Project acronym ABC
Project Targeting Multidrug Resistant Cancer
Researcher (PI) Gergely Szakacs
Host Institution (HI) MAGYAR TUDOMANYOS AKADEMIA TERMESZETTUDOMANYI KUTATOKOZPONT
Call Details Starting Grant (StG), LS7, ERC-2010-StG_20091118
Summary Despite considerable advances in drug discovery, resistance to anticancer chemotherapy confounds the effective treatment of patients. Cancer cells can acquire broad cross-resistance to mechanistically and structurally unrelated drugs. P-glycoprotein (Pgp) actively extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. The central tenet of my work is that Pgp, a universally accepted biomarker of drug resistance, should in addition be considered as a molecular target of multidrug-resistant (MDR) cancer cells. Successful targeting of MDR cells would reduce the tumor burden and would also enable the elimination of ABC transporter-overexpressing cancer stem cells that are responsible for the replenishment of tumors. The proposed project is based on the following observations:
- First, by using a pharmacogenomic approach, I have revealed the hidden vulnerability of MDRcells (Szakács et al. 2004, Cancer Cell 6, 129-37);
- Second, I have identified a series of MDR-selective compounds with increased toxicity toPgp-expressing cells
(Turk et al.,Cancer Res, 2009. 69(21));
- Third, I have shown that MDR-selective compounds can be used to prevent theemergence of MDR (Ludwig, Szakács et al. 2006, Cancer Res 66, 4808-15);
- Fourth, we have generated initial pharmacophore models for cytotoxicity and MDR-selectivity (Hall et al. 2009, J Med Chem 52, 3191-3204).
I propose a comprehensive series of studies that will address thefollowing critical questions:
- First, what is the scope of MDR-selective compounds?
- Second, what is their mechanism of action?
- Third, what is the optimal therapeutic modality?
Extensive biological, pharmacological and bioinformatic analyses will be utilized to address four major specific aims. These aims address basic questions concerning the physiology of MDR ABC transporters in determining the mechanism of action of MDR-selective compounds, setting the stage for a fresh therapeutic approach that may eventually translate into improved patient care.
Summary
Despite considerable advances in drug discovery, resistance to anticancer chemotherapy confounds the effective treatment of patients. Cancer cells can acquire broad cross-resistance to mechanistically and structurally unrelated drugs. P-glycoprotein (Pgp) actively extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. The central tenet of my work is that Pgp, a universally accepted biomarker of drug resistance, should in addition be considered as a molecular target of multidrug-resistant (MDR) cancer cells. Successful targeting of MDR cells would reduce the tumor burden and would also enable the elimination of ABC transporter-overexpressing cancer stem cells that are responsible for the replenishment of tumors. The proposed project is based on the following observations:
- First, by using a pharmacogenomic approach, I have revealed the hidden vulnerability of MDRcells (Szakács et al. 2004, Cancer Cell 6, 129-37);
- Second, I have identified a series of MDR-selective compounds with increased toxicity toPgp-expressing cells
(Turk et al.,Cancer Res, 2009. 69(21));
- Third, I have shown that MDR-selective compounds can be used to prevent theemergence of MDR (Ludwig, Szakács et al. 2006, Cancer Res 66, 4808-15);
- Fourth, we have generated initial pharmacophore models for cytotoxicity and MDR-selectivity (Hall et al. 2009, J Med Chem 52, 3191-3204).
I propose a comprehensive series of studies that will address thefollowing critical questions:
- First, what is the scope of MDR-selective compounds?
- Second, what is their mechanism of action?
- Third, what is the optimal therapeutic modality?
Extensive biological, pharmacological and bioinformatic analyses will be utilized to address four major specific aims. These aims address basic questions concerning the physiology of MDR ABC transporters in determining the mechanism of action of MDR-selective compounds, setting the stage for a fresh therapeutic approach that may eventually translate into improved patient care.
Max ERC Funding
1 499 640 €
Duration
Start date: 2012-01-01, End date: 2016-12-31
Project acronym CosNeD
Project Radio wave propagation in heterogeneous media: implications on the electronics of Cosmic Neutrino Detectors
Researcher (PI) Alina Mihaela BADESCU
Host Institution (HI) UNIVERSITATEA POLITEHNICA DIN BUCURESTI
Call Details Starting Grant (StG), PE7, ERC-2016-STG
Summary Detection of cosmic neutrinos can answer very important questions related to some extremely energetic yet unexplained astrophysical sources such as: compact binary stars, accreting black holes, supernovae etc., key elements in understanding the evolution and fate of the Universe. Moreover, these particles carry the highest
energies per particle known to man, impossible to achieve in any present or foreseen man made accelerator devices thus their detection can test and probe extreme high energy physics.
One of the newest techniques for measuring high energy cosmic neutrinos regards their radio detection in natural salt mines. A first and essential step is to determine experimentally the radio wave attenuation length in salt mines, and this will represent the main goal of this project. The results shall be used to estimate the implications on the construction of the detector. The outcome of this project may rejuvenate the radio detection in salt technique and be a compelling case for Romanian involvement. The same measurements can be used: to validate and improve previous work on theoretical simulation models of propagation in heterogeneous media –a regime not very well understood (which represents another goal of the project), and to study the behavior of classical antennas in non-conventional media (the third major goal).
The results to be obtained would be immediately relevant in determination of the key parameters that describe a cosmic neutrino detector, its performances and limitations. The events detected by such a telescope will allow identification of individual sources indicating a step forward in “neutrino astronomy”. The extensive propagation and antenna behavior studies in heterogeneous media will be in the direct interest for the scientific community and have a prompt impact in telecommunications theory and industry.
Summary
Detection of cosmic neutrinos can answer very important questions related to some extremely energetic yet unexplained astrophysical sources such as: compact binary stars, accreting black holes, supernovae etc., key elements in understanding the evolution and fate of the Universe. Moreover, these particles carry the highest
energies per particle known to man, impossible to achieve in any present or foreseen man made accelerator devices thus their detection can test and probe extreme high energy physics.
One of the newest techniques for measuring high energy cosmic neutrinos regards their radio detection in natural salt mines. A first and essential step is to determine experimentally the radio wave attenuation length in salt mines, and this will represent the main goal of this project. The results shall be used to estimate the implications on the construction of the detector. The outcome of this project may rejuvenate the radio detection in salt technique and be a compelling case for Romanian involvement. The same measurements can be used: to validate and improve previous work on theoretical simulation models of propagation in heterogeneous media –a regime not very well understood (which represents another goal of the project), and to study the behavior of classical antennas in non-conventional media (the third major goal).
The results to be obtained would be immediately relevant in determination of the key parameters that describe a cosmic neutrino detector, its performances and limitations. The events detected by such a telescope will allow identification of individual sources indicating a step forward in “neutrino astronomy”. The extensive propagation and antenna behavior studies in heterogeneous media will be in the direct interest for the scientific community and have a prompt impact in telecommunications theory and industry.
Max ERC Funding
185 925 €
Duration
Start date: 2016-11-01, End date: 2018-10-31
Project acronym EPIDELAY
Project Delay differential models and transmission dynamics of infectious diseases
Researcher (PI) Gergely Röst
Host Institution (HI) SZEGEDI TUDOMANYEGYETEM
Call Details Starting Grant (StG), PE1, ERC-2010-StG_20091028
Summary The aim of this project is to develop and analyse infinite dimensional dynamical models for the transmission dynamics and propagation of infectious diseases. We use an integrated approach which spans from the abstract theory of functional differential equations to the practical problems of epidemiology, with serious implications to public health policy, prevention, control and mitigation strategies in cases such as the ongoing battle against the nascent H1N1 pandemic.
Delay differential equations are one of the most powerful mathematical modeling tools and they arise naturally in various applications from life sciences to engineering and physics, whenever temporal delays are important. In abstract terms, functional differential equations describe dynamical systems, when their evolution depends on the solution at prior times.
The central theme of this project is to forge strong links between the abstract theory of delay differential equations and practical aspects of epidemiology. Our research will combine competencies in different fields of mathematics and embrace theoretical issues as well as real life applications.
In particular, the theory of equations with state dependent delays is extremely challenging, and this field is at present on the verge of a breakthrough. Developing new theories in this area and connecting them to relevant applications would go far beyond the current research frontier of mathematical epidemiology and could open a new chapter in disease modeling.
Summary
The aim of this project is to develop and analyse infinite dimensional dynamical models for the transmission dynamics and propagation of infectious diseases. We use an integrated approach which spans from the abstract theory of functional differential equations to the practical problems of epidemiology, with serious implications to public health policy, prevention, control and mitigation strategies in cases such as the ongoing battle against the nascent H1N1 pandemic.
Delay differential equations are one of the most powerful mathematical modeling tools and they arise naturally in various applications from life sciences to engineering and physics, whenever temporal delays are important. In abstract terms, functional differential equations describe dynamical systems, when their evolution depends on the solution at prior times.
The central theme of this project is to forge strong links between the abstract theory of delay differential equations and practical aspects of epidemiology. Our research will combine competencies in different fields of mathematics and embrace theoretical issues as well as real life applications.
In particular, the theory of equations with state dependent delays is extremely challenging, and this field is at present on the verge of a breakthrough. Developing new theories in this area and connecting them to relevant applications would go far beyond the current research frontier of mathematical epidemiology and could open a new chapter in disease modeling.
Max ERC Funding
796 800 €
Duration
Start date: 2011-05-01, End date: 2016-12-31
Project acronym MGUS screening RCT
Project Screening for monoclonal gammopathy of undetermined significance: A population-based randomized clinical trial
Researcher (PI) Sigurdur Yngvi KRISTINSSON
Host Institution (HI) HASKOLI ISLANDS
Call Details Starting Grant (StG), LS7, ERC-2016-STG
Summary Monoclonal gammopathy of undetermined significance (MGUS) is a very common precursor condition to multiple myeloma (MM), and related diseases, and can be found in approximately 4-5% of individuals over the age of 50 years. MM is always preceded by MGUS. Current risk stratification schemes, designed to predict those that will progress, are based on retrospective data and rely almost solely on serum protein markers. While they can differentiate high and low-risk patients, they cannot predict outcome for individual patients, are not integrated with one another, and have limited biological correlation. Based on retrospective data, it is recommended that individuals with MGUS are followed indefinitely; however no prospective study has ever been performed to evaluate this or identify optimal monitoring in MGUS individuals. We recently showed that MM patients with a prior knowledge of MGUS had superior survival compared to MM patients without, which raises the question whether routine screening for MGUS in the population might improve survival. To evaluate the impact of screening for MGUS on overall survival, to provide evidence for the optimal MGUS follow-up, and to integrate biological, imaging, and germline genetic markers in evaluating individual risk of progression, we propose to invite all individuals >50 years in Iceland (N=104,000) to participate in a screening study for MGUS. This will be done by utilizing already present infrastructure for screening in Iceland and the fact that most individuals >50 years have their blood drawn for various reasons during 3 years. We plan to perform electrophoresis and free light chain analyses in these individuals to diagnose MGUS. Individuals with MGUS will be invited to be included in a randomized clinical trial with 3 different arms to identify the optimal work-up and follow-up strategy and to build a new risk model for progression. Our large, unique, population-based study has major clinical and scientific implications.
Summary
Monoclonal gammopathy of undetermined significance (MGUS) is a very common precursor condition to multiple myeloma (MM), and related diseases, and can be found in approximately 4-5% of individuals over the age of 50 years. MM is always preceded by MGUS. Current risk stratification schemes, designed to predict those that will progress, are based on retrospective data and rely almost solely on serum protein markers. While they can differentiate high and low-risk patients, they cannot predict outcome for individual patients, are not integrated with one another, and have limited biological correlation. Based on retrospective data, it is recommended that individuals with MGUS are followed indefinitely; however no prospective study has ever been performed to evaluate this or identify optimal monitoring in MGUS individuals. We recently showed that MM patients with a prior knowledge of MGUS had superior survival compared to MM patients without, which raises the question whether routine screening for MGUS in the population might improve survival. To evaluate the impact of screening for MGUS on overall survival, to provide evidence for the optimal MGUS follow-up, and to integrate biological, imaging, and germline genetic markers in evaluating individual risk of progression, we propose to invite all individuals >50 years in Iceland (N=104,000) to participate in a screening study for MGUS. This will be done by utilizing already present infrastructure for screening in Iceland and the fact that most individuals >50 years have their blood drawn for various reasons during 3 years. We plan to perform electrophoresis and free light chain analyses in these individuals to diagnose MGUS. Individuals with MGUS will be invited to be included in a randomized clinical trial with 3 different arms to identify the optimal work-up and follow-up strategy and to build a new risk model for progression. Our large, unique, population-based study has major clinical and scientific implications.
Max ERC Funding
1 474 304 €
Duration
Start date: 2017-02-01, End date: 2022-01-31
