ERC FUNDED PROJECTS

The oral cavity is the gateway to the lower respiratory tract, and oral bacteria are likely to play a role in lung health. This may be the case for pathogens as well as commensal bacteria and the balance between species. The oral bacterial community of patients with periodontitis is dominated by gram-negative bacteria and a higher lipopolysaccharide (LPS) activity than in healthy microbiota. Furthermore, bacteria with especially potent pro-inflammatory LPS have been shown to be more common in the lungs of asthmatic than in healthy individuals. The working hypothesis of BRuSH is that microbiome communities dominated by LPS-producing bacteria which induce a particularly strong pro-inflammatory immune response in the host, will have a negative effect on respiratory health. I will test this hypothesis in two longitudinally designed population-based lung health studies. I aim to identify whether specific bacterial composition and types of LPS producing bacteria in oral and dust samples predict lung function and respiratory health over time; and if the different types of LPS-producing bacteria affect LPS in saliva saliva and dust. BRuSH will apply functional genome annotation that can assign biological significance to raw bacterial DNA sequences. With this bioinformatics tool I will cluster microbiome data into various LPS-producers: bacteria with LPS with strong inflammatory effects and others with weak- or antagonistic effects. The epidemiological studies will be supported by mice-models of asthma and cell assays of human bronchial epithelial cells, by exposing mice and bronchial cells to chemically synthesized Lipid A (the component that drive the LPS-induced immune responses) of various potency. The goal of BRuSH is to prove a causal relationship between oral microbiome and lung health, and gain knowledge that will enable us to make oral health a feasible target for intervention programs aimed at optimizing lung health and preventing respiratory disease.

1 499 938 €

Start date: 2019-01-01, End date: 2023-12-31

The goal of the proposed research is to examine how the independent and combined effects of childhood adiposity (assessed by body mass index [BMI]; kg/m2) height, change in BMI and height, and pubertal timing from the ages of 7 to 13 years are associated with the risk of cancer incidence in adulthood. Greater body size (adipose tissue and different types of lean tissue) reflecting past or ongoing growth may increase the risk of cancer in individuals as greater numbers of proliferating cells increase the risk that mutations leading to the subsequent development of cancer occur. As childhood is a period of growth, it is plausible that it is of particular relevance for the early establishment of the risk of cancer. Data from the Copenhagen School Health Records Register, which is based on a population of schoolchildren born between 1930-1983 and contains computerised weight and height measurements on >350.000 boys and girls in the capital city of Denmark, as well as data from other cohorts will be used. Survival analysis techniques and the newly developed Dynamic Path Analysis model will be used to examine how body size (BMI and height) at each age from 7 to 13 years as well as change in body size during this period is associated with the risk of multiple forms of cancer in adulthood with a simultaneous exploration of the effects of birth weight and pubertal timing. Additionally, potential effects of childhood and adult health and social circumstances will be investigated in sub-cohorts with this information available. Results from this research will demonstrate if childhood is a critical period for the establishment of the risk for cancer in adulthood and will lead into mechanistic explorations of the associations at the biological level, investigations into associations between childhood body size and mortality and contribute to developing improved definitions of childhood overweight and obesity that are based upon long-term health outcomes.

1 199 998 €

Start date: 2012-02-01, End date: 2017-01-31

Background: Acrylamide is a chemical formed in many commonly consumed foods and beverages. It is neurotoxic, crosses the placenta and has been associated with restriction of fetal growth in humans. In animals, acrylamide causes heritable mutations, tumors, developmental toxicity, reduced fertility and impaired growth. Therefore, the discovery of acrylamide in food in 2002 raised concern about human health effects worldwide. Still, epidemiological studies are limited and effects on health of prenatal exposure have never been evaluated. Research gaps: Epidemiological studies have mostly addressed exposure during adulthood, focused on cancer risk in adults, and relied on questionnaires entailing a high degree of exposure misclassification. Biomarker studies on prenatal exposure to acrylamide from diet are critically needed to improve exposure assessment and to determine whether acrylamide leads to major diseases later in life. Own results: I have first authored a prospective European study showing that prenatal exposure to acrylamide, estimated by measuring hemoglobin adducts in cord blood, was associated with fetal growth restriction, for the first time. Objectives: To determine the effects of prenatal exposure to acrylamide alone and in combination with other potentially toxic adduct-forming exposures on the health of children and young adults. Methods: Both well-established and innovative biomarker methods will be used for characterization of prenatal exposure to acrylamide and related toxicants in blood from pregnant women and their offspring in prospective cohort studies with long-term follow-up. Risk of neurological disorders, impaired cognition, disturbed reproductive function and metabolic outcomes such as obesity and diabetes will be evaluated. Perspectives: CHIPS project will provide a better understanding of the impact of prenatal exposure to acrylamide from diet on human health urgently needed for targeted strategies for the protection of the health.

1 499 531 €

Start date: 2018-07-01, End date: 2023-06-30

Bulky DNA adducts formed from chemical carcinogens dictate structure, reactivity, and mechanism of chemical-biological reactions; therefore, their identification is central to evaluating and mitigating cancer risk. Natural food components, or others associated with certain food preparations or metabolic conversions, initiate potentially damaging genetic mutations after forming DNA adducts, which contribute critically to carcinogenesis, despite the fact that they are typically repaired biochemically and they are formed at extremely low levels. This situation places significant limitations on our ability to understand the role of formation, repair, and mutagenesis on the basis of the complex DNA reactivity profiles of food components. The long-term goals of this research are to contribute basic knowledge and advanced experimental tools required to understand, on the basis of chemical structure, the contributions of chronic, potentially adverse, dietary chemical carcinogen exposure to cancer development. It is proposed that a new class of synthetic nucleosides, devised on the basis of preliminary discoveries made in the independent laboratory of the applicant, will serve as molecular probes for bulky DNA adducts and can be effectively used to study and AMPlify, i.e. as a sensitive diagnostic tool, low levels of chemically-specific modes of DNA damage. The proposed research is a chemical biology-based approach to the study of carcinogenesis. Experiments involve chemical synthesis, thermodynamic and kinetic characterization DNA-DNA and enzyme-DNA interactions, and nanoparticle-based molecular probes. The proposal describes a potentially ground-breaking approach for profiling the biological reactivities of chemical carcinogens, and we expect to gain fundamental knowledge and chemical tools that can contribute to the prevention of diseases influenced by gene-environment interactions.

1 500 000 €

Start date: 2010-09-01, End date: 2015-08-31

Even the perfect cancer drug must reach its target to have an effect. The ImPRESS project main objective is to develop a novel imaging paradigm coined Restricted Perfusion Imaging (RPI) to reveal - for the first time in humans - vascular restrictions in solid cancers caused by mechanical solid stress, and use RPI to demonstrate that alleviating this force will repair the cancerous microenvironment and improve therapeutic response. Delivery of anti-cancer drugs to the tumor is critically dependent on a functional vascular bed. Developing biomarkers that can measure how mechanical forces in a solid tumor impair perfusion and promotes therapy resistance is essential for treatment of disease. The ImPRESS project is based on the following observations; (I) pre-clinical work suggests that therapies targeting the tumor microenvironment and extracellular matrix may enhance drug delivery by decompressing tumor vessels; (II) results from animal models may not be transferable because compressive forces in human tumors in vivo can be many times higher; and (III) there are no available imaging technologies for medical diagnostics of solid stress in human cancers. Using RPI, ImPRESS will conduct a comprehensive series of innovative studies in brain cancer patients to answer three key questions: (Q1) Can we image vascular restrictions in human cancers and map how the vasculature changes with tumor growth or treatment? (Q2) Can we use medical engineering to image solid stress in vivo? (Q3) Can RPI show that matrix-depleting drugs improve patient response to conventional chemo- and radiation therapy as well as new targeted therapies? The ImPRESS project holds a unique position to answer these questions by our unrivaled experience with advanced imaging of cancer patients. With successful delivery, ImPRESS will have a direct impact on patient treatment and establish an imaging paradigm that will pave the way for new scientific knowledge on how to revitalize cancer therapies.

1 499 638 €

Start date: 2018-01-01, End date: 2022-12-31

Spatial and temporal changes in the underlying biochemistry of cancer control disease progression and response/resistance to treatment. Developing methods to detect changes in oncogenic signaling at an early stage is vital to further our understanding of cancer, and will advance the next generation of anti-cancer therapies. Nanomedicine is the medical application of nanotechnology to diagnose or treat disease. In light of the recent introduction of tools like Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) scanners, there is now a new opportunity to develop hybrid imaging protocols that can simultaneously take advantage of the functional and anatomic information available from PET/MRI to address changes in oncogenic signaling pathways. The work outlined in this interdisciplinary ERC Project is designed to advance new chemistry and imaging methods to measure changes in oncogenic signaling in various cancers before, during and after treatment using PET/MRI. The long-term goals are to expand the scope and utility of radiolabelled nanomedicines as dual-modality PET/MRI probes for detecting changes in oncogenic signaling in various cancers and develop efficient methods for translating new technologies to the clinic. Successful completion of this ERC Project has the potential to transform personalised clinical management of cancer patients via advanced PET/MRI detection of oncogenic signaling processes.

1 700 000 €

Start date: 2016-09-01, End date: 2021-08-31

This project aims to improve the treatment of metastasized colorectal carcinoma (mCRC), as treatment options after first line chemotherapy are desperately needed. The key to improvement of cancer therapy resides in optimal combination of drugs. Optimally combining drugs is non-trivial due to the large number of possibilities, especially when more than two drugs are combined at various doses. In the current research program I propose to use a differential evolution guided stochastic search algorithm to guide the way in finding optimal combination therapies. In previous research I have applied this feedback system control (FSC) technique to navigate through the enormous parametric space of nine angiostatic drugs at four doses. The straightforward iterative approach of in vitro cell viability testing and algorithm-based analysis identified optimal synergistic low-dose drug combinations. In vivo translation by maintaining the drug dose ratio led to effective anti-cancer activity, without evidence of side-effects. A new screen for optimal targeted combination treatment of advanced CRC will be performed. A series of 7 genetically different human CRC cell lines will be used in this screen, thus simulating personalized treatment. The optimized combinations will be ‘ratiometrically’ translated into orthotopic and metastasizing preclinical CRC mouse models and tested in parallel to standard chemotherapy regimens. Development of a method for a personalized screen using freshly isolated tumor cells will prepare the technology for application in the clinic. Using an innovative strategy I previously identified a series of novel markers of the tumor endothelium. After validation of these targets, this project aims for the design of new drugs to be used in a screen for optimal combination therapy for mCRC. The translational and multidisciplinary nature of the current proposal aims for preparing an improved therapeutic combination regimen for testing in cancer patients.

1 199 436 €

Start date: 2016-05-01, End date: 2020-04-30

This proposal aims to harness a novel type of senescence that we have identified in response to acute Pten inactivation, and which we believe offers a radical therapeutic approach to target the quiescent cancer stem cell in vivo. In characterizing Pten loss Induced Cellular Senescence, which we have named PICS for short, we have discovered that PICS is distinct from other forms of cellular senescence including oncogene-induced senescence (OIS) and replicative senescence. These distinct differences are characterized by a lack of DNA damage and hyper-replication, breaking the current dogma for senescence induction. The ability to induce senescence, an irreversible growth arrest, in cells by targeting Pten signaling, without a requirement for hyper-replication and DNA damage opens up the possibility to target quiescent cells, including stem cells, that have a low proliferative index. This approach has tremendous therapeutic potential and represents one of the most exciting developments for the advancement of prostate cancer therapy in recent years. Through the manipulation of senescence induction pathways we will identify PICS enhancing drugs and redefine the paradigm for cancer therapy. By developing novel mouse models that target prostate stem cells we will evaluate these PICS pro-senescence drugs in a pre-clinical setting. Finally, these results will be cross referenced with data from human prostate stem cells and we will lay the ground work to translate this to the clinical setting, further developing the clinical potential of these findings to eradicate prostate cancer.

1 500 000 €

Start date: 2011-04-01, End date: 2016-03-31

Overtreatment in prostate cancer (PCa) is a burden for health care economy and for quality of life. Correct diagnosis of early stage PCa is challenging given the limitations of the currently available clinical tools and the biological understanding of PCa. In this inter-disciplinary project, I propose an innovative approach enabling several cutting-edge ‘omics’ technologies (spatial metabolomics, genomics, transcriptomics) as well as histopathology to be performed on the same tissue sample. My goal is to reveal the molecular mechanisms of novel, but also promising metabolite biomarkers (citrate, polyamines, succinate and zinc) and their connection to recurrence, tissue heterogeneity and immune responses in complex human tissues. Such markers can personalize PCa diagnosis, open up new treatment strategies and fundamentally change the view of how to analyze tissue samples in the future. Furthermore, I want to demonstrate that citrate and polyamines are reliable prognostic markers that can be analyzed both in tissue and in patients in vivo by MR spectroscopic imaging. This work is made possible by the availability of high-quality fresh frozen tissue biobanks of prostatectomy biopsies with 5-10 years of follow-up data (N=1000)/slices (N=1000) and targeted in vivo snap-shot biopsies from clinical MR guided procedures (N=100). Among other techniques, I will implement high speed MALDI imaging (RapifleX MALDI TissueTyper) to the multi-omics protocol to study the spatial distribution and provide high resolution metabolic maps for each cell type, and which can be matched to both histopathology and MR Imaging. Multi-disciplinary platforms on large cohorts are needed to explore the clinical potential of the suggested molecular mechanisms. I expect that this ambitious proposal will address the diagnostic challenges of PCa and will further inspire the clinic and scientific community to follow the multi-omics approach within diagnosis and cancer research.

1 500 000 €

Start date: 2018-02-01, End date: 2023-01-31