Project acronym CRADLE
Project Cancer treatment during pregnancy: from fetal safety to maternal efficacy
Researcher (PI) Frederic Amant
Host Institution (HI) KATHOLIEKE UNIVERSITEIT LEUVEN
Call Details Consolidator Grant (CoG), LS7, ERC-2014-CoG
Summary The evolution in drug regulation of the last 50 years has left pregnant women and their fetuses orphaned. This is particularly problematic for cancer during pregnancy, which raises a difficult and conflicting medical ethical decision process and which has recently become increasingly frequent. In 2012 we published the first prospective study indicating that antenatal exposure to cancer treatment can overall be considered safe. Building on this proof of concept, the current proposal wants to take a groundbreaking step towards developing a standard of care for cancer during pregnancy by addressing –in an integrated fashion- the challenges at the level of the fetus, the mother and the fetomaternal barrier. At the core of this proposal lies an international registry of pregnant women with cancer, along with a registry of their children, and biobanks of maternal, placental, cord blood and tumoral tissues. Research track ‘child’ aims to deliver robust evidence of fetal safety. Research track ‘mother’ aims to address the emerging concerns in the oncological management of the mother, and specifically, the possible distinct biology of pregnancy-associated breast cancer, the most frequent cancer type in pregnancy. The research approach includes large-scale clinical follow-up studies along with laboratory studies on patient biomaterials, including pharmacological investigations and RNA-sequencing studies. Complementary to these studies is research track ‘placenta’ in which cutting-edge models of human placental research are used to address the poorly understood physiological basis of the placental barrier function in this specific situation. This ambitious program will rely on a multidisciplinary team of experts. Not only may the scientific deliverables of this proposal constitute a major step forward to the well-being of both mother and fetus in a pregnancy complicated by cancer, the methodological approach may also provide critical impetus to further research in this field.
Summary
The evolution in drug regulation of the last 50 years has left pregnant women and their fetuses orphaned. This is particularly problematic for cancer during pregnancy, which raises a difficult and conflicting medical ethical decision process and which has recently become increasingly frequent. In 2012 we published the first prospective study indicating that antenatal exposure to cancer treatment can overall be considered safe. Building on this proof of concept, the current proposal wants to take a groundbreaking step towards developing a standard of care for cancer during pregnancy by addressing –in an integrated fashion- the challenges at the level of the fetus, the mother and the fetomaternal barrier. At the core of this proposal lies an international registry of pregnant women with cancer, along with a registry of their children, and biobanks of maternal, placental, cord blood and tumoral tissues. Research track ‘child’ aims to deliver robust evidence of fetal safety. Research track ‘mother’ aims to address the emerging concerns in the oncological management of the mother, and specifically, the possible distinct biology of pregnancy-associated breast cancer, the most frequent cancer type in pregnancy. The research approach includes large-scale clinical follow-up studies along with laboratory studies on patient biomaterials, including pharmacological investigations and RNA-sequencing studies. Complementary to these studies is research track ‘placenta’ in which cutting-edge models of human placental research are used to address the poorly understood physiological basis of the placental barrier function in this specific situation. This ambitious program will rely on a multidisciplinary team of experts. Not only may the scientific deliverables of this proposal constitute a major step forward to the well-being of both mother and fetus in a pregnancy complicated by cancer, the methodological approach may also provide critical impetus to further research in this field.
Max ERC Funding
2 000 000 €
Duration
Start date: 2015-10-01, End date: 2020-09-30
Project acronym GlycoTarget
Project Exploring the targeted delivery of biopharmaceuticals enabled by glycosylation control
Researcher (PI) Nico Luc Marc Callewaert
Host Institution (HI) VIB
Call Details Consolidator Grant (CoG), LS7, ERC-2013-CoG
Summary Most biotechnological therapeutics used in the clinic today and under current development, are of protein nature. Eukaryotic expression systems (such as yeasts and mammalian cells) for these therapeutic proteins add carbohydrate moieties (glycans) to the proteins, and these glycans strongly modulate the protein's in vivo biodistribution and therapeutic efficacy. Until recently, no adequate tools were available to accurately control glycosylation structure in these expression systems, but bio-engineering research in our lab and elsewhere has now largely overcome this problem.
In the GlycoTarget ERC Consolidator grant project, we aim at exploring the relation between the structure of the glycans on therapeutic proteins and the in vivo targeting properties of these modified proteins to different tissues/cells/subcellular organelles.
As highly medically relevant test cases for this exploration, we have selected three diseases with strong unmet therapeutic need, that could potentially be treated with glyco-targeted biopharmaceuticals through three different routes of protein delivery: progressive liver disease (intravenous), allergic asthma (subcutaneous immunization) and active tuberculosis (intrapulmonary delivery).
Summary
Most biotechnological therapeutics used in the clinic today and under current development, are of protein nature. Eukaryotic expression systems (such as yeasts and mammalian cells) for these therapeutic proteins add carbohydrate moieties (glycans) to the proteins, and these glycans strongly modulate the protein's in vivo biodistribution and therapeutic efficacy. Until recently, no adequate tools were available to accurately control glycosylation structure in these expression systems, but bio-engineering research in our lab and elsewhere has now largely overcome this problem.
In the GlycoTarget ERC Consolidator grant project, we aim at exploring the relation between the structure of the glycans on therapeutic proteins and the in vivo targeting properties of these modified proteins to different tissues/cells/subcellular organelles.
As highly medically relevant test cases for this exploration, we have selected three diseases with strong unmet therapeutic need, that could potentially be treated with glyco-targeted biopharmaceuticals through three different routes of protein delivery: progressive liver disease (intravenous), allergic asthma (subcutaneous immunization) and active tuberculosis (intrapulmonary delivery).
Max ERC Funding
1 994 760 €
Duration
Start date: 2014-03-01, End date: 2019-02-28
Project acronym ImmunoBioSynth
Project Synergistic engineering of anti-tumor immunity by synthetic biomaterials
Researcher (PI) Bruno DE GEEST
Host Institution (HI) UNIVERSITEIT GENT
Call Details Consolidator Grant (CoG), LS7, ERC-2018-COG
Summary Immunotherapy holds the potential to dramatically improve the curative prognosis of cancer patients. However, despite significant progress, a huge gap remains to be bridged to gain board success in the clinic. A first limiting factor in cancer immunotherapy is the low response rate in large fraction of the patients and an unmet need exists for more efficient - potentially synergistic - immunotherapies that improve upon or complement existing strategies. The second limiting factor is immune-related toxicity that can cause live-threatening situations as well as seriously impair the quality of life of patients. Therefore, there is an urgent need for safer immunotherapies that allow for a more target-specific engineering of the immune system. Strategies to engineer the immune system via a materials chemistry approach, i.e. immuno-engineering, have gathered major attention over the past decade and could complement or replace biologicals, and holds promise to contribute to resolving the current issues faced by the immunotherapy field. I hypothesize that synthetic biomaterials can play an important role in anti-cancer immunotherapy with regard to synergistic, safe, but potent, instruction of innate and adaptive anti-cancer immunity and to revert the tumor microenvironment from an immune-suppressive into an immune-susceptible state. Hereto, the overall scientific objective of this proposal is to fully embrace the potential of immuno-engineering and develop several highly synergistic biomaterials strategies to engineer the immune system to fight cancer. I will develop a series of biomaterials and address a number of fundamental questions with regard to optimal biomaterial design for immuno-engineering. Based on these findings, I will elucidate those therapeutic strategies that lead to synergistic engineering of innate and adaptive immunity in combination with remodeling the tumor microenvironment from an immune-suppressive into an immune-susceptible state.
Summary
Immunotherapy holds the potential to dramatically improve the curative prognosis of cancer patients. However, despite significant progress, a huge gap remains to be bridged to gain board success in the clinic. A first limiting factor in cancer immunotherapy is the low response rate in large fraction of the patients and an unmet need exists for more efficient - potentially synergistic - immunotherapies that improve upon or complement existing strategies. The second limiting factor is immune-related toxicity that can cause live-threatening situations as well as seriously impair the quality of life of patients. Therefore, there is an urgent need for safer immunotherapies that allow for a more target-specific engineering of the immune system. Strategies to engineer the immune system via a materials chemistry approach, i.e. immuno-engineering, have gathered major attention over the past decade and could complement or replace biologicals, and holds promise to contribute to resolving the current issues faced by the immunotherapy field. I hypothesize that synthetic biomaterials can play an important role in anti-cancer immunotherapy with regard to synergistic, safe, but potent, instruction of innate and adaptive anti-cancer immunity and to revert the tumor microenvironment from an immune-suppressive into an immune-susceptible state. Hereto, the overall scientific objective of this proposal is to fully embrace the potential of immuno-engineering and develop several highly synergistic biomaterials strategies to engineer the immune system to fight cancer. I will develop a series of biomaterials and address a number of fundamental questions with regard to optimal biomaterial design for immuno-engineering. Based on these findings, I will elucidate those therapeutic strategies that lead to synergistic engineering of innate and adaptive immunity in combination with remodeling the tumor microenvironment from an immune-suppressive into an immune-susceptible state.
Max ERC Funding
2 000 000 €
Duration
Start date: 2019-04-01, End date: 2024-03-31
Project acronym METAPTPs
Project PROTEIN TYROSINE PHOSPHATASES IN METABOLIC DISEASES: OXIDATION, DYSFUNCTION AND THERAPEUTIC POTENTIAL
Researcher (PI) Esteban GURZOV AMARELO
Host Institution (HI) UNIVERSITE LIBRE DE BRUXELLES
Call Details Consolidator Grant (CoG), LS7, ERC-2018-COG
Summary Diabetes mellitus is characterised by hyperglycaemia caused by an absolute or relative insulin deficiency. The global prevalence of diabetes has reached more than 410 million individuals, underscoring the need for novel therapeutic strategies targeting the pathology as a multi-organ disease. Protein tyrosine phosphatases (PTPs) constitute a superfamily of enzymes that dephosphorylate tyrosine-phosphorylated proteins and oppose the actions of protein tyrosine kinases. My previous studies and preliminary data suggest that PTPs act as molecular switches for key signalling events in the development of diabetes, i.e. insulin/glucose/cytokine signalling. Dysregulation of these pathways results in metabolic consequences that are cell-specific. Oxidative stress abrogates the nucleophilic properties of the PTP active site and induces conformational changes that inhibit PTP activity and prevent substrate-binding. I have recently developed an innovative proteomic approach to quantify PTP oxidation in vivo and demonstrated that this occurs in liver/pancreas under pathological conditions, including obesity and inflammation. In this proposal, I aim to fully characterise the activity and oxidation status of PTPs in dysfunctional metabolic relevant cells in obesity and diabetes. Importantly, the crucial role of PTPs make them promising candidates for the treatment of metabolic disorders. I hypothesise that specific antioxidants, diets and/or adenovirus will restore PTP function and ameliorate the metabolic deleterious defects in pre-clinical studies. Over the next 5 years, I aim to:
• Identify the major oxidised PTPs in metabolic relevant tissues/cells in both obesity and diabetes.
• Determine the contribution of PTP inactivation in cellular responses to metabolic signalling in human samples.
• Assess the impact of tissue-specific PTP deficiency on the development of obesity and diabetes.
• Test novel therapeutic approaches targeting PTPs to prevent/reverse metabolic disorders.
Summary
Diabetes mellitus is characterised by hyperglycaemia caused by an absolute or relative insulin deficiency. The global prevalence of diabetes has reached more than 410 million individuals, underscoring the need for novel therapeutic strategies targeting the pathology as a multi-organ disease. Protein tyrosine phosphatases (PTPs) constitute a superfamily of enzymes that dephosphorylate tyrosine-phosphorylated proteins and oppose the actions of protein tyrosine kinases. My previous studies and preliminary data suggest that PTPs act as molecular switches for key signalling events in the development of diabetes, i.e. insulin/glucose/cytokine signalling. Dysregulation of these pathways results in metabolic consequences that are cell-specific. Oxidative stress abrogates the nucleophilic properties of the PTP active site and induces conformational changes that inhibit PTP activity and prevent substrate-binding. I have recently developed an innovative proteomic approach to quantify PTP oxidation in vivo and demonstrated that this occurs in liver/pancreas under pathological conditions, including obesity and inflammation. In this proposal, I aim to fully characterise the activity and oxidation status of PTPs in dysfunctional metabolic relevant cells in obesity and diabetes. Importantly, the crucial role of PTPs make them promising candidates for the treatment of metabolic disorders. I hypothesise that specific antioxidants, diets and/or adenovirus will restore PTP function and ameliorate the metabolic deleterious defects in pre-clinical studies. Over the next 5 years, I aim to:
• Identify the major oxidised PTPs in metabolic relevant tissues/cells in both obesity and diabetes.
• Determine the contribution of PTP inactivation in cellular responses to metabolic signalling in human samples.
• Assess the impact of tissue-specific PTP deficiency on the development of obesity and diabetes.
• Test novel therapeutic approaches targeting PTPs to prevent/reverse metabolic disorders.
Max ERC Funding
1 966 906 €
Duration
Start date: 2019-04-01, End date: 2024-03-31
Project acronym NANOBUBBLE
Project Laser-induced vapour nanobubbles for intracellular delivery of nanomaterials and treatment of biofilm infections
Researcher (PI) Kevin Braeckmans
Host Institution (HI) UNIVERSITEIT GENT
Call Details Consolidator Grant (CoG), LS7, ERC-2014-CoG
Summary Lasers have found widespread application in medicine, such as for photothermal therapy. Gold nanoparticles (AuNPs), are often used as enhancers of the photothermal effect since they can efficiently absorb laser light and convert it into thermal energy. When absorbing intense nano- or picosecond laser pulses, AuNPs can become extremely hot and water vapor nanobubbles (VNBs) can emerge around these particles in tissue. A VNB will expand up to several hundred nm until the thermal energy from the AuNP is consumed, after which the bubble violently collapses, causing mechanical damage to neighbouring structures. In this project the aim is to make use of the disruptive mechanical force of VNBs to enable highly controlled and efficient delivery of macromolecules and nanoparticles in cells and biofilms. First, optical set-ups and microfluidics devices will be developed for high-throughput treatment of cells and biofilms. Second, VNBs will be used to achieve efficient cytosolic delivery of functional macromolecules in mammalian cells by cell membrane perforation or by inducing endosomal escape of endocytosed nanomedicine formulations that are functionalized with AuNPs. These concepts will be applied to tumorigenesis research, generation of induced pluripotent stem cells and modulation of effector T-cells for adoptive T-cell anti-cancer therapy. Third, contrast nanoparticles for cell imaging will be delivered into the cytosol of mammalian cells through VNB induced cell membrane perforation. This will enable more reliable in vivo imaging of labelled cells, labelling of subcellular structures for time-lapse microscopy and intracellular biosensing. Finally, [... confidential...] laser-induced VNBs will be used [... confidential...] for improved eradication of biofilms. This concept will be applied to biofilm infections in dental root canals and chronic wounds.
Summary
Lasers have found widespread application in medicine, such as for photothermal therapy. Gold nanoparticles (AuNPs), are often used as enhancers of the photothermal effect since they can efficiently absorb laser light and convert it into thermal energy. When absorbing intense nano- or picosecond laser pulses, AuNPs can become extremely hot and water vapor nanobubbles (VNBs) can emerge around these particles in tissue. A VNB will expand up to several hundred nm until the thermal energy from the AuNP is consumed, after which the bubble violently collapses, causing mechanical damage to neighbouring structures. In this project the aim is to make use of the disruptive mechanical force of VNBs to enable highly controlled and efficient delivery of macromolecules and nanoparticles in cells and biofilms. First, optical set-ups and microfluidics devices will be developed for high-throughput treatment of cells and biofilms. Second, VNBs will be used to achieve efficient cytosolic delivery of functional macromolecules in mammalian cells by cell membrane perforation or by inducing endosomal escape of endocytosed nanomedicine formulations that are functionalized with AuNPs. These concepts will be applied to tumorigenesis research, generation of induced pluripotent stem cells and modulation of effector T-cells for adoptive T-cell anti-cancer therapy. Third, contrast nanoparticles for cell imaging will be delivered into the cytosol of mammalian cells through VNB induced cell membrane perforation. This will enable more reliable in vivo imaging of labelled cells, labelling of subcellular structures for time-lapse microscopy and intracellular biosensing. Finally, [... confidential...] laser-induced VNBs will be used [... confidential...] for improved eradication of biofilms. This concept will be applied to biofilm infections in dental root canals and chronic wounds.
Max ERC Funding
2 236 250 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym PV-COAT
Project PROSTHETIC VALVE BIOACTIVE SURFACE COATING TO REDUCE THE PREVALENCE OF THROMBOSIS
Researcher (PI) Patrizio Lancellotti
Host Institution (HI) UNIVERSITE DE LIEGE
Call Details Consolidator Grant (CoG), LS7, ERC-2014-CoG
Summary Heart valve prostheses are currently among the most widely used cardiovascular devices. To maintain enduring optimal biomechanical properties, the mechanical prostheses, based on carbon, metallic and polymeric components, require permanent anticoagulation, which often leads to adverse reactions, i.e. higher risks of thromboembolism, hemorrhage, and hemolysis.
Continuing advances in heart valve prosthesis design and in techniques for implantation have improved the survival length and quality of life of patients who receive these devices. In an ongoing effort to develop a more durable and biocompatible heart valve prosthesis, researchers have used a variety of techniques to determine the suitability of given valve materials for a given implant application. In recent years, advances in polymer science have given rise to new ways of improving artificial cardiovascular devices biostability and hemocompatibility.
To date, no polymer coated mechanical prosthetic heart valve exists.
The present research project aims to improve the hemocompatibility and long-term in vivo performance of mechanical prosthetic heart valves by reducing contact-induced thrombosis through bioactive polymer prosthetic valve surface coating.
These new coated prosthetic heart valves will be designed for hemodynamic performance and durability similar to uncoated materials, combined with a greater thromboresistance, both in vitro and in animal studies.
With these promising advances, bioactive surface coated prosthetic heart valves could replace previous generation of prosthetic valves in the near future. The utmost perspective of the current project paves the way for the development of new bioactive coating for other implantable cardiovascular devices or materials.
Summary
Heart valve prostheses are currently among the most widely used cardiovascular devices. To maintain enduring optimal biomechanical properties, the mechanical prostheses, based on carbon, metallic and polymeric components, require permanent anticoagulation, which often leads to adverse reactions, i.e. higher risks of thromboembolism, hemorrhage, and hemolysis.
Continuing advances in heart valve prosthesis design and in techniques for implantation have improved the survival length and quality of life of patients who receive these devices. In an ongoing effort to develop a more durable and biocompatible heart valve prosthesis, researchers have used a variety of techniques to determine the suitability of given valve materials for a given implant application. In recent years, advances in polymer science have given rise to new ways of improving artificial cardiovascular devices biostability and hemocompatibility.
To date, no polymer coated mechanical prosthetic heart valve exists.
The present research project aims to improve the hemocompatibility and long-term in vivo performance of mechanical prosthetic heart valves by reducing contact-induced thrombosis through bioactive polymer prosthetic valve surface coating.
These new coated prosthetic heart valves will be designed for hemodynamic performance and durability similar to uncoated materials, combined with a greater thromboresistance, both in vitro and in animal studies.
With these promising advances, bioactive surface coated prosthetic heart valves could replace previous generation of prosthetic valves in the near future. The utmost perspective of the current project paves the way for the development of new bioactive coating for other implantable cardiovascular devices or materials.
Max ERC Funding
2 367 055 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym TransMID
Project Translational and Transdisciplinary research in Modeling Infectious Diseases
Researcher (PI) Niel Hens
Host Institution (HI) UNIVERSITEIT HASSELT
Call Details Consolidator Grant (CoG), LS7, ERC-2015-CoG
Summary TransMID focuses on the development of novel methods to estimate key epidemiological parameters from both serological and social contact data, with the aim to significantly expand the range of public health questions that can be adequately addressed using such data. Using new statistical and mathematical theory and newly collected as well as readily available serological and social contact data (mainly from Europe), fundamental mathematical and epidemiological challenges as outlined in the following work packages will be addressed: (a) frequency and density dependent mass action relating potential effective contacts to transmission dynamics in (sub)populations of different sizes with an empirical assessment using readily available contact data, (b) behavioural and temporal variations in contact patterns and their impact on the dynamics of infectious diseases, (c) close contact household networks and the assumption of homogeneous mixing within households, (d) estimating parameters from multivariate and serial cross-sectional serological data taking temporal effects and heterogeneity in acquisition into account in combination with the use of social contact data, and (e) finally the design of sero- and social contact surveys with specific focus on serial cross-sectional surveys. TransMID is transdisciplinary in nature with applications on diseases of major public health interest, such as pertussis, cytomegalovirus and measles. Translational methodology is placed at the heart of TransMID resulting in the development of a unifying methodology for other diseases and settings. The development of a toolbox and accompanying software allow easy and effective application of these fundamentally improved techniques on many infectious diseases and in different geographic contexts, which should maximize TransMID’s impact on public health in Europe and beyond.
Summary
TransMID focuses on the development of novel methods to estimate key epidemiological parameters from both serological and social contact data, with the aim to significantly expand the range of public health questions that can be adequately addressed using such data. Using new statistical and mathematical theory and newly collected as well as readily available serological and social contact data (mainly from Europe), fundamental mathematical and epidemiological challenges as outlined in the following work packages will be addressed: (a) frequency and density dependent mass action relating potential effective contacts to transmission dynamics in (sub)populations of different sizes with an empirical assessment using readily available contact data, (b) behavioural and temporal variations in contact patterns and their impact on the dynamics of infectious diseases, (c) close contact household networks and the assumption of homogeneous mixing within households, (d) estimating parameters from multivariate and serial cross-sectional serological data taking temporal effects and heterogeneity in acquisition into account in combination with the use of social contact data, and (e) finally the design of sero- and social contact surveys with specific focus on serial cross-sectional surveys. TransMID is transdisciplinary in nature with applications on diseases of major public health interest, such as pertussis, cytomegalovirus and measles. Translational methodology is placed at the heart of TransMID resulting in the development of a unifying methodology for other diseases and settings. The development of a toolbox and accompanying software allow easy and effective application of these fundamentally improved techniques on many infectious diseases and in different geographic contexts, which should maximize TransMID’s impact on public health in Europe and beyond.
Max ERC Funding
1 639 168 €
Duration
Start date: 2016-10-01, End date: 2021-09-30
