Research Jan van Meerbeeck

Abstract

Volatile and semivolatile chemicals are recognised as byproducts of disease, boosting volatile analysis as paramount instrument to monitor health and disease, personalize health care and objectively establish the effect of different treatment strategies. Next to volatile organic compounds (VOCs), semivolatile compounds (SVOCS) are present in the environment and in biological matrices, but most of them need to be chemically and structurally identified and their role in health and disease is yet to be explored. In this proposal, we describe the set-up of a highend GCxGC-QTOF-MS facility for analysis of VOCs and SVOCs in biological samples like breath, blood, urine, faeces of humans and animals, and in the headspace of cells. The goal is to set up an infrastructure that allows to assess and investigate multiple biological sample types and their headspace for monitoring health and disease, to identify disease biomarkers, to intensify research on the environmental health issues of modern life, and to tackle the hurdles presently encountered in the metabolomics analysis of steroids and small organic acids. By this means, we intend to team up and complement with international volatomics research groups. In Flanders, such a specialised facility is lacking, and will be unique. It combines high sensitivity, ultralow detection limits for analysis and validation of the molecular composition of biological and headspace samples, with specific sampling devices and advanced data processing.

Researcher(s)

• Promoter: De Winter Benedicte
• Co-promoter: Covaci Adrian
• Co-promoter: Lamote Kevin
• Co-promoter: Lapperre Therese
• Co-promoter: Laukens Kris
• Co-promoter: Samson Roeland
• Co-promoter: van Meerbeeck Jan
• Co-promoter: van Nuijs Alexander
• Co-promoter: Wouters An

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive asbestos-related cancer, presently mostly incurable. This is mainly due to non-specific symptoms only appearing in advanced stage and the lack of sensitive imaging. However, early diagnosis is believed to improve patient outcome. Therefore, our research group has focused for several years on the development of a non-invasive breath test for the diagnosis of MPM, which aims to be used as enrichment tool to screen at-risk asbestos-exposed persons. This breath test is currently being externally validated, showing promising results. Before this test can be used as diagnostic tool, the next step in biomarker development requires determining its clinical utility. Therefore, we want to use the test to follow-up professionally asbestos-exposed individuals at risk for MPM over time to investigate the utility of detecting early-stage MPM. This could allow treatment to be effective and potentially improve patient outcome.

Researcher(s)

• Promoter: van Meerbeeck Jan

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Exposure to air pollution is an important public health issue and has been associated with burden of disease, and increased mortality and morbidity. However, there is no safe threshold under which no health effects occur and only associations have been found so far. The goal of this pilot project is to prove the causal relation by assessing the impact of air pollution exposure on health and respiratory functioning, by combining air pollution monitoring with lung response measurements and exhaled breath analysis in order to minimize morbidity.

Researcher(s)

• Promoter: van Meerbeeck Jan
• Co-promoter: De Winter Benedicte
• Co-promoter: Lamote Kevin
• Co-promoter: Lapperre Therese
• Co-promoter: Samson Roeland

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

The air we breathe is essential for a healthy live. Health and disease reflect in the exhaled air and already, diseases were linked to its scent. Breath contains both volatile organic compounds (VOCs), and non-volatile components (exhaled breath condensate (EBC), and exhaled particles (PEx)). These include metabolites, signalling molecules and cell constituents which relate to the individual's metabolism and are induced by (patho)fysiological processes as inflammation, infection or carcinogenesis in the body. Compounds in the breath are formed in the respiratory system or originate from processes in the body and are transported to the lungs where they can be exhaled. The molecular composition of VOCs and EBC, hence, may reflect both systemic and local processes in the airways, whereas the PEx specifically reflect the composition of the lining fluid of small airways. Since volatile chemicals are recognized as sources of disease, the molecular analysis, or so called 'omics' study of exhaled air ('breathomics') emerges as a paramount instrument in monitoring health and disease in a non-invasive way. Considering the breath volatiles, there are close to 1000 reported compounds in the breath, of which little are unambiguously identified. The compounds belonged to several chemical classes, of which hydrocarbons were the most numerous chemical family. Other well-represented classes were ketones, terpenes, heterocyclic compounds and aromatic compounds. Exhaled breath volatiles and non-volatiles are explored in patients with asthma, renal and liver diseases, lung cancer, chronic obstructive pulmonary disease, inflammatory lung disease, or metabolic disorders and have been shown promising as diagnostic biomarkers. Breath tests can furthermore be used for diagnosing specific enzymes' phenotypic functionality since exhaled metabolisation products of 13C-labeled compounds gives information about the activity of metabolisation enzymes, important information in supporting personalized medicine. VOCs can also originate from exogenous exposure, such as food and drugs intake, and inhalation of chemicals (environmental, occupational 'exposome'). It is a relevant matrix to study exposure, uptake metabolism and elimination of toxic chemicals. Breath analysis, and in general the human volatolome, was first reported to investigate VOCs over forty years ago. Since that time, many methodological and technical improvements have been made. The analysis of VOCs can be done either by chemical analysis or by pattern recognition. Therefore, this project will include the following instruments to measure VOCs: Gas Chromatography-quadrupole-time-of-flight-Mass Spectrometry, sensor technology (field asymmetric ion mobility spectrometry), and selected ion flow tube-mass spectrometry. This will be combined with liquid chromatography instruments considering the analysis of non-volatiles. To analyse the high-throughput data, supervised and unsupervised data mining techniques will be used. Although the 'breath' matrix is highly interesting, there is still a great need for validation, standardization, and improved sensitivity and specificity of the process of breath collection until breath analysis. This project has the ambition to study and explore exhaled breath in its most innovative way: full molecular profiling, including characterization and quantification of volatile and non-volatile breath compounds in vivo in patients, but also ex vivo and in experimental cellular/animal models for biological translation. Therefore, this project's applications are multiple, ranging from medical/toxicological applications for non-invasive monitoring and detection of disease in humans, to research on exhalations/perspirations in the headspace of cell lines, plants, or even consumer goods. This makes the facility an attractive centre for research for several disciplines.

Researcher(s)

• Promoter: van Meerbeeck Jan
• Fellow: Lamote Kevin

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

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

Approximately 75% of patients with lung cancer present with advanced disease and hence, have a bad prognosis. For those with stage 1 disease, the chance of cure is up to 70%. Therefore, companion diagnostics, which may aid identification of those with early stage lung cancer, will play an important role in future screening programs. It is assumed that lung cancer starts as an intrapulmonary nodule, before expanding and spreading to loco-regional lymph nodes and resulting in distant metastases. Because all cancer cells are characterized by an uncontrolled growth that changes their metabolism, the detection of the resulting metabolites may be a novel diagnostic tool to differentiate between early stage lung cancer among incidental pulmonary nodules. Subsets of these metabolites are volatile and are exhaled as so-called volatile organic compounds (VOCs). Analysis of those VOCs suggests they differ between patients with advanced lung cancer and healthy controls. This study aims to validate the use of a high-throughput breath analysis technique in a population of patients who present with an incidental pulmonary nodule. This study will be a case-control study. Six hundred consecutive patients with various underlying conditions and in whom a pulmonary nodule is found on CT scan performed in the course of their illness, will be invited to participate and will be asked to provide a breath sample prior to the diagnostic procedures –if any- for this nodule. Breath sampling is a non-invasive procedure that will require the patient to breath normally into a facemask for 10 minutes to collect 2.5L of breath. The resulting samples will be analysed by Field Asymmetrical Ion Mobility Spectrometry (FAIMS). The resulting VOC profiles will be used to generate a diagnostic algorithm in order to try to differentiate between benign and malignant nodules. The results of this study will provide detailed insights into the accuracy of the test for the detection of early stage lung cancer in incidentally found pulmonary nodules and will form the base for a subsequent study in a population at high risk for the development of lung cancer ((ex-)smokers of at least 15 pack years with emphysema). If sufficiently accurate for early stage disease, analysis of breath VOCs could help implement large-scale screening for lung cancer, significantly decreasing the morbidity and mortality of the disease.

Researcher(s)

• Promoter: van Meerbeeck Jan
• Fellow: Lamote Kevin

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer, characterized by a long latency period between the presumed causal asbestos exposure and diagnosis. Its aspecific clinical manifestation hampers earlystage diagnosis, leading to a dismal prognosis of the disease. Although different blood biomarkers have been investigated, none of them are currently applied for screening. The search for new, non-invasive biomarkers allowing early detection has shifted towards the field of "breathomics". Exhaled breath contains a plethora of volatile organic compounds (VOCs) that originate either from exogenous sources or from endogenous biochemical processes. As the presence of mesothelioma cancer cells alters certain processes in the body by inducing both chronic inflammation and oxidative stress, we can state that changes in the metabolic status of a patient is reflected in changes in the breath profile. Our research group already initiated several sequential MesoBreath Studies evaluating the potential of breath analysis as a screening tool for an at-risk population. The MesoBreath 1 and 2 studies isolated several breath compounds which are currently being identified and confirmed by in vitro analysis in MesoBreath 3. In this third part of our study, we are performing in vitro work involving the analysis of the VOCs in the headspace air of mesothelioma cell lines. The aim of this 4th Meso Breath study is to perform the external validation of these compounds, in an independent patient group included by an international consortium. This prospective validation is the necessary step before clinical implementation.

Researcher(s)

• Promoter: van Meerbeeck Jan

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

There is a presently unmet need for improvement of the outcome in patients with non-small cell lung cancer, who present with locoregional extension, are not fit for concurrent chemoradiotherapy and are sequentially treated with induction chemotherapy followed by definitive radiotherapy. The present project aims at reducing their locoregional relapse rate. We hypothesize that the administration of oral metformin during radiotherapy will decrease the hypoxic fraction of tumour cells which are then better targeted by definitive radiation and become apoptotic. This will be evaluated using a randomised design where all patients will receive definitive radiotherapy with or without metformin. In addition, the validated biomarker of tumour hypoxia 18FMISO PET scintigraphy, and biomarkers of resistance, apoptosis and glucose metabolism will be evaluated for their potential predictive value.

Researcher(s)

• Promoter: van Meerbeeck Jan

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Malignant pleural mesothelioma (MPM) is a rare cancer, characterized by a long latency period between the presumed causal asbestos exposure and diagnosis, by an aspecific clinical manifestation, hampering early-stage diagnosis and dismal prognosis. Although different blood biomarkers have been investigated, none of them is currently applied for screening. The search for new, non-invasive biomarkers allowing early detection, has recently shifted towards the field of "breathomics". Our research group initiated the MesoBreath Studies evaluating the potential of breath analysis as a screening tool for an at-risk population. MesoBreath 1 and 2 pinpointed 5 breath compounds which are currently being identified and confirmed by in vitro analysis in MesoBreath 3. The aim of this 4thMesoBreath study is to perform an external validation of these compounds, in an international consortium. This prospective validation is the necessary step to go before clinical implementation.

Researcher(s)

• Promoter: van Meerbeeck Jan

Research team(s)

Project website

Project type(s)

• Research Project

Abstract

There still is a large unmet need to improve the diagnosis, treatment and treatment monitoring of patients suffering from Malignant Pleural Mesothelioma (MPM). In other cancer types, the detection of genomic alterations, resulting in the identification of actionable or prognostic biomarkers, has been proven helpful to improve treatment. Hence, the objectives of this research project are: (i) to gain insight into recurrent, actionable genetic alterations in MPM, which can be useful to monitor disease progression and treatment effectiveness; (ii) to understand the genetic factors involved in resistance to chemotherapy and (iii) to explore the detection of genetic alterations in circulating tumour DNA for its potential in early diagnosis and disease monitoring. To achieve this, a meta-analysis will be performed on in-house and publicly available sequencing data, samples of responding and non-responding patients will be sequenced by whole exome sequencing, and serial blood samples of MPM-patients will be analysed.

Researcher(s)

• Promoter: van Meerbeeck Jan
• Co-promoter: Van Camp Guy

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Malignant pleural mesothelioma (MPM) is a rare and highly aggressive cancer originating from the mesothelial cells of the pleura. A causal relationship between the development of MPM and exposure to asbestos has been demonstrated, with up to 80% of all patients being exposed in the past. Taking into account the long latency (± 40 years) between asbestos exposure and MPM-development, and considering the continued use of asbestos in some non-Western and developing countries, MPM will remain a global health issue for years to come. Despite improvements in outcome with the advent of -palliative- chemotherapy, MPM-patients still face a very poor prognosis. Hence, there is ample room for the development of novel treatment strategies. The presented project focuses on investigating the use of next-generation sequencing techniques for the detection of genetic changes in mesothelioma cells, gathered both by solid and liquid biopsy. These genetic alterations might then have the potential to be targeted by new and innovative medication types. To achieve this, mesothelioma tissue, collected during a solid biopsy, will be investigated for the presence of genetic alterations that are not present in matched normal material. In this respect, copy number changes will be studied using low-pass whole genome sequencing, whereas point mutations and small insertions and deletions will be detected by means of whole exome sequencing. Potentially actionable alterations that are traced in this way, will be validated in an external patient group. Hereafter, the possibility of detecting these actionable mutations in easily and repeatedly accessible liquid biopsies (i.e. in circulating tumor DNA) will be studied. We are convinced that the aims pursued in this project will contribute to the identification of differences between normal and transformed mesothelial cells, that will have the potential to be targeted by new medication.

Researcher(s)

• Promoter: van Meerbeeck Jan
• Fellow: Hylebos Marieke

Research team(s)

Project type(s)

• Research Project

Abstract

Malignant pleural mesothelioma (MPM) is a highly aggressive and fatal cancer that affects the membranes lining the lung and is mostly associated with previous exposure to asbestos. Till today, prognosis of patients diagnosed with MPM remains dismal with a median overall survival of only 9-12 months and currently available treatment methods have only a limited impact on it. Therefore there is an urgent need for new treatment methods. During my PhD project I will investigate the immune checkpoint programmed death-1 (PD-1) and its ligands, PD-L1 and PD-L2, as immunotherapeutic targets in MPM. It is presently unknown if blocking these targets have any effect in MPM but clinical trials in several tumor types have already shown promising results for PD-1 and PD-L1 immunotherapy.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: van Meerbeeck Jan
• Fellow: Marcq Elly

Research team(s)

Project type(s)

• Research Project

Abstract

The prognosis of malignant pleural mesothelioma (MPM) patients remains dismal with a median overall survival of only 9-12 months. The immune system plays a critica I role in protection against MPM with preliminary clinical evidence that immunotherapy can lead to MPM contro!. Here, we will be the first to investigate the immune checkpoint programmed-death 1 (PD-1) and its ligands as novel and potentially highly effective immunotherapeutic targets in MPM.

Researcher(s)

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

Research team(s)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: van Meerbeeck Jan
• Co-promoter: Op de Beeck Ken
• Fellow: Hylebos Marieke

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: van Meerbeeck Jan

Research team(s)

Project type(s)

• Research Project