Research Filip Lardon

Abstract

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide. Despite advances in treatment options, conventional chemotherapy remains a pivotal part of NSCLC treatment, regardless of stage, even though it is accompanied with serious side effects and therapy-induced senescence (TIS). Cellular senescence is a durable cell cycle arrest and is characterized by the secretion of a strong pro-inflammatory senescence-associated secretory phenotype (SASP). Evidence indicates that TIS induces deleterious long-term effects including therapy resistance, disease progression, metastasis and recurrence. Thus, TIS acts as a barrier to complete eradication of the tumor, indicating the importance of targeting senescent cells during cancer therapy. Therefore, I will investigate a novel combination treatment in this project, specifically designed to eliminate therapy-induced senescent cells. Senescent tumor cells will be targeted by two strategies: senolytics to specifically kill these cells and senostatics to suppress or modulate the SASP. Moreover, I will identify the core senescent secretory profile of NSCLC, that will be used as a blood-based biomarker to identify and select patients that would benefit from our new senescence-focused therapy. The successful completion of my project will ultimately improve overall survival of NSCLC patients with a tumoral senescence signature, regardless of stage, by enhancing treatment efficacy and tumor eradication.

Researcher(s)

• Promoter: Wouters An
• Co-promoter: Deben Christophe
• Co-promoter: Lardon Filip
• Fellow: Verswyvel Jasper

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

In this application, we request financing for three benchtop CERO 3D Cell Culture Bioreactor units for the culture of 3D cell cultures, including spheroids and organoids, that are increasingly being used in biomedical research. Currently, 3D organoids and spheroids are cultured in traditional cell culture plates under static or shaking (using orbital shaker) conditions in a standard CO2 cell culture incubator, which is suboptimal for long-term and large-scale culture of spheroids and organoids. A bioreactor system would take organoid and spheroid culture at the campus to a next level in terms of quality (improved viability, maturation and homogeneity) as well as quantity. Each CERO 3D Cell culture bioreactor unit can maintain four 50 mL organoid cultures, including monitoring and control of temperature, pH and carbon dioxide levels. In total, the envisaged bioreactor infrastructure will be able to accommodate twelve simultaneous organoid cultures under highly controlled conditions. The envisaged CERO 3D Bioreactor units will be applied for multiple research domains at the University of Antwerp, and more specifically for upscaled culture of stem cell-derived spheroids and organoids, tumoroids derived from primary tumour material of patients, stem cell-derived cardiomyocytes, stem cell-derived cartilage tissue and intestinal organoids. Furthermore, based on our own experience in upscaled organoid culture, the instalment of bioreactor units has become an urgent need to progress towards future valorisation activities.

Researcher(s)

• Promoter: Ponsaerts Peter
• Co-promoter: Alaerts Maaike
• Co-promoter: Lardon Filip
• Co-promoter: Verstraeten Aline

Research team(s)

• Laboratory for Experimental Hematology (LEH)

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

Both targeted and immunotherapies are the key to precision medicine for the treatment of cancer patients. Deregulated signalling of the epidermal growth factor receptor (EGFR) plays an integral role in the tumourigenesis of multiple cancer types. Furthermore, it is well established that immune checkpoints are crucial for the tumour cell's escape from the immune system. The presence of drug resistance and/or immune evasion is a major obstacle to progress in the field. In our project, we will concentrate specifically on head and neck squamous cell carcinoma (HNSCC), a highly relevant tumour type with poor prognosis that is intensively studied at the Centre for Oncological Research (CORE) Antwerp. To date, there is still an urgent need to enhance the response to cetuximab treatment in recurrent/metastatic (R/M) HNSCC. Over the last years, cetuximab-related resistance mechanisms have been extensively studied at CORE. Based on our results and reports in literature, we hypothesize that inhibiting oncogenic bypass pathways responsible for cetuximab resistance, by a novel treatment strategy can lead to elimination of HNSCC cells that are resistant to treatment with cetuximab alone. In the proposed project, we will investigate the potency of a novel triple combination strategy in order to enhance the response to cetuximab therapy in HNSCC patients. To achieve this, cetuximab will be combined with buparlisib, a selective PI3K inhibitor, and an immune checkpoint inhibitor. Importantly, we will investigate the role of human papilloma virus (HPV) in this response, as HPV positive HNSCC patients represent a biologically distinct group. Furthermore, the nature of our project is translational, as from the beginning, we will use patient-derived HNSCC tumour organoids to validate our results from cell line experiments. These patient-derived tumour organoids are a very innovative and reliable model to identify effective treatment strategies and can actually be considered as a 'patient in the lab'. We are convinced that precision medicine using combinations of targeted therapies with immunotherapy may achieve the much-needed progress in HNSCC treatment. As reported in literature, both cetuximab and buparlisib treatment are able to promote anti-tumour immune response. Therefore, in the first work package, we will characterize the anti-tumour activity and immunomodulating effects of cetuximab in combination with buparlisib in HNSCC cell lines and patient-derived HNSCC organoids. Secondly, we will investigate the immunomodulating effects of cetuximab in combination with buparlisib on immune cells. In parallel, the effect of this combination treatment on the immune checkpoint profile will be assessed. Finally, the novel triple combination therapy consisting of cetuximab, buparlisib and an immune checkpoint inhibitor will be investigated in a humanized, PBMC engrafted HNSCC mouse model. This preclinical work will ultimately guide the start-up of a clinical trial to demonstrate feasibility of the novel triple combination therapy to treat HNSCC patients. Given the extensive preclinical (both in vitro and in vivo) and translational work packages to optimise the novel triple combination strategy, we are confident that the data generated in this project will provide insight into how therapeutic response to cetuximab treatment can be optimized, thus favouring the setup of a successful clinical trial with the newly identified triple combination therapy.

Researcher(s)

• Promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: Peeters Marc
• Co-promoter: Prenen Hans
• Co-promoter: Smits Evelien
• Co-promoter: Wouters An

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

Malignant pleural mesothelioma (MPM) is a fatal cancer that is in most patients causally associated with asbestos exposure. Due to its aggressive nature and despite the effectiveness of conventional anti-cancer treatment, the prognosis of patients diagnosed with MPM remains dismal with a median overall survival of only 9-12 months and a 5- year survival rate of only 5%. In the last decade, no improvement of survival has been achieved in this disease. Therefore, new therapeutic strategies are needed in order to prolong survival of MPM patients. Smart combination strategies might improve the anti-tumor response by interfering with different hallmarks of cancer and multiple immune escape mechanisms. In this research project tumor-induced immunosuppression will be tackled via two different pathways: immune checkpoint blockade will be used to reactivate silenced anti-tumor immune responses while blockade of the VEGF/VEGFR signaling pathway will be used to target the tumor vasculature in order to reduce angiogenesis thereby reducing tumor growth. In addition, we are keen to assess the positive impact that exercise may have on these combination strategies.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: van Meerbeeck Jan

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Wouters An
• Co-promoter: Lardon Filip
• Co-promoter: Peeters Marc
• Co-promoter: Smits Evelien
• Co-promoter: Specenier Pol

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

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)

• Promoter: Lardon Filip
• Promoter: Peeters Marc
• Promoter: Smits Evelien

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide. Despite advances in treatment options, conventional chemotherapy remains a pivotal part of NSCLC treatment, regardless of stage, even though it is accompanied with serious side effects and therapy-induced senescence (TIS). Cellular senescence is a durable cell cycle arrest and is characterized by the secretion of a strong pro-inflammatory senescence-associated secretory phenotype (SASP). Evidence indicates that TIS induces deleterious long-term effects including disease progression, metastasis and recurrence. Thus, TIS acts as a barrier to complete eradication of the tumor, indicating the importance of targeting senescent cells during cancer therapy. Therefore, I will investigate a novel combination treatment in this project, specifically designed to eliminate therapy-induced senescent cells. Senescent tumor cells will be targeted by two strategies: senolytics to specifically kill these cells and senostatics to suppress or modulate the SASP. Moreover, I will identify the core senescent secretory profile of NSCLC, that will be used as a blood-based biomarker to identify and select patients that would benefit from our new senescence-focused therapy. The successful completion of my project will ultimately improve overall survival of NSCLC patients with a tumoral senescence signature, regardless of stage, by enhancing treatment efficacy and preventing relapse.

Researcher(s)

• Promoter: Wouters An
• Co-promoter: Deben Christophe
• Co-promoter: Lardon Filip
• Fellow: Verswyvel Jasper

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: Lardon Filip

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

SARS-CoV-2 is a respiratory virus making the lungs the primary site of infection. However, little is currently known about the interaction between SARS-CoV-2 and lung cancer cells. SARS-CoV-2 needs certain proteins on the host cell to recognize and infect them. If more of these proteins are present, it may mean that these cells are more easily infected by the virus. The aim of this study is to investigate the presence of these proteins on patients' cancer cells to determine whether lung cancer cells express these proteins more than normal lung cells and can therefore be infected by SARS-CoV-2. The second aim of this study is to investigate how cancer treatments used as standard for lung cancer patients (chemotherapy, targeted and immunotherapy) influence the expression of these proteins. We will check this on patient samples, but also in the lab on cancer and normal lung organoids. These organoids are directly derived from lung cancer patients and can be considered a patient in the lab who very well retain the characteristics of the original tissue. Using advanced equipment, we can quickly check the expression of SARS-CoV-2 related proteins after treatment with 15 different therapies. This study can therefore quickly provide us with more information about how anti-cancer treatments can influence the course of SARS-CoV-2 infections.

Researcher(s)

• Promoter: Lardon Filip

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Fusion genes are identified as clinically relevant drivers in non-small cell lung cancer (NSCLC), but emerging evidence shows these are present and are becoming clinically actionable in other cancer types as well. Therefore, the consortium consisting of CORE (UA) and Biocartis will study the potential of the Idylla™ GeneFusion Assay to detect gene fusions (ALK, ROS1, RET, and NTRK1-3) in other cancer types beyond NSCLC. Specifically, research will mostly focus on NTRK1-2-3 fusions, which have gained high clinical interest due to recent approval of the NTRK inhibitor larotrectinib for NTRK fusion positive cancers regardless of cancer type. Therefore, studies will be conducted in MSI-High colorectal cancer (MSI-H CRC), glioblastoma multiforme (GBM), (papillary) thyroid carcinoma ((P)TC) and melanoma, which have been shown contain kinase gene fusions and hence represent an ideal set of clinically relevant cancer types to study gene fusions. The IdyllaTM GeneFusion Assay can generically detect gene fusions irrespective of the fusion partner. However, in order to properly detect these kinase gene expression imbalances, knowledge on the baseline expression levels of kinases in different cancer types will need to be gained. Once this is determined, clinical sensitivity and specificity of the IdyllaTM GeneFusion Assay for each kinase in different cancer types will be determined by comparing the results of the IdyllaTM assay to the results of routine diagnostic tests, as well as to the ArcherDX® FusionPlex Lung Panel assay as an unbiased independent reference method. Another part of the research project will focus on maximizing the compatibility of the IdyllaTM GeneFusion Assay with cytological samples, which are increasingly used for diagnostics due to advances in minimally invasive sampling procedures. The research will study the effect of different pre-analytical variables in the cytological sample preparation workflow on the quantity and quality of RNA, which is essential for any downstream RNA-based test to be successful. Based on a literature review and an extensive questionnaire taken by Biocartis, several key variables were identified, e.g. sample transport conditions, type of fixative, sample type (smear or cell block), etc, which will be systematically studied using mimicked cytological samples (cell culture material) to identify 1 optimal workflow for RNA-based testing that is feasible to implement in routine clinical practice. Finally, a series of NSCLC cytological samples prepared using this optimal workflow will be prospectively collected to confirm clinical performance, i.e. low invalid rate and high sensitivity and specificity of the Idylla™ GeneFusion Assay on this prospective cohort of NSCLC cytological samples. Finally, snap frozen samples will also be studied since these are yet another sample type that, due to instant freezing without fixation after biopsy sampling, will yield very high RNA quality and quantity, thus representing a 'best-case' scenario to illustrate the potential of RNA-based testing in a clinical setting. While most routine diagnostic test samples will be FFPE, some clinical centres in fact have validated workflows for routine testing of snap frozen samples. Therefore, snap frozen NSCLC tissue samples will be tested using the Idylla™ GeneFusion Assay to demonstrate technical compatibility and to evaluate the degree of similarity between typical FFPE and cytological sample-derived NSCLC mRNA expression profiles.

Researcher(s)

• Promoter: Lardon Filip

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: Lardon Filip

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Lardon Filip
• Co-promoter: Wouters An

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Colorectal cancer (CRC) retains its position as one of the most prevalent types of cancer with around 700,000 deaths per year worldwide. Treatments focused on altering the immune system have recently paved their way into oncology with clinical achievements seen in a broad spectrum of solid tumors. However, signals of activity in CRC are largely involving microsatellite instable tumors, leaving a great need for effective immunotherapy in the majority of patients. The biologica! complexity of the tumor microenvironment seems to be an obstacle for cancer immunotherapy, suggesting that a strategy to solely targeting tumor cells is inadequate to overwhelm the aggressively growing tumor in CRC. Cancer-associated fibroblasts (CAFs) represent the dominant constituents of the tumor stroma and play a critica! role in the proliferative and invasive behavior of CRC. Additionally, CAFs provide a physical barrier for the efficient delivery of systemic therapy to the tumor making it an attractive target to combine with conventional treatment. Clinically addressing CAFs has been challenging due to its heterogeneous nature with both cancer-promoting and cancer-restraining features. We have recently identified a phenotypically distinct subset of CAFs in invasive CRC specimens, marked by the expression of CD70, and associated with poor prognosis of the patient. Moreover, CD70-positive CAFs proved to stimulate tumor invasion and to promote immune escape by the accumulation of immune suppressive regulatory T-cells. lnterestingly, CD70 is totally absent from normal epithelial tissue making it a safe target to eradicate the tumor-promoting CAFs. Based on our preliminary data, we hypothesize that targeting CD70-positive CAFs in CRC has a potential triple mode of action by enhancing anti-tumor immunity, eradicating a permissive niche for tumor invasion and increasing the efficacy of first-line chemotherapeutics. The primary objective of the proposed project is to find the ideal approach to deplete CD70-positive CAFs. The second objective is to design a combination strategy of CD70-targeted therapy with a first-line chemotherapeutic agent that elicits a potent anti-tumor immune response. The third objective is to identify potential bloodbased biomarkers for diagnosis and to monitor treatment response. Experiments will be performed in vitro under normoxic and hypoxic conditions and in vivo in an orthotopic syngeneic mouse model to identify the ideal timing and dosing of our combination strategy. This translational research project wil! lead to the launch of a phase 1/11 clinical trial in patients with advanced CRC with a grim prognosis of only 12 to 14 months. Since we have also found CD70 expression in the desmoplastic stroma of pancreatic cancer, this study will also pave the way to application in one of the most therapeutically resistant maliçinancies.

Researcher(s)

• Promoter: Pauwels Patrick
• Co-promoter: Jacobs Julie
• Co-promoter: Lardon Filip
• Co-promoter: Peeters Marc
• Co-promoter: Rolfo Christian
• Co-promoter: Smits Evelien

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: Peeters Marc
• Co-promoter: Smits Evelien
• Co-promoter: Wouters An

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: Lardon Filip

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Wouters An
• Co-promoter: Lardon Filip
• Fellow: Domen Andreas

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

This gift is used for cancer research at the Center for Oncological Research to develop novel combination treatments for cancer types with a hig need, as well as for biomarker research and gaining new insight into resistance mechanisms.

Researcher(s)

• Promoter: Lardon Filip

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

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)

• Promoter: Lardon Filip
• Co-promoter: Smits Evelien
• Co-promoter: Wouters An
• Fellow: Baysal Hasan

Research team(s)

Project type(s)

• Research Project

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)

• Promoter: Lardon Filip
• Fellow: Wouters An

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Important advances have been made in our understanding of the molecular pathways governing cell function in cancer. This has led to an explosive interest in molecular targeted agents. Targeting mitotic cell division is a validated approach to inhibit tumor growth and agents that affect the mitotic spindle are well-established components of many oncotherapeutic regimes. One such mitotic cancer target is Polo-like kinase 1 (Plk1), a key regulator of multiple steps during mitosis. Several studies have demonstrated overexpression of Plk1 in a number of human malignancies, indicating a therapeutic potential for Plk1 inhibitors in a range of solid tumor types. Previously, we investigated volasertib, currently considered as the most promising Plk1 inhibitor, in a series of non-small cell lung carcinoma (NSCLC) cell lines with different P53 status. Volasertib established a dose-dependent growth inhibition in all cell lines tested. Interestingly, apoptotic cell death was induced in P53 wild type cells, while P53 deficient cells arrested in the G2/M phase of the cell cycle upon Plk1 inhibition. In the current research project, the relationship between Plk1 and P53 will be further investigated in order to increase the therapeutic efficacy of volasertib, possibly by using P53 as a predictive biomarker. Therefore, the effect of Plk1 inhibition on the mitotic spindle and several P53 targets will be tested. Furthermore, our experiments demonstrated that Plk1 inhibition can induce senescence, a terminal growth arrest resulting from serious DNA damage or cellular stress. Hence, the correlation between cellular stress, the TP53 status of cancer cells and the induction of senescence will be examined. To end with, most cancer treatments are combinations of chemotherapeutic agents and/or radiotherapy, and it is expected that Plk1 inhibitors will acheive their greatest efficacy in combination with conventional treatments. Preliminary data showed a strong radiosensitising effect of volasertib in A549 NSCLC cells. In the final part of this research project, the molecular pathways underlying the observed radiosensitizing effect will be investigated, focussing also on the P53 status of cancer cells.

Researcher(s)

• Promoter: Lardon Filip
• Fellow: Van den Bossche Jolien

Research team(s)

Project type(s)

• Research Project

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)

• Promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: Peeters Marc
• Co-promoter: Wouters An

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Non-small cell lung cancer (NSCLC) retains its position as the most lethal type of cancer with around 1.3 million deaths per year worldwide and a marginally improving 5-year overall survival rate which remains below 20%, pointing to the need for new therapeutic options. Immunotherapy, in which the patient's immune system is used to selectively eliminate cancer cells, is considered a very promising candidate. Results of the recently approved immunotherapeutic agent nivolumab underscore the potential of immunotherapy in NSCLC, but also leave room for improvement. This study will focus on the CD70-CD27 signaling pathway as an interesting novel target to enhance anti-tumoral immune responses in NSCLC in combination with low doses of chemotherapy. CD70 is a member of the tumor necrosis factor family and its expression is normally restricted to activated T and B cells. Constitutive expression of CD70 by tumor cells can facilitate immune evasion by increasing the amount of suppressive regulatory T cells, inducing T cell apoptosis and skewing T cells towards T cell exhaustion. Previously, we have detected constitutive overexpression of CD70 in NSCLC tumor specimens, also in patients that lack other targeted treatment options. This CD70 expression can be exploited by CD70-targeting antibody-dependent cellular cytotoxicity (ADCC)-inducing antibodies. Our preliminary data show that the combination of anti-CD70 therapy with low doses of chemotherapy significantly increases cytotoxicity of the drug, compared to single treatment regimens. The main objective of the current project proposal is to rationally design and to preclinically evaluate a combination therapy of chemotherapy with CD70-targeted immunotherapy as a novel treatment option for patients with NSCLC.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: Rolfo Christian
• Co-promoter: Van Schil Paul

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

This research project focuses on DFNA5 based upon strong indications for its role as tumour suppressor gene, its function in apoptosis and its potential role as early biomarker in cancer. DFNA5 was identified in 1998 in our lab, as a gene causing autosomal dominant non syndromic hearing loss [3]. Since then, a number of papers on DFNA5 have been published pointing towards a possible involvement in cancer [4-15].

Researcher(s)

• Promoter: Peeters Marc
• Co-promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: Van Camp Guy
• Fellow: Croes Lieselot

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: Lardon Filip

Research team(s)

Project type(s)

• Research Project

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)

• Promoter: Lardon Filip
• Co-promoter: Peeters Marc
• Co-promoter: Wouters An
• Fellow: De Pauw Ines

Research team(s)

Project type(s)

• Research Project

Abstract

This research project focuses on DFNA5 based upon strong indications for its role as tumour suppressor gene, its function in apoptosis and its potential role as early biomarker in cancer. DFNA5 was identified in 1998 in our lab, as a gene causing autosomal dominant non syndromic hearing loss [3]. Since then, a number of papers on DFNA5 have been published pointing towards a possible involvement in cancer [4-15].

Researcher(s)

• Promoter: Peeters Marc
• Co-promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: Van Camp Guy
• Fellow: Croes Lieselot

Research team(s)

Project type(s)

• Research Project

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)

• Promoter: Lardon Filip

Research team(s)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: Lardon Filip

Research team(s)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: Vanden Berghe Wim
• Co-promoter: Kooy Frank
• Co-promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: Van Ostade Xaveer

Research team(s)

Project type(s)

• Research Project

Abstract

The objective of this research project is to evaluate the clinical significance of mutation analysis on circulating free DNA and circulating tumour cells (CTC), shedded directly from the actually present tumour mass into the bloodstream, as an alternative for the archival tumour biopsy in patients with KRAS wild type mCRC.

Researcher(s)

• Promoter: Peeters Marc
• Co-promoter: Deschoolmeester Vanessa
• Co-promoter: Lardon Filip

Research team(s)

Project type(s)

• Research Project

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)

• Promoter: Lardon Filip
• Co-promoter: Peeters Marc
• Co-promoter: Wouters An
• Fellow: Van den Bossche Jolien

Research team(s)

Project type(s)

• Research Project

Abstract

Pancreatic cancer is characterized by a poor prognosis and shows an almost inevitable mortality. It is shown that the tumor microenvironment, mainly the stroma around the tumor, which can constitute up to 80% of the tumor mass, would facilitate the rapid progress of pancreatic cancer. The precise role of this stroma as well as his contribution to tumor progression and therapeutic resistance is still poorly understood in pancreatic cancer and other solid tumors. This in vitro study aims at elucidating the presence and functional impact of critical components of the stroma, which can affect the behavior of pancreatic tumor cells.

Researcher(s)

• Promoter: Peeters Marc
• Co-promoter: Deschoolmeester Vanessa
• Co-promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Fellow: Quix Céline

Research team(s)

Project type(s)

• Research Project

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)

• Promoter: Lardon Filip
• Co-promoter: Peeters Marc
• Fellow: Wouters An

Research team(s)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: Lardon Filip
• Fellow: Limame Ridha

Research team(s)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: Lardon Filip

Research team(s)

Project type(s)

• Research Project

Abstract

Development of new diagnostic approaches and treatment modalities in the health field depends on translational research with close contact between the clinical field and the latest biotechnological development in immunology and genetics. Totally integrated translation research networks are rare, especially when it comes to solving health problems endemic in the poorer parts of the world, especially in Africa. There is a need for creation of strong networks between laboratories at the forefront of basic research on tropical parasitic diseases and field projects trying to solve such health issues on the ground. Moreover, gender issues are highly in focus after decades of research without such attention, bringing another focus to development of projects. Our network of six European and one African University was established in order to study the gender-based health problem of Female Genital Schistosomiasis. The parasite schistosoma infects 200 million people across the tropical sphere, causing serious disease, and reduced labour- and school capacity in at least 20 million people. It is thus the second most important parasite affecting human health after malaria. The parasite is waterborne, affecting people with water contact, such as women doing laundry or children bathing and playing in rivers. Female Genital Schistosomiasis (FGS, Bilharzia) is a previously unknown disease that may create gynaecological contact bleeding, friable blood vessels and inflammation. In a cross-sectional Zimbabwean study we found that women with genital schistosomiasis had an almost 3-fold higher odds ratio of having HIV. Others report that immune cells from people with schistosomiasis are more susceptible to HIV, and blood cells in cases with schistosomiasis have more HIV receptors. In a project in South Africa, financed by the Bill and Melinda Gates Foundation through the University of Copenhagen, we intend to collect evidence of the preventive effects of school-based anti-schistosomal mass treatment on genital lesions and effects on HIV susceptibility and transmission. The result of this project will have a major impact on the possibility of preventing female suffering, including HIV-transmission. This IRSES application focuses on the strengthening of the human network and of capacities between those laboratories and universities in Europe and Africa attached to the South African project. The primary objective of this project is to strengthen research partnership among partner organisations and their scientific competence in the field of parasite-related clinical research and basic laboratory research in the fields of immunology, cell biology and genetics. • To strengthen cooperation among partner organisations, being they European partners or third country partners, for the purpose of developing long-lasting research partnership at the organisational level • To investigate various diagnostic and intervention strategies for the control of Female Genital Schistosomiasis, gender problems and HIV • To enhance the research quality and lift the scientific competence of participating organisations through joint research activities • To educate more and better qualified Masters- and PhD candidates at the international level The application is based on a bottom-up approach, following the ethos of the Marie Curie actions. The partners have developed collaborative links during some years, based on clinical and translational needs for researching together. The participating senior researchers in this project are 13 in number in the seven universities involved. There will be an additional number of students at the PhD and Masters level.

Researcher(s)

• Promoter: Baay Marc
• Promoter: Lardon Filip

Research team(s)

Project website

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: Augustyns Koen
• Co-promoter: Bogers John-Paul
• Co-promoter: De Visscher Geofrey
• Co-promoter: Joossens Jurgen
• Co-promoter: Lardon Filip
• Co-promoter: Peeters Marc
• Co-promoter: Stroobants Sigrid
• Co-promoter: Van Der Linden Annemie

Research team(s)

• Medicinal Chemistry (UAMC)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: Lardon Filip
• Co-promoter: Augustyns Koen
• Co-promoter: Peeters Marc
• Co-promoter: Stroobants Sigrid

Research team(s)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: Lardon Filip

Research team(s)

Project type(s)

• Research Project

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world. Overexpression of epidermal growth factor receptor (EGFR) is found in 80-90% of HNSCC. Nevertheless, anti-EGFR therapeutics have a limited clinical application. Therefore, in this study, biomarkers which predict a response to anti-EGFR therapy in HNSCC will be investigated. Sensitive and resistant cell lines will be compared, and potential markers will be validated in retrospective and prospective studies.

Researcher(s)

• Promoter: Lardon Filip
• Fellow: Boeckx Carolien

Research team(s)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: Lardon Filip
• Fellow: Sas Leen

Research team(s)

Project type(s)

• Research Project

Abstract

Colorectal cancer (CRC) remains the third most common form of cancer and cancer related deaths in developed countries. The prognosis of CRC is largely determined by the extent of primary disease at the time of diagnosis. Although the introduction of new chemotherapeutic agents improved the prognosis of CRC over the past decades, the outlook for most patients remains poor and difficult to predict. Tumor recurrence after curative resection continues to be a significant problem in the management of CRC. Since CRC is not uniformly fatal and large differences in survival exist depending on stage of the disease, optimal patient selection for therapeutic intervention mandates strategies to individualize patient treatment using both prognostic and predictive indicators. These robust markers can better quantify the risks and benefits of a particular treatment approach for an individual patient. The TNM staging system is currently the most important determent of prognosis, however it does not allow for an accurate prediction of the postoperative risk of tumor recurrence for individual patients. Therefore, identification of additional prognostic markers to supplement the standard clinical and pathological staging of the tumor is warranted. This study aims at investigating the prognostic value of several immunological parameters, as well as the role of two viral infections in CRC.

Researcher(s)

• Promoter: Lardon Filip
• Co-promoter: Vermorken Jan

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Lardon Filip
• Co-promoter: Vermorken Jan

Research team(s)

Project type(s)

• Research Project

Abstract

This is a fundamental research project financed by the Research Foundation - Flanders (FWO). The project was subsidized after selection by the FWO-expert panel.

Researcher(s)

• Promoter: Lardon Filip
• Co-promoter: Vermorken Jan

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Pauwels Patrick
• Promoter: Van Marck Eric
• Co-promoter: Lardon Filip
• Co-promoter: Peeters Marc

Research team(s)

Project type(s)

• Research Project

Abstract

The aim of the project is 1) Research on different signal transduction pathways to clarify the mechanism of radiosensitisation under normoxic and hypoxic conditions, and to elucidate the mechanism of resistance under hypoxia; 2) In depth study of the involvement of proteins with altered gene expression using western blot analysis and flow cytometry.

Researcher(s)

• Promoter: Vermorken Jan
• Co-promoter: Lardon Filip
• Fellow: Pauwels Bea

Research team(s)

Project type(s)

• Research Project

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)

• Promoter: Lardon Filip
• Fellow: Wouters An

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Vermorken Jan
• Co-promoter: Lardon Filip

Research team(s)

Project type(s)

• Research Project

Abstract

Because of promising results in the clinic and a vast interest for in vitro research to the combination of chemotherapy and radiotherapy, an efficient in vitro hypoxia model will be developed to study the interactions between chemotherapy and radiotherapy under hypoxic conditions. This model will be used to investigate the interaction both under normoxic and hypoxic conditions and to study possible regulating factors and signal transduction of the radiosensitizing mechanism.

Researcher(s)

• Promoter: Lardon Filip
• Co-promoter: Pauwels Bea
• Co-promoter: Vermorken Jan

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Lardon Filip
• Co-promoter: Vermorken Jan

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Lardon Filip
• Co-promoter: Vermorken Jan
• Fellow: Simoens Cindy

Research team(s)

Project type(s)

• Research Project

Abstract

The combination of chemo- and radiotherapy is a promising treatment of cancer. This combination results often in an increase of apoptotic cell death. The molecular mechanism resulting in the increased induction of apoptosis with radiosensitisation will be investigated in this in vitro study. Knowledge of the apoptotic pathway might lead to a more efficient design of in vivo and clinical studies considering the application of the chemoradiotherapy combination in a clinical setting.

Researcher(s)

• Promoter: Lardon Filip
• Fellow: Pauwels Bea

Research team(s)

Project type(s)

• Research Project

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)

• Promoter: Lardon Filip
• Co-promoter: Vermorken Jan
• Fellow: Wouters An

Research team(s)

Project type(s)

• Research Project

Abstract

Objectives of the project: 1. To study of the influence af gemcitabine and/or radiotherapy on the cell cycle checkpoint-mechanism ta understand the molecular mechanism af cell cycle arrest. 2. To clarify the apoptotic pathway: Is the increased apoptosis observed after treatment with gemcitabine/radiotherapy reached by the mitochondria' ar by the receptor-mediated pathway? 3. To Investigate the influence af gemcitabine on the repair af radiation-induced DNA damage as a possible mechanism for radiosensitisation.

Researcher(s)

• Promoter: Vermorken Jan
• Co-promoter: Lardon Filip
• Fellow: Pauwels Bea

Research team(s)

Project type(s)

• Research Project

Abstract

There is an urgent need for preclinical research to the interaction between chemo- and radiotherapy, to optimise the clinical application. Gemcitabine is a nucleoside analogue with radiosensitising properties. In this project, the molecular mechanism of this enhancement effect will be investigated. The radiosensitising effect is correlated with the cell cycle effect of gemcitabine. Therefore, the checkpoint mechanism will be studied to determine its responsibility for the enhancement effect. Secondly, the increased apoptotic cell death will be further investigated to clarify the pathway of apoptosis. The interaction between gemcitabine and radiation might be caused bya reduction of the sublethal damage repair. In the third part of the study, the influence of gemcitabine on the repair of radiation-induced DNA damage and the characteristics of the DNA repair mechanism playing a role in the radiosensitising effect will be investigated.

Researcher(s)

• Promoter: Lardon Filip
• Co-promoter: Vermorken Jan
• Fellow: Pauwels Bea

Research team(s)

Project type(s)

• Research Project

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)

• Promoter: Lardon Filip
• Co-promoter: Vermorken Jan
• Fellow: Wouters An

Research team(s)

Project type(s)

• Research Project

Abstract

Treatment with some cytostatic agents can result in an increased sensitvity for radiotherapy. In particular gemcitabine is a cytostatic agent with very strong radiosensitizing properties. In this project we will investigate whether this radiosensitizing effect is caused by a reduced repair of radiation-induced sublethal DNA damage, When this is the case, we will further investigate which DNA repair mechanism is influenced by gemcitabine,

Researcher(s)

• Promoter: Lardon Filip

Research team(s)

Project type(s)

• Research Project

Abstract

The project focuses on the use of antigen-modified human dendritic cells (DC) as a potential cancer vaccine. Human dendritic cells (DC) from cancer patients will be cultured starting from peripheral blood monocytes. The major aim is to transfer tumor proteins from autologous tumor cells towards DC by means of transfection of DC with mRNA encoding defined antigens or with total tumor mRNA, or by pulsing of DC with apoptotic/necrotic tumor cells. Tumor antigen-loaded DC will be used for induction of tumor-specific autologous cytotoxic T cells ex vivo. As a first step, DC from cervix carcinoma patients will be loaded with mRNA encoding a single defined antigen (e.g. human papilloma virus E7 antigen) for ex vivo tumor vaccination against defined antigens. In a later phase, DC will be loaded with unfractionated tumor antigens (total tumor mRNA, apoptotic tumor cells). This approach will be tested using tumor material derived from lymphoma patients.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Lardon Filip
• Co-promoter: Van Bockstaele Dirk
• Co-promoter: Vermorken Jan

Research team(s)

Project type(s)

• Research Project

Abstract

The project focuses on the use of antigen-modified human dendritic cells (DC) for induction of tumor-specific autologous cytotoxic T cells in vitro in an immunotherapy model. In vitro generated DC will be either genetically modified by cDNA or mRNA transfection to express tumor-associated gene products, or loaded with the full antigenic spectrum of tumor cells, i.e. tumor extracts, cell lysates and total RNA. Loading methods will first be optimized in a melanoma tumor model. Afterwards, this knowledge will be applied for the development of a DC-based in vitro immunotherapy protocol for colon and cervix carcinoma.

Researcher(s)

• Promoter: Lardon Filip
• Co-promoter: Berneman Zwi

Research team(s)

Project type(s)

• Research Project

Abstract

The evaluation of the function or dysfunction of specific cells within a given organ requires in many cases the preceding viable isolation of these cells from a -sometimes- abundant amount of unwanted accessory cells. For this a number of cell separation techniques are available based on physical properties such as differences in cell density, cell adhesion, immunoaffinity etc' However, the flow cytometric cell sorting technique (based on electrostatic droplet formation) is the only separation technique that permits to separate different cell populations (up to 4) while simultaneously evaluating quite a number of properties such as size, internal complexity, DNA-content, presence or absence of up to 4 or 5 surface or cytoplasmic antigens. Since different cell populations may differ in subtle ways from others, this multiparametric flow cytometric sorting approach is in many cases a prerequisite to isolate the cells of interest: the primitive hematopoietic cell can only be defined by multiparametric labelling, kidney cell subpopulations, malignant versus normal cells, cell populations that are different in terms of cell cycle rate etc' It is clear that the availability of a cell sorter is a prerequisite for the four applying groups to study their respective cell(s) of interest. From 1990 onwards three of the four groups have built up expertise in the field, by joining forces and collaborating in the purchase of a FACStarPlus cell sorter. The output of numerous articles and several PhD theses may serve as proof of the good management of this interdisciplinary sorting facility. After 8 years of continuous heavy use, and in order to guarantee continuity in their research, the three initial groups, together with a fourth group (Tropical Medicine, Immunology) that meanwhile established close collaboration, now consider the purchase of a new generation cell sorter to be a priority. The growing number of users and applications have made the workload on the old instrument critically high. More elaborate simultaneous labelling and multiple and faster sorts are necessary to efficiently use the 'sometimes- scarce available starting material. This can only be accomplished by the new generation machines that guarantee much higher sort rates (up to > 30,000 cells/second, compared to 3000 cells/second on the old equipment) . Aerosol control systems implemented in the new machines offers prospects for work with potentially infectuous material (tropical medicine) The laser configuration of the old system is inadequate and the storage capacity and compatibility of the old computer system do not satisfy anymore the actual needs of a multi-user multidisciplinary facility. In what follows we will highlight the objectives and activities of the different research groups. It should be clear that no effort is made to link the respective topics: indeed the research topics described in this funding application are heterogeneous. Apart from some obvious common interests, the major link of these groups is the awareness that they all need cell sorting facilities to reach their goals.

Researcher(s)

• Promoter: Van Bockstaele Dirk
• Co-promoter: Berneman Zwi
• Co-promoter: De Broe Marc
• Co-promoter: D'Haese Patrick
• Co-promoter: Lardon Filip

Research team(s)

Project type(s)

• Research Project

Abstract

In (pre)clinical studies the cytoprotective agent amifostine was shown to selectively protect normal tissues against chemo- and radiotherapy without a reduction of the antitumor activity. To investigate the mechanism of action of amifostine and to optimize its clinical use, the combination of amifostine and chemo- and radiotherapy is studied in vitro in normal and (sensitive and resistant) tumor cells. Several aspects will be studied: cytotoxicity, pharmacodynamics (especially interaction with DNA) and pharmacokinetics. Also new cytostatic agents will be studied.

Researcher(s)

• Promoter: Lardon Filip

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Peetermans Marc
• Fellow: Lardon Filip

Research team(s)

Project type(s)

• Research Project