cancer types, this has remained a standstill in GBM for nearly 15 years. Immunotherapy has generated remarkable clinical success in the past decade, in particular with immune checkpoint blockade (ICB). Recent preclinical evidence has suggested that combination therapy can render GBM sensitive to ICB. In this project, we will develop an immunometabolic therapy in murine GBM models in vivo as innovative treatment option. We hypothesize that our combination strategy will ameliorate clinical outcome while improving quality of life.

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Research team(s)

Combined targeting of the epidermal growth factor receptor and the innate immune system: a novel therapeutic approach for the treatment of head and neck cancer. 01/01/2019 - 31/12/2022

Abstract

Both targeted therapies and immunotherapies are now at the forefront of personalized cancer medicine. Aberrant signalling of the epidermal growth factor receptor (EGFR) plays an integral role in the tumorigenesis of multiple cancer types, making it a compelling drug target. In addition, it is well established that natural killer (NK) cells possess natural anti-tumour activity and can mediate antibody dependent cellular cytotoxicity (ADCC) upon binding with monoclonal antibodies, such as the EGFR inhibitor cetuximab. However, the presence of drug resistance and/or immune evasion is a major obstacle to progress in this field. In our project, we will concentrate specifically on head and neck squamous carcinoma (HNSCC), a highly relevant tumour type with poor prognosis that is intensively studied at the Center for Oncological Research (CORE) Antwerp. In this research project, we hypothesize that increasing the NK cell activity by cetuximab in combination with targeting NK cell immune checkpoint molecules can synergistically generate immune mediated elimination of HNSCC cells that are resistant to treatment with cetuximab alone. Importantly, we will investigate the role of human papilloma virus (HPV) in this response, as HPV positive HNSCC patients represent a biologically distinct group. By characterizing NK cell functionality and, by extension, the whole immune checkpoint profile in HNSCC, we aim to rationally design new combination strategies to overcome cetuximab resistance, with the ultimate goal to improve the prognosis and life quality of HNSCC patients. Hereby, we will focus on HPV status and the hypoxic microenvironment as important mediators of treatment response. Therefore, the nature of our project is translational, as from the beginning, the link with clinical data is considered to be imperative before moving on to further preclinical investigation of the identified combination strategies. Successful combinations will be validated in animal studies, which will ultimately guide the start-up of a clinical trial to demonstrate feasibility of the most promising combination therapy to treat HNSCC patients. Given the extensive preclinical (both in vitro and in vivo) and translational work packages to optimise the novel combination strategy, we are confident that the data generated in this project will favour the setup of a successful clinical trial with the newly identified combination regimen.

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Research team(s)

Targeting Polo-like kinase 1 for treatment of NSCLC patients: focus on the induction of cellular senescence, the TP53 status and hypoxia. 01/10/2018 - 30/09/2022

Abstract

Non-small cell lung cancer (NSCLC), accounting for an estimated 85% of all lung cancers, retains its position as the most lethal type of cancer worldwide, with a 5-year survival rate for newly diagnosed cases below 20%. Despite the remarkable progress that has been made in the development of new treatment modalities, chemotherapy consisting of platinum-based doublets remains the standard first-line treatment for NSCLC patients. Anti-mitotic drugs are well-established components of the current combination treatment schedules in NSCLC patients. Nevertheless, serious adverse effects remain the dose-limiting factor. New approaches target cardinal regulatory proteins of mitosis, with Polo-like kinase 1 (Plk1) as one of the most promising targets in this research field. Our previous research showed Plk1 overexpression in 65% of NSCLC patients while no or weak Plk1 expression was noted in normal lung tissue, making it a compelling target for the treatment of NSCLC. Volasertib, at present the lead agent in category of Plk1 inhibitors, has been shown to be highly effective in multiple carcinoma cell lines and xenograft models, with minimal toxicity in normal cells. However, only modest anti-tumour activity was reported for volasertib monotherapy in patients with solid tumours, including NSCLC. Remarkably, an encouraging percentage of these patients reaches stable disease, providing an intriguing window for improving patient outcome. Based on promising results of our recent preclinical research at the Center for Oncological Research (CORE, UA), this proposed project will focus on (i) the identification of predictive biomarkers for Plk1 inhibition; and (ii) novel, rationally designed combination strategies with Plk1 inhibitors to improve therapeutic benefit. We previously identified p53 and hypoxia as potential biomarkers for response to Plk1 inhibition. However, no conclusive evidence could be found yet. As such, in the first objective of the proposed study, we will gain conclusive insights in the predictive role of p53 and hypoxia for the response to Plk1 inhibition. Therefore, we will investigate the effect of Plk1 inhibitors in a panel of isogenic cell lines with a different p53 background, under both normoxic and hypoxic conditions. Our second objective is to identify promising combination strategies with Plk1-inhibitors. In this regard, we will especially focus on drugs that eliminate senescent cells upon Plk1 inhibition. Recently, preclinical research by us has identified cellular senescence as an important outcome of Plk1 inhibition. Senescent cells are irreversibly growth-arrested, but remain metabolically active, thereby secreting multiple tumour-promoting factors to adjacent tumour cells. In-depth evaluation of the molecular pathways involved in induction of senescence after Plk1 inhibition will lead to the identification of potential targets to kill senescent NSCLC cells after Plk1 inhibition. At the time of writing this application, no investigation has been performed yet on the molecular pathways important for the survival of senescent cells after treatment, making this project challenging yet essential to enhance anti-tumour responses after Plk1 inhibition. Lastly, our third objective is to evaluate a novel combination therapy of Plk1 inhibitors with agents eliminating senescent cancer cells, in both vitro and in vivo models of NSCLC. We hypothesize that the anti-cancer effect of Plk1 inhibitors is synergistic with agents eliminating senescent cancer cells, so that this innovative combination strategy will ultimately result in improved survival and quality of life for patients with NSCLC. The proposed research project has the exciting potential to create a breakthrough in the optimization of Plk1 inhibition for patients with advanced NSCLC. Moreover, since Plk1 overexpression is found in multiple tumour types, our study results might also pave the way for improved treatment options for other malignancies.

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Research team(s)

Development of next-generation 3D brain organoids for the study and modulation of immunemediated neurodegeneration in cerebrovascular disease. 01/01/2018 - 31/12/2021

Abstract

Developing novel neuroprotective and/or immune-modulating therapeutic strategies for almost every neurological disease or trauma requires, both for academia and pharmaceutical industry, the existence of robust in vitro cell culture models to mimic disease-associated pathological events. Unfortunately, a complex interplay between multiple central nervous system (CNS) cell types and multiple cell types from the body's peripheral immune system, cannot be easily recapitulated by currently used 2-dimensional (2D) co-culture assays. It is exactly therefore that successful pre-clinical experimental efficacy has proved to be very difficult to translate into clinical benefit, and as a consequence there is an increasing gap in knowledge and progress between bench and bed side. One highly promising novel approach to improve the predictive power of in vitro human neuro-immune research consists in developing modular 3D brain organoids that resemble brain tissue at the structural, cellular and functional level. Within this project we aim to develop and optimize a new method for generating isogenic 3D brain organoids, comprising human pluripotent stem cell (hPSC)-derived neurons, astrocytes and microglia. Furthermore, hPSC-derived astrocytes and endothelial cells will be used to create a blood-brain-barrier model for physical separation of hPSC-derived macrophages from the generated human 3D brain organoids. Together, this integrated cell system will represent a powerful new 3D human neuro-immune cell culture paradigm. Within this multidisciplinary IOF-SBO project, the methodological approach to generate 3D brain organoids, combined with the experience in the field of clinical research and the availability of patient samples, is truly unique and will - in first instance - highly contribute to the field of in vitro cerebrovascular disease modelling and treatment validation. Furthermore, our aims to install an integrated 3D brain organoid technology platform at the University of Antwerp, will - given the current scientific and economic interests – allow for both short-term and long-term valorisation of our combined efforts, with both intellectual (PhD-theses, A1 publications) as well as financial (contract research) revenues.

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Research team(s)

Identifying rational combination therapies to overcome intrinsic and acquired resistance to EGFR-targeting agents. 01/10/2016 - 31/03/2021

Abstract

The introduction of targeted therapies is now at the forefront of personalised medicine in cancer treatment. After the initial promise of targeted therapies, drug resistance is however emerging as the major obstacle to progress in this field. In this project, we will focus on identification of new combination therapies to overcome intrinsic and acquired resistance to cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR). Hereby, we will concentrate specifically on head and neck squamous carcinoma (HNSCC), a highly relevant tumour type with poor prognosis that is intensively studied at the Center for Oncological Research (CORE) Antwerp. First, we will screen for new drug combinations by next-generation whole-exome sequencing and tumour kinome profiling of cetuximab-sensitive versus -resistant (intrinsic and acquired) HNSCC cell lines. Next, based on an integrative analysis of both the genetic profile and the kinome profile of cetuximab resistance, new combination treatments can be designed rationally to overcome cetuximab resistance. The molecular pathways underlying the cytotoxic effects of the selected compounds, in combination with chemotherapy and/or irradiation, will be investigated thoroughly, with focus on the hypoxic microenvironment as an important additional cause of therapy resistance. In conclusion, based on our screening results, new combination therapies will be designed rationally in order to thwart resistance to EGFR-targeting agents. Successful combinations will be forwarded into animal studies and ultimately into a clinical trail to demonstrate feasibility of the most promising combination therapy to treat HNSCC patients.

Researcher(s)

Research team(s)

Combined targeting of the epidermal growth factor receptor and the innate immune system: a novel therapeutic approach for the treatment of head and neck cancer. 01/01/2018 - 31/12/2018

Abstract

Both targeted therapies and immunotherapies are now at the forefront of personalized cancer medicine. Aberrant signaling of the epidermal growth factor receptor (EGFR) plays an integral role in the tumorigenesis of head and neck squamous cell carcinoma (HNSCC), making it a compelling drug target. In addition, it is well established that natural killer (NK) cells possess natural antitumor activity and can mediate antibody dependent cellular cytotoxicity (ADCC) upon binding with monoclonal antibodies, such as the EGFR inhibitor cetuximab. However, the presence of drug resistance and/or immune evasion is a major obstacle to progress in this field. In this research project, we hypothesize that increasing the NK cell activity by cetuximab in combination with targeting of NK cell immune checkpoint molecules can synergistically generate an immune mediated elimination of HNSCC cells that are resistant to treatment with cetuximab alone. Importantly, we will investigate the role of human papilloma virus (HPV), as HPV positive HNSCC patients represent a biologically distinct group. By characterizing NK cell functionality and, by extension, the whole immune checkpoint profile in HNSCC, we aim to rationally design new combination strategies to overcome cetuximab resistance, with the ultimate goal to improve the prognosis and life quality of HNSCC patients. Hereby, we will focus on HPV status and the hypoxic microenvironment as important mediators of treatment response.

Researcher(s)

Research team(s)

    Targeting polo-like kinase 1 for cancertreatment: focus on combination therapy and the role of the hypoxic microenvironment. 01/01/2017 - 30/09/2020

    Abstract

    Currently, there is an explosive interest in novel molecular targeted agents for cancer therapy and new approaches to mitosis inhibition target cardinal regulatory proteins, like polo-like kinase 1 (Plk1). Based on our previous promising findings with the Plk1 inhibitor volasertib, the overall objective is to further decipher the Plk1 pathway as a target for drug development. As such, this project aims to draw conclusions on the therapeutic potential of Plk1 inhibition, which will be investigated in vitro and in vivo, with emphasis on the impact of a hypoxic microenvironment, the role of combination therapy and the molecular pathways involved in NSCLC.

    Researcher(s)

    Research team(s)

    Overcoming intrinsic and acquired resistance to EGFR-targeting agents in cancer treatment: focus on identification of predictive biomarkers and novel therapeutic strategies. 01/01/2015 - 31/12/2018

    Abstract

    The introduction of targeted therapies is now at the forefront of personalised medicine in cancer treatment. However, after the initial promise of targeted therapies, drug resistance is emerging as the major obstacle to progress in this field. In the proposed project, we will focus on unravelling and overcoming intrinsic and acquired resistance to cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR). Hereby, we will concentrate specifically on two highly relevant tumour types with poor prognosis, i.e. head and neck squamous carcinoma (HNSCC) and colorectal cancer (CRC). We will be the first to unravel drug resistant mechanisms and identify functional biomarkers by tumour kinome profiling. Using state-of-the-art PamGene technology, microarrays with kinase peptide substrates, mainly representing tyrosine residues, will be applied to analyse cetuximab-sensitive versus -resistant (intrinsic and acquired) HNSCC and CRC cell lines. As such, kinase activity (rather than presence) will be analysed, which is crucial to elucidate the underlying signal transduction pathways responsible for drug resistance. Afterwards, the in vitro kinase signature predicting intrinsic/acquired cetuximab resistance will be validated using HNSCC and CRC tumour patient material. Importantly, unravelling the molecular pathways underlying cetuximab resistance could have important implications not only regarding patient selection, but also regarding identification of new drug targets. Based on results from the above-mentioned kinome profiling, new (combination) treatments can be designed to overcome cetuximab resistance. In addition, the ongoing challenge of therapy resistance has already prompted a new approach to treat cancer patients, notably multiple inhibition of ErbB receptors simultaneously or irreversible inhibition, for example with the highly innovative, dual targeting agents afatinib and MEHD7945A. The molecular pathways underlying the cytotoxic effects of the selected compounds, either as monotherapy or in combination with chemotherapy and/or irradiation, will be investigated thoroughly, with focus on the hypoxic microenvironment as an important additional cause of therapy resistance. In conclusion, the strength of the proposed project lies in our multidisciplinary approach of drug resistance. The proposed model offers an attractive platform to investigate therapy resistance and action mechanisms of additional molecular targeted agents.

    Researcher(s)

    Research team(s)

      Polo-like kinase 1 as a target for cancer treatments: focus on combination therapies and the role of the hypoxic tumour micro environment. 01/01/2013 - 31/12/2013

      Abstract

      This project represents a research contract awarded by the University of Antwerp. The supervisor provides the Antwerp University research mentioned in the title of the project under the conditions stipulated by the university.

      Researcher(s)

      Research team(s)

        Targeting polo-like kinase 1 for cancer treatment: focus on combination therapy and the role of the hypoxic microenvironment. 01/10/2012 - 30/09/2016

        Abstract

        In this project, we specifically wish to focus on two highly relevant tumour types, non-small cell lung cancer and pancreatic cancer. Firstly, the clinicopathological significance of Plk1 expression as a prognostic marker will be evaluated in a retrospective study investigating Plk1 gene amplification, Plk1 mRNA and protein expression. Secondly, the integration of a small-molecule Plk1 inhibitor with radiotherapy and chemotherapeutic agents for improving chemoradiation protocols will be studied. The interactions and underlying molecular biological pathways (p53 status, cell cycle progression, apoptosis, DNA repair, hypoxia-related signalling) will be investigated under both normal and reduced oxygen conditions, in parallel in an in vitro and in vivo setting. Elucidating these mechanisms could enable us to individually tailor the use of molecular targeted drugs in order to fully utilise their high potential in cancer therapy. Moreover, the proposed model offers an attractive platform to investigate the interactions and action mechanisms of additional molecular targeted agents in combination with chemoradation.

        Researcher(s)

        Research team(s)

          Preclinical study of the combination of EGFR inhibitors with gemcitabine and/or radiotherapie under normoxic versus hypoxic conditions 01/01/2011 - 31/12/2012

          Abstract

          In order to improve the efficacy of cancer therapy, the development of molecularly targeted agents has received a lot of attention. Their effects under hypoxia or in combination with radiotherapy are however largely unknown. Therefore, the integration of 2 types of EGFR inhibitors (cetuximab, a monoclonal antibody and erlotinib, a tyrosine kinase inhibitor) with gemcitabine and radiotherapy seems a promising strategy for improving chemoradiation.

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          Research team(s)

            In vitro interaction between chemotherapy and radiotherapy in hypocisic conditions. 01/02/2010 - 31/12/2012

            Abstract

            Objectives: 1) Study of the interactions between chemotherapy and radiotherapy under normoxic versus hypoxic conditions 2) Study of the molecular mechanisms underlying the radiosensitizing effect, under normoxic versus hypoxic conditions 3) Study of survival and apoptotic signal transduction pathways underlying the radiosensitizing effect, under normoxic versus hypoxic conditions

            Researcher(s)

            Research team(s)

              In vitro interaction between chemo- and radiotherapy under hypoxic conditions. 01/10/2007 - 30/09/2009

              Abstract

              It is well established that solid tumours frequently contain regions of hypoxia. Tumour hypoxia may induce resistance or a reduced sensitivity to radiation and chemotherapy. In that respect, it is very important to investigate new therapies in preclinical research under hypoxic conditions. However, an efficient in vitro hypoxia model is not available so far. Therefore, it seems very desirable to develop and optimize an hypoxic model. In this way, it will be possible to study the interaction between cytotoxic agents (for example cisplatin, gemcitabine) and irradiation under normoxic and hypoxic conditions in vitro. In addition, the hypoxia model can be used to analyse factors that contribute to radiosensitization under normoxia and hypoxia.

              Researcher(s)

              Research team(s)

                In vitro interaction between chemo- and radiotherapy under hypoxic conditions. 01/10/2005 - 30/09/2007

                Abstract

                It is well established that solid tumours frequently contain regions of hypoxia. Tumour hypoxia may induce resistance or a reduced sensitivity to radiation and chemotherapy. In that respect, it is very important to investigate new therapies in preclinical research under hypoxic conditions. However, an efficient in vitro hypoxia model is not available so far. Therefore, it seems very desirable to develop and optimize an hypoxic model. In this way, it will be possible to study the interaction between cytotoxic agents (for example cisplatin, gemcitabine) and irradiation under normoxic and hypoxic conditions in vitro. In addition, the hypoxia model can be used to analyse factors that contribute to radiosensitization under normoxia and hypoxia.

                Researcher(s)

                Research team(s)

                  In vitro interaction between chemo- and radiotherapy under hypoxic conditions. 01/10/2004 - 30/09/2005

                  Abstract

                  It is well established that solid tumours frequently contain regions of hypoxia. Tumour hypoxia may induce resistance or a reduced sensitivity to radiation and chemotherapy. In that respect, it is very important to investigate new therapies in preclinical research under hypoxic conditions. However, an efficient in vitro hypoxia model is not available so far. Therefore, it seems very desirable to develop and optimize an hypoxic model. In this way, it will be possible to study the interaction between cytotoxic agents (for example cisplatin, gemcitabine) and irradiation under normoxic and hypoxic conditions in vitro. In addition, the hypoxia model can be used to analyse factors that contribute to radiosensitization under normoxia and hypoxia.

                  Researcher(s)

                  Research team(s)