Project acronym ANGIOFAT
Project New mechanisms of angiogenesis modulators in switching between white and brown adipose tissues
Researcher (PI) Yihai Cao
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Advanced Grant (AdG), LS4, ERC-2009-AdG
Summary Understanding the molecular mechanisms underlying adipose blood vessel growth or regression opens new fundamentally insight into novel therapeutic options for the treatment of obesity and its related metabolic diseases such as type 2 diabetes and cancer. Unlike any other tissues in the body, the adipose tissue constantly experiences expansion and shrinkage throughout the adult life. Adipocytes in the white adipose tissue have the ability to switch into metabolically highly active brown-like adipocytes. Brown adipose tissue (BAT) contains significantly higher numbers of microvessels than white adipose tissue (WAT) in order to adopt the high rates of metabolism. Thus, an angiogenic phenotype has to be switched on during the transition from WAT into BAT. We have found that acclimation of mice in cold could induce transition from inguinal and epidedymal WAT into BAT by upregulation of angiogenic factor expression and down-regulations of angiogenesis inhibitors (Xue et al, Cell Metabolism, 2009). The transition from WAT into BAT is dependent on vascular endothelial growth factor (VEGF) that primarily targets on vascular endothelial cells via a tissue hypoxia-independent mechanism. VEGF blockade significantly alters adipose tissue metabolism. In another genetic model, we show similar findings that angiogenesis is crucial to mediate the transition from WAT into BAT (Xue et al, PNAS, 2008). Here we propose that the vascular tone determines the metabolic switch between WAT and BAT. Characterization of these novel angiogenic pathways may reveal new mechanisms underlying development of obesity- and metabolism-related disease complications and may define novel therapeutic targets. Thus, the benefit of this research proposal is enormous and is aimed to treat the most common and highly risk human health conditions in the modern time.
Summary
Understanding the molecular mechanisms underlying adipose blood vessel growth or regression opens new fundamentally insight into novel therapeutic options for the treatment of obesity and its related metabolic diseases such as type 2 diabetes and cancer. Unlike any other tissues in the body, the adipose tissue constantly experiences expansion and shrinkage throughout the adult life. Adipocytes in the white adipose tissue have the ability to switch into metabolically highly active brown-like adipocytes. Brown adipose tissue (BAT) contains significantly higher numbers of microvessels than white adipose tissue (WAT) in order to adopt the high rates of metabolism. Thus, an angiogenic phenotype has to be switched on during the transition from WAT into BAT. We have found that acclimation of mice in cold could induce transition from inguinal and epidedymal WAT into BAT by upregulation of angiogenic factor expression and down-regulations of angiogenesis inhibitors (Xue et al, Cell Metabolism, 2009). The transition from WAT into BAT is dependent on vascular endothelial growth factor (VEGF) that primarily targets on vascular endothelial cells via a tissue hypoxia-independent mechanism. VEGF blockade significantly alters adipose tissue metabolism. In another genetic model, we show similar findings that angiogenesis is crucial to mediate the transition from WAT into BAT (Xue et al, PNAS, 2008). Here we propose that the vascular tone determines the metabolic switch between WAT and BAT. Characterization of these novel angiogenic pathways may reveal new mechanisms underlying development of obesity- and metabolism-related disease complications and may define novel therapeutic targets. Thus, the benefit of this research proposal is enormous and is aimed to treat the most common and highly risk human health conditions in the modern time.
Max ERC Funding
2 411 547 €
Duration
Start date: 2010-03-01, End date: 2015-02-28
Project acronym ATHEROPROTECT
Project Structure-Function Analysis of the Chemokine Interactome for Therapeutic Targeting and Imaging in Atherosclerosis
Researcher (PI) Christian Weber
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Advanced Grant (AdG), LS4, ERC-2009-AdG
Summary Atherosclerosis is characterized by chronic inflammation of the arterial wall. Mononuclear cell recruitment is driven by chemokines that can be deposited e.g. by activated platelets on inflamed endothelium. Chemokines require oligomerization and immobilization for efficient function, and recent evidence supports the notion that heterodimer formation between chemokines constitutes a new regulatory principle amplifying specific chemokine activities while suppressing others. Although crucial to inflammatory disease, this has been difficult to prove in vivo, primarily as chemokine heterodimers exist in equilibrium with their homodimer counterparts. We introduce the paradigm that heteromerization of chemokines provides the combinatorial diversity for functional plasticity and fine-tuning, coining this interactome. Given the relevance of chemokine heteromers in vivo, we aim to exploit this in an anti-inflammatory approach to selectively target vascular disease. In a multidisciplinary project, we plan to generate covalently-linked heterodimers to establish their biological significance. Obligate heterodimers of CC and CXC chemokines will be designed using computer-assisted modeling, chemically synthesized and cross-linked, structurally assessed using NMR spectroscopy and crystallography, and subjected to functional characterization in vitro and reconstitution in vivo. Conversely, we will develop cyclic beta-sheet-based peptides binding chemokines to specifically disrupt heteromers and we will generate mice with conditional deletion or knock-in of chemokine mutants with defects in heteromerization or proteoglycan binding to be analyzed in models of atherosclerosis. Peptides will be used for molecular imaging and chemokine heteromers will be quantified in cardiovascular patients.
Summary
Atherosclerosis is characterized by chronic inflammation of the arterial wall. Mononuclear cell recruitment is driven by chemokines that can be deposited e.g. by activated platelets on inflamed endothelium. Chemokines require oligomerization and immobilization for efficient function, and recent evidence supports the notion that heterodimer formation between chemokines constitutes a new regulatory principle amplifying specific chemokine activities while suppressing others. Although crucial to inflammatory disease, this has been difficult to prove in vivo, primarily as chemokine heterodimers exist in equilibrium with their homodimer counterparts. We introduce the paradigm that heteromerization of chemokines provides the combinatorial diversity for functional plasticity and fine-tuning, coining this interactome. Given the relevance of chemokine heteromers in vivo, we aim to exploit this in an anti-inflammatory approach to selectively target vascular disease. In a multidisciplinary project, we plan to generate covalently-linked heterodimers to establish their biological significance. Obligate heterodimers of CC and CXC chemokines will be designed using computer-assisted modeling, chemically synthesized and cross-linked, structurally assessed using NMR spectroscopy and crystallography, and subjected to functional characterization in vitro and reconstitution in vivo. Conversely, we will develop cyclic beta-sheet-based peptides binding chemokines to specifically disrupt heteromers and we will generate mice with conditional deletion or knock-in of chemokine mutants with defects in heteromerization or proteoglycan binding to be analyzed in models of atherosclerosis. Peptides will be used for molecular imaging and chemokine heteromers will be quantified in cardiovascular patients.
Max ERC Funding
2 500 000 €
Duration
Start date: 2010-04-01, End date: 2016-03-31
Project acronym ER_PARTNERS
Project Chromatin Mediators of Estrogen Receptor Biology
Researcher (PI) Jason Scott Carroll
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARSOF THE UNIVERSITY OF CAMBRIDGE
Call Details Starting Grant (StG), LS4, ERC-2009-StG
Summary Estrogen Receptor (ER) drives proliferation in breast cancers and drugs such as tamoxifen and Aromatase Inhibitors, that target ER activity, are first line treatments in clinical practice. However drug resistance is a significant clinical problem. My laboratory has reported that chromatin-modifying pioneer factors are required for ER to bind the genome, and may constitute a unique opportunity for treating drug resistant cancer. My proposal consists of two complementary approaches to comprehensively explore how Estrogen Receptor interacts with these factors to direct transcription. (1) We will demonstrate that FoxA1 and the Groucho protein TLE1 are critical mediators of ER-chromatin interactions by mapping TLE1 binding sites on a genome-wide basis, and functionally testing the roles these factors play with ER in genomic remodeling, gene transcription, cell proliferation, and endocrine resistance. (2) More globally, to characterise ER transcriptional partners on a molecular basis, we will identify the complete complement of ER-associated proteins using novel proteomic approaches. Taken together, these approaches will explore how ER employs pioneer factors mechanistically, and will identify other potential players.
Summary
Estrogen Receptor (ER) drives proliferation in breast cancers and drugs such as tamoxifen and Aromatase Inhibitors, that target ER activity, are first line treatments in clinical practice. However drug resistance is a significant clinical problem. My laboratory has reported that chromatin-modifying pioneer factors are required for ER to bind the genome, and may constitute a unique opportunity for treating drug resistant cancer. My proposal consists of two complementary approaches to comprehensively explore how Estrogen Receptor interacts with these factors to direct transcription. (1) We will demonstrate that FoxA1 and the Groucho protein TLE1 are critical mediators of ER-chromatin interactions by mapping TLE1 binding sites on a genome-wide basis, and functionally testing the roles these factors play with ER in genomic remodeling, gene transcription, cell proliferation, and endocrine resistance. (2) More globally, to characterise ER transcriptional partners on a molecular basis, we will identify the complete complement of ER-associated proteins using novel proteomic approaches. Taken together, these approaches will explore how ER employs pioneer factors mechanistically, and will identify other potential players.
Max ERC Funding
1 500 345 €
Duration
Start date: 2009-10-01, End date: 2014-09-30
Project acronym LUNELY
Project ALK as a common target for the pathogenesis and therapy in lymphoma, lung carcinoma and neuroblastoma
Researcher (PI) Roberto Chiarle
Host Institution (HI) UNIVERSITA DEGLI STUDI DI TORINO
Call Details Starting Grant (StG), LS4, ERC-2009-StG
Summary The Anaplastic Lymphoma Kinase (ALK) has been discovered as the result of chromosomal translocations in Anaplastic Large Cell Lymphomas (ALCL) (Chiarle et al Nat Rev Cancer. 2008, 8:11). In ALCL, the role of the ALK oncogenic translocations has been established in vitro and in transgenic mouse models. Recent findings have shown ALK translocations, mutations or amplifications in other types of solid cancers, such as lung carcinoma (Soda et al. Nature. 2007, 448:561) and neuroblastoma (Mossè et al. Nature 2008, 455: 930). However, the role of ALK gene mutations in these solid tumours remains largely undetermined. This lack of knowledge is even worse given the fact that a therapy that targets ALK in these tumours could be feasible. Aim 1. Targeting of ALK in ALCL lymphomas. ALCL ALK positive lymphomas will be tested for small molecule inhibitors of the activity of ALK. In addition, a combination of gene silencing, such as small interfering RNA (siRNA), and vaccination against ALK will be validated as selective ALK therapies. Aim 2. Characterization of the role of ALK in lung cancer through the generation of mouse models. We propose to characterize the pathogenetic role of ALK in lung cancer by in vitro studies and by generating mouse models for ALK positive lung cancers. These mouse models will be fundamental to validate the innovative therapies against ALK positive lung carcinoma. Aim 3. Validation of ALK as an oncogene and a therapeutic target in neuroblastoma. We plan to develop mouse models of neuroblastoma to investigate the pathogenetic role of ALK in the onset and maintenance of neuroblastoma in vivo. These mouse model of neuroblastoma will be used for the validation of ALK specific therapies. Overall, the proposed project will define the role of ALK in lymphoma, neuroblastoma and lungcancer and validate its potential use as a a target for therapy in those tumours. The impact of these novel therapies will be of great value in these deadly tumours.
Summary
The Anaplastic Lymphoma Kinase (ALK) has been discovered as the result of chromosomal translocations in Anaplastic Large Cell Lymphomas (ALCL) (Chiarle et al Nat Rev Cancer. 2008, 8:11). In ALCL, the role of the ALK oncogenic translocations has been established in vitro and in transgenic mouse models. Recent findings have shown ALK translocations, mutations or amplifications in other types of solid cancers, such as lung carcinoma (Soda et al. Nature. 2007, 448:561) and neuroblastoma (Mossè et al. Nature 2008, 455: 930). However, the role of ALK gene mutations in these solid tumours remains largely undetermined. This lack of knowledge is even worse given the fact that a therapy that targets ALK in these tumours could be feasible. Aim 1. Targeting of ALK in ALCL lymphomas. ALCL ALK positive lymphomas will be tested for small molecule inhibitors of the activity of ALK. In addition, a combination of gene silencing, such as small interfering RNA (siRNA), and vaccination against ALK will be validated as selective ALK therapies. Aim 2. Characterization of the role of ALK in lung cancer through the generation of mouse models. We propose to characterize the pathogenetic role of ALK in lung cancer by in vitro studies and by generating mouse models for ALK positive lung cancers. These mouse models will be fundamental to validate the innovative therapies against ALK positive lung carcinoma. Aim 3. Validation of ALK as an oncogene and a therapeutic target in neuroblastoma. We plan to develop mouse models of neuroblastoma to investigate the pathogenetic role of ALK in the onset and maintenance of neuroblastoma in vivo. These mouse model of neuroblastoma will be used for the validation of ALK specific therapies. Overall, the proposed project will define the role of ALK in lymphoma, neuroblastoma and lungcancer and validate its potential use as a a target for therapy in those tumours. The impact of these novel therapies will be of great value in these deadly tumours.
Max ERC Funding
1 010 000 €
Duration
Start date: 2009-11-01, End date: 2014-04-30
Project acronym METABOLOMIRS
Project Elucidation of MicroRNAs as Regulators of Metabolism and Targets for Therapeutic Intervention
Researcher (PI) Markus Stoffel
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Call Details Advanced Grant (AdG), LS4, ERC-2009-AdG
Summary Small RNA-mediated regulation of gene expression is a recent addition to fundamental gene regulatory mechanisms that directly or indirectly affect possibly every gene of a eukaryotic genome. The predominant sources of small RNA in somatic tissues are microRNA genes that encode short dsRNA hairpins of evolutionary conserved sequence. Disorders of metabolism, such as obesity and type 2 diabetes are poorly understood at a molecular level. In this application we propose to explore if miRNA regulatory networks play a role in these diseases. We will employ state of the art methods for identification of small RNAs and their regulated targets and use biochemical, cell and animal model systems to study the detailed molecular mechanisms of metabolic gene regulation by miRNAs. In addition, we will investigate the underlying principles of how RNAs are taken up by cells and develop methods that will improve delivery of miRNA mimetics or inhibitors through cell-specific uptake. The specific aims of this study are: Aim 1: To define the small regulatory miRNA content of liver, muscle and adipose tissue that are associated with abnormal glucose and lipid homeostasis and to dissect the underlying molecular pathways that govern their expression. Aim 2: To characterize the functions of miRNAs in insulin resistance, glucose uptake and production, fatty acid oxidation and lipogenesis. Aim 3: To identify factors and dissect the pathways that regulate RNA uptake by cells and to develop novel pharmacological treatment strategies to manipulate miRNA-expression. Together, this proposal will shed light on the function that miRNA regulatory networks play in metabolism and in the pathophysiology of obesity/type 2 diabetes. In addition, these studies will contribute to the development of new RNA delivery technologies that are urgently needed as experimental tools as well as for novel therapeutic strategies.
Summary
Small RNA-mediated regulation of gene expression is a recent addition to fundamental gene regulatory mechanisms that directly or indirectly affect possibly every gene of a eukaryotic genome. The predominant sources of small RNA in somatic tissues are microRNA genes that encode short dsRNA hairpins of evolutionary conserved sequence. Disorders of metabolism, such as obesity and type 2 diabetes are poorly understood at a molecular level. In this application we propose to explore if miRNA regulatory networks play a role in these diseases. We will employ state of the art methods for identification of small RNAs and their regulated targets and use biochemical, cell and animal model systems to study the detailed molecular mechanisms of metabolic gene regulation by miRNAs. In addition, we will investigate the underlying principles of how RNAs are taken up by cells and develop methods that will improve delivery of miRNA mimetics or inhibitors through cell-specific uptake. The specific aims of this study are: Aim 1: To define the small regulatory miRNA content of liver, muscle and adipose tissue that are associated with abnormal glucose and lipid homeostasis and to dissect the underlying molecular pathways that govern their expression. Aim 2: To characterize the functions of miRNAs in insulin resistance, glucose uptake and production, fatty acid oxidation and lipogenesis. Aim 3: To identify factors and dissect the pathways that regulate RNA uptake by cells and to develop novel pharmacological treatment strategies to manipulate miRNA-expression. Together, this proposal will shed light on the function that miRNA regulatory networks play in metabolism and in the pathophysiology of obesity/type 2 diabetes. In addition, these studies will contribute to the development of new RNA delivery technologies that are urgently needed as experimental tools as well as for novel therapeutic strategies.
Max ERC Funding
2 021 235 €
Duration
Start date: 2010-07-01, End date: 2015-06-30
Project acronym MORPHOSTASIS
Project Morphostasis of the intestinal mucosa and it's deregulation in cancer and inflammation
Researcher (PI) Gijs Van Den Brink
Host Institution (HI) ACADEMISCH MEDISCH CENTRUM BIJ DE UNIVERSITEIT VAN AMSTERDAM
Call Details Starting Grant (StG), LS4, ERC-2009-StG
Summary Stem cells at the base of the intestinal crypts are in a dynamic equilibrium with their differentiated derivatives. Homeostatic equilibria depend on the presence of negative feedback loops. The role of the Wnt signaling pathway as a driver of epithelial stem cell self renewal and proliferation in the intestine has been relatively well characterized. Much less is known about the negative feedback signals that must exist to control stem cell behavior and the way these may be deregulated in disease. We found that Indian hedgehog is secreted by differentiated intestinal epithelial cells and acts as a negative feedback signal. Hedgehog signaling acts as a break on Wnt signaling in intestinal precursor cells via a secondary signal in the mesenchyme. We will use conditional mutant mice, our large biobank of patient materials and in vitro experiments to further characterize the signals involved in this feedback loop. Our objective is to study the role of this epithelial mesenchymal signaling circuit in the normal intestine and examine the way it is deregulated in intestinal cancer development and inflammation.
Summary
Stem cells at the base of the intestinal crypts are in a dynamic equilibrium with their differentiated derivatives. Homeostatic equilibria depend on the presence of negative feedback loops. The role of the Wnt signaling pathway as a driver of epithelial stem cell self renewal and proliferation in the intestine has been relatively well characterized. Much less is known about the negative feedback signals that must exist to control stem cell behavior and the way these may be deregulated in disease. We found that Indian hedgehog is secreted by differentiated intestinal epithelial cells and acts as a negative feedback signal. Hedgehog signaling acts as a break on Wnt signaling in intestinal precursor cells via a secondary signal in the mesenchyme. We will use conditional mutant mice, our large biobank of patient materials and in vitro experiments to further characterize the signals involved in this feedback loop. Our objective is to study the role of this epithelial mesenchymal signaling circuit in the normal intestine and examine the way it is deregulated in intestinal cancer development and inflammation.
Max ERC Funding
1 524 462 €
Duration
Start date: 2009-10-01, End date: 2014-09-30
Project acronym NEUROAGE
Project From Environment to Physiology: Neuroendocrine Circuits and Genetic Mechanisms that Modulate Ageing and Development
Researcher (PI) Queelim Ch'ng
Host Institution (HI) KING'S COLLEGE LONDON
Call Details Starting Grant (StG), LS4, ERC-2009-StG
Summary We seek to understand how organisms interpret complex environments to generate appropriate changes in their physiology. Specifically, we will focus on how food and temperature affect lifespan and a switch between reproductive growth versus a specialised developmental arrest (dauer) in C. elegans. Extensive work has indicated that the daf-2 insulin-like peptide (ILP) receptor plays a pivotal role in these processes, but key questions remain about how environmental inputs are linked to secretion of relevant ILP ligands. We propose to address these questions using a quantitative approach. We will use new tools to measure and manipulate the activity of neuroendocrine circuits, and exploit new technologies for automated microscopy of live C. elegans. First, we will delineate the neuroendocrine circuit by identifying ILPs, neurons and the type of neurosecretory activity that affects lifespan and dauer development. Second, we will detail how environmental information is transduced, by measuring the magnitude, kinetics and duration of environment-responsive expression of ILPs and other genes in specific neurons. Using gene expression as a new functional readout for neuroendocrine activity, we will determine how environmental, neuronal and genetic inputs regulate the activity of this neuroendocrine circuit. Third, we will address how environmental, neuronal and genetic inputs affect ILP secretion to influence lifespan and development. By combining quantitative analysis of environmental responses, neuroendocrine activity and physiological outcomes, we will determine how environmental inputs are linked to dauer development and lifespan. This integrated in vivo approach is currently only feasible in simple organisms such as C. elegans.
Summary
We seek to understand how organisms interpret complex environments to generate appropriate changes in their physiology. Specifically, we will focus on how food and temperature affect lifespan and a switch between reproductive growth versus a specialised developmental arrest (dauer) in C. elegans. Extensive work has indicated that the daf-2 insulin-like peptide (ILP) receptor plays a pivotal role in these processes, but key questions remain about how environmental inputs are linked to secretion of relevant ILP ligands. We propose to address these questions using a quantitative approach. We will use new tools to measure and manipulate the activity of neuroendocrine circuits, and exploit new technologies for automated microscopy of live C. elegans. First, we will delineate the neuroendocrine circuit by identifying ILPs, neurons and the type of neurosecretory activity that affects lifespan and dauer development. Second, we will detail how environmental information is transduced, by measuring the magnitude, kinetics and duration of environment-responsive expression of ILPs and other genes in specific neurons. Using gene expression as a new functional readout for neuroendocrine activity, we will determine how environmental, neuronal and genetic inputs regulate the activity of this neuroendocrine circuit. Third, we will address how environmental, neuronal and genetic inputs affect ILP secretion to influence lifespan and development. By combining quantitative analysis of environmental responses, neuroendocrine activity and physiological outcomes, we will determine how environmental inputs are linked to dauer development and lifespan. This integrated in vivo approach is currently only feasible in simple organisms such as C. elegans.
Max ERC Funding
1 501 957 €
Duration
Start date: 2009-10-01, End date: 2014-09-30
Project acronym OVER-HER2
Project OVErcoming Resistance to anti-HER2 therapy
Researcher (PI) Jose Manuel Baselga Torres
Host Institution (HI) FUNDACIO PRIVADA INSTITUT D'INVESTIGACIO ONCOLOGICA DE VALL-HEBRON
Call Details Advanced Grant (AdG), LS4, ERC-2009-AdG
Summary HER2 is a membrane receptor tyrosine kinase overexpressed in 30% of breast tumors and results in an aggressive clinical course. Anti-HER2 therapies including monoclonal antibodies (trastuzumab) and small-molecule tyrosine kinase inhibitors (lapatinib) are active and have improved survival of patients with HER2 overexpressing breast cancer. However, the emergence of primary or acquired resistance to these agents limits their efficacy. We have previously identified mechanisms of resistance to anti-HER2 therapies such as the co-expression of a truncated form of HER2 that correlates with trastuzumab resistance or the presence of downstream oncogenic mutations of PI3K or PTEN loss that result in resistance to lapatinib . Not surprisingly, PI3K/mTOR inhibitors overcome lapatinib resistance in the later example. Building on our results to date, this proposal is aimed at identifying novel mechanisms of resistance to anti-HER2 agents and to devise therapeutic strategies to revert it. To uncover such mechanisms, we have generated cancer cells with acquired resistance to lapatinib or trastuzumab by continuous exposure to increasing concentrations of these agents. We will perform genome wide screens, including shRNA libraries, gene expression and SNPs arrays, to discover candidate genes responsible for decreased sensitivity to anti-HER2 agents. To overcome anti-HER2 therapy resistance we will study several therapeutic strategies, such as combinations of different anti-HER2 compounds and the use of alternative agents targeting downstream/parallel pathways. Among the novel targeted therapies, we plan to study the use of PI3K, Akt, CDK2 and Hsp90 inhibitors, for which we will also start resistance-screens. It is anticipated that any promising preclinical leads will stimulate trial design and conduct for subsequent evaluation and confirmation in the clinic.
Summary
HER2 is a membrane receptor tyrosine kinase overexpressed in 30% of breast tumors and results in an aggressive clinical course. Anti-HER2 therapies including monoclonal antibodies (trastuzumab) and small-molecule tyrosine kinase inhibitors (lapatinib) are active and have improved survival of patients with HER2 overexpressing breast cancer. However, the emergence of primary or acquired resistance to these agents limits their efficacy. We have previously identified mechanisms of resistance to anti-HER2 therapies such as the co-expression of a truncated form of HER2 that correlates with trastuzumab resistance or the presence of downstream oncogenic mutations of PI3K or PTEN loss that result in resistance to lapatinib . Not surprisingly, PI3K/mTOR inhibitors overcome lapatinib resistance in the later example. Building on our results to date, this proposal is aimed at identifying novel mechanisms of resistance to anti-HER2 agents and to devise therapeutic strategies to revert it. To uncover such mechanisms, we have generated cancer cells with acquired resistance to lapatinib or trastuzumab by continuous exposure to increasing concentrations of these agents. We will perform genome wide screens, including shRNA libraries, gene expression and SNPs arrays, to discover candidate genes responsible for decreased sensitivity to anti-HER2 agents. To overcome anti-HER2 therapy resistance we will study several therapeutic strategies, such as combinations of different anti-HER2 compounds and the use of alternative agents targeting downstream/parallel pathways. Among the novel targeted therapies, we plan to study the use of PI3K, Akt, CDK2 and Hsp90 inhibitors, for which we will also start resistance-screens. It is anticipated that any promising preclinical leads will stimulate trial design and conduct for subsequent evaluation and confirmation in the clinic.
Max ERC Funding
1 666 700 €
Duration
Start date: 2011-01-01, End date: 2014-12-31
Project acronym PRECORT
Project Pre-receptor cortisol metabolism and human ageing
Researcher (PI) Paul Michael Stewart
Host Institution (HI) UNIVERSITY OF LEEDS
Call Details Advanced Grant (AdG), LS4, ERC-2009-AdG
Summary The number of people over the age of 80 years in the 25 EU member states is currently 18.2 million or 4% of the total population; by 2020, 20% of the EU population will be >65 years old which will place considerable burden upon limited health care resources. 70% of older adults report at least one chronic disease that contributes to a reduction in healthspan or the number of extra years spent in good health. The European Commission is committed to identify rational and evidence based approaches to improve health in old age and as such has identified Ageing research as a priority. The most prevalent conditions that contribute to the ageing phenotype are sarcopaenia, hypertension and cardiovascular disease, central adiposity and type 2 diabetes mellitus and osteoporosis. Here there are remarkable similarities to patients with Cushing s syndrome caused by excessive secretion of glucocortiocoids such as cortisol. PRECORT Prereceptor Cortisol metabolism and human Ageing will test the hypothesis that age-related changes in body composition (central adiposity, reduced bone and muscle mass, skin thinning) and resulting chronic disease (diabetes, osteoporosis, sarcopaenia, hypertension, cardiovascular disease) are caused by excessive glucocorticoids as a result of age-related activation of the pituitary-adrenal axis and/or increased 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1), an enzyme that can generate cortisol locally within fat, bone, muscle and skin. The proposal will complete the full cycle of translational research and will potentially offer a new therapeutic approach through selective 11b-HSD1 inhibitors to modulate the ageing phenotype thereby improving the healthspan of the Ageing EU community.
Summary
The number of people over the age of 80 years in the 25 EU member states is currently 18.2 million or 4% of the total population; by 2020, 20% of the EU population will be >65 years old which will place considerable burden upon limited health care resources. 70% of older adults report at least one chronic disease that contributes to a reduction in healthspan or the number of extra years spent in good health. The European Commission is committed to identify rational and evidence based approaches to improve health in old age and as such has identified Ageing research as a priority. The most prevalent conditions that contribute to the ageing phenotype are sarcopaenia, hypertension and cardiovascular disease, central adiposity and type 2 diabetes mellitus and osteoporosis. Here there are remarkable similarities to patients with Cushing s syndrome caused by excessive secretion of glucocortiocoids such as cortisol. PRECORT Prereceptor Cortisol metabolism and human Ageing will test the hypothesis that age-related changes in body composition (central adiposity, reduced bone and muscle mass, skin thinning) and resulting chronic disease (diabetes, osteoporosis, sarcopaenia, hypertension, cardiovascular disease) are caused by excessive glucocorticoids as a result of age-related activation of the pituitary-adrenal axis and/or increased 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1), an enzyme that can generate cortisol locally within fat, bone, muscle and skin. The proposal will complete the full cycle of translational research and will potentially offer a new therapeutic approach through selective 11b-HSD1 inhibitors to modulate the ageing phenotype thereby improving the healthspan of the Ageing EU community.
Max ERC Funding
2 499 760 €
Duration
Start date: 2010-05-01, End date: 2016-04-30
Project acronym PTPSBDC
Project The role of protein-tyrosine phosphatases in breast development and cancer
Researcher (PI) Mohamed Bentires-Alj
Host Institution (HI) FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Call Details Starting Grant (StG), LS4, ERC-2009-StG
Summary Each year 1.1 million new cases of breast cancer will occur among women worldwide and 400,000 women will die from this disease. Although progress has been made in understanding breast tumor biology, most of the relevant molecules and pathways remain undefined. Their delineation is critical to a rational approach to breast cancer therapy. This proposal focuses on the role of the under-explored family of protein-tyrosine phosphatases (PTPs) in the normal and neoplastic breast. Virtually all cell signaling pathways are modulated by reversible protein tyrosine phosphorylation, which is regulated by two classes of enzymes: protein-tyrosine kinases (PTKs) and PTPs. Not surprisingly, tyrosine phosphorylation has an important role in breast development and cancer. Whereas the role of specific PTKs, like the HER2 receptor, in breast cancer is well studied, almost nothing is known about the function of specific PTPs in this disease. Our preliminary data suggest that PTP1B has an important role in breast differentiation and that both PTP1B and SHP2 play positive roles in breast cancer. The two predominant goals of this proposal are: First, to delineate the role of PTP1B and other PTPs in normal breast development and differentiation; second, to address the roles of PTP1B and other PTPs in the maintenance of breast cancer and metastasis and to assess their merits as drug targets. These studies not only use state-of-the-art ex vivo and in vivo models for studying breast pathophysiology, but also cross the boundaries between the developmental and cancer research fields and between basic science and clinical applications. Our research should ultimately lead to the rational design of targeted therapies that will improve the clinical management of patients with breast cancer.
Summary
Each year 1.1 million new cases of breast cancer will occur among women worldwide and 400,000 women will die from this disease. Although progress has been made in understanding breast tumor biology, most of the relevant molecules and pathways remain undefined. Their delineation is critical to a rational approach to breast cancer therapy. This proposal focuses on the role of the under-explored family of protein-tyrosine phosphatases (PTPs) in the normal and neoplastic breast. Virtually all cell signaling pathways are modulated by reversible protein tyrosine phosphorylation, which is regulated by two classes of enzymes: protein-tyrosine kinases (PTKs) and PTPs. Not surprisingly, tyrosine phosphorylation has an important role in breast development and cancer. Whereas the role of specific PTKs, like the HER2 receptor, in breast cancer is well studied, almost nothing is known about the function of specific PTPs in this disease. Our preliminary data suggest that PTP1B has an important role in breast differentiation and that both PTP1B and SHP2 play positive roles in breast cancer. The two predominant goals of this proposal are: First, to delineate the role of PTP1B and other PTPs in normal breast development and differentiation; second, to address the roles of PTP1B and other PTPs in the maintenance of breast cancer and metastasis and to assess their merits as drug targets. These studies not only use state-of-the-art ex vivo and in vivo models for studying breast pathophysiology, but also cross the boundaries between the developmental and cancer research fields and between basic science and clinical applications. Our research should ultimately lead to the rational design of targeted therapies that will improve the clinical management of patients with breast cancer.
Max ERC Funding
1 571 365 €
Duration
Start date: 2010-02-01, End date: 2015-01-31
