Project acronym BEAT
Project The functional interaction of EGFR and beta-catenin signalling in colorectal cancer: Genetics, mechanisms, and therapeutic potential.
Researcher (PI) Andrea BERTOTTI
Host Institution (HI) UNIVERSITA DEGLI STUDI DI TORINO
Call Details Consolidator Grant (CoG), LS7, ERC-2016-COG
Summary Monoclonal antibodies against the EGF receptor (EGFR) provide substantive benefit to colorectal cancer (CRC) patients. However, no genetic lesions that robustly predict ‘addiction’ to the EGFR pathway have been yet identified. Further, even in tumours that regress after EGFR blockade, subsets of drug-tolerant cells often linger and foster ‘minimal residual disease’ (MRD), which portends tumour relapse.
Our preliminary evidence suggests that reliance on EGFR activity, as opposed to MRD persistence, could be assisted by genetically-based variations in transcription factor partnerships and activities, gene expression outputs, and biological fates controlled by the WNT/beta-catenin pathway. On such premises, BEAT (Beta-catenin and EGFR Abrogation Therapy) will elucidate the mechanisms of EGFR dependency, and escape from it, with the goal to identify biomarkers for more efficient clinical management of CRC and develop new therapies for MRD eradication.
A multidisciplinary approach will be pursued spanning from integrative gene regulation analyses to functional genomics in vitro, pharmacological experiments in vivo, and clinical investigation, to address whether: (i) specific genetic alterations of the WNT pathway affect anti-EGFR sensitivity; (ii) combined neutralisation of EGFR and WNT signals fuels MRD deterioration; (iii) data from analysis of this synergy can lead to the discovery of clinically meaningful biomarkers with predictive and prognostic significance.
This proposal capitalises on a unique proprietary platform for high-content studies based on a large biobank of viable CRC samples, which ensures strong analytical power and unprecedented biological flexibility. By providing fresh insight into the mechanisms whereby WNT/beta-catenin signalling differentially sustains EGFR dependency or drug tolerance, the project is expected to put forward an innovative reinterpretation of CRC molecular bases and advance the rational application of more effective therapies.
Summary
Monoclonal antibodies against the EGF receptor (EGFR) provide substantive benefit to colorectal cancer (CRC) patients. However, no genetic lesions that robustly predict ‘addiction’ to the EGFR pathway have been yet identified. Further, even in tumours that regress after EGFR blockade, subsets of drug-tolerant cells often linger and foster ‘minimal residual disease’ (MRD), which portends tumour relapse.
Our preliminary evidence suggests that reliance on EGFR activity, as opposed to MRD persistence, could be assisted by genetically-based variations in transcription factor partnerships and activities, gene expression outputs, and biological fates controlled by the WNT/beta-catenin pathway. On such premises, BEAT (Beta-catenin and EGFR Abrogation Therapy) will elucidate the mechanisms of EGFR dependency, and escape from it, with the goal to identify biomarkers for more efficient clinical management of CRC and develop new therapies for MRD eradication.
A multidisciplinary approach will be pursued spanning from integrative gene regulation analyses to functional genomics in vitro, pharmacological experiments in vivo, and clinical investigation, to address whether: (i) specific genetic alterations of the WNT pathway affect anti-EGFR sensitivity; (ii) combined neutralisation of EGFR and WNT signals fuels MRD deterioration; (iii) data from analysis of this synergy can lead to the discovery of clinically meaningful biomarkers with predictive and prognostic significance.
This proposal capitalises on a unique proprietary platform for high-content studies based on a large biobank of viable CRC samples, which ensures strong analytical power and unprecedented biological flexibility. By providing fresh insight into the mechanisms whereby WNT/beta-catenin signalling differentially sustains EGFR dependency or drug tolerance, the project is expected to put forward an innovative reinterpretation of CRC molecular bases and advance the rational application of more effective therapies.
Max ERC Funding
1 793 421 €
Duration
Start date: 2017-10-01, End date: 2022-09-30
Project acronym ContraNPM1AML
Project Dissecting to hit the therapeutic targets in nucleophosmin (NPM1)-mutated acute myeloid leukemia
Researcher (PI) Maria Paola MARTELLI
Host Institution (HI) UNIVERSITA DEGLI STUDI DI PERUGIA
Call Details Consolidator Grant (CoG), LS7, ERC-2016-COG
Summary Acute myeloid leukemia (AML) is a group of hematologic malignancies which, due to their molecular and clinical heterogeneity, have been traditionally difficult to classify and treat. Recently, next-generation, whole-genome sequencing has uncovered several recurrent somatic mutations that better define the landscape of AML genomics. Despite these advances in deciphering AML molecular subsets, there have been no concurrent improvements in AML therapy which still relies on the ‘antracycline+cytarabine’ scheme. Hereto, only about 40-50% of adult young patients are cured whilst most of the elderly succumb to their disease. Therefore, new therapeutic approaches which would take advantage of the new discoveries are clearly needed. In the past years, we discovered and characterized nucleophosmin (NPM1) mutations as the most frequent genetic alteration (about 30%) in AML, and today NPM1-mutated AML is a new entity in the WHO classification of myeloid neoplasms. However, mechanisms of leukemogenesis and a specific therapy for this leukemia are missing. Here, I aim to unravel the complex network of molecular interactions that take place in this distinct genetic subtype, and find their vulnerabilities to identify new targets for therapy. To address this issue, I will avail of relevant pre-clinical models developed in our laboratories and propose two complementary strategies: 1) a screening-based approach, focused either on the target, by analyzing synthetic lethal interactions through CRISPR-based genome-wide interference, or on the drug, by high-throughput chemical libraries screenings; 2) a hypothesis-driven approach, based on our recent gained novel insights on the role of specific intracellular pathways/genes in NPM1-mutated AML and on pharmacological studies with ‘old’ drugs, which we have revisited in the specific AML genetic context. I expect our discoveries will lead to find novel therapeutic approaches and make clinical trials available to patients as soon as possible.
Summary
Acute myeloid leukemia (AML) is a group of hematologic malignancies which, due to their molecular and clinical heterogeneity, have been traditionally difficult to classify and treat. Recently, next-generation, whole-genome sequencing has uncovered several recurrent somatic mutations that better define the landscape of AML genomics. Despite these advances in deciphering AML molecular subsets, there have been no concurrent improvements in AML therapy which still relies on the ‘antracycline+cytarabine’ scheme. Hereto, only about 40-50% of adult young patients are cured whilst most of the elderly succumb to their disease. Therefore, new therapeutic approaches which would take advantage of the new discoveries are clearly needed. In the past years, we discovered and characterized nucleophosmin (NPM1) mutations as the most frequent genetic alteration (about 30%) in AML, and today NPM1-mutated AML is a new entity in the WHO classification of myeloid neoplasms. However, mechanisms of leukemogenesis and a specific therapy for this leukemia are missing. Here, I aim to unravel the complex network of molecular interactions that take place in this distinct genetic subtype, and find their vulnerabilities to identify new targets for therapy. To address this issue, I will avail of relevant pre-clinical models developed in our laboratories and propose two complementary strategies: 1) a screening-based approach, focused either on the target, by analyzing synthetic lethal interactions through CRISPR-based genome-wide interference, or on the drug, by high-throughput chemical libraries screenings; 2) a hypothesis-driven approach, based on our recent gained novel insights on the role of specific intracellular pathways/genes in NPM1-mutated AML and on pharmacological studies with ‘old’ drugs, which we have revisited in the specific AML genetic context. I expect our discoveries will lead to find novel therapeutic approaches and make clinical trials available to patients as soon as possible.
Max ERC Funding
1 883 750 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
Project acronym NeuroTRACK
Project Tracking and predicting neurodegeneration spreading across the brain connectome
Researcher (PI) Federica Agosta
Host Institution (HI) OSPEDALE SAN RAFFAELE SRL
Call Details Starting Grant (StG), LS7, ERC-2016-STG
Summary Current knowledge of neurodegenerative diseases is limited by poor understanding of how they progress through the central nervous system (CNS). It has recently been hypothesized that clinical progression in these conditions involves the systematic spreading of protein misfolding along neuronal pathways. Protein aggregates would trigger misfolding of adjacent homologue proteins in newly-affected regions, and this would propagate in a “prion-like” fashion across anatomical connections. This proposal seeks to decipher the mechanisms of network-based neurodegeneration by understanding how the complex architecture of brain networks (the connectome) shapes the evolving pathology of neurodegenerative diseases, and to develop tools for monitoring disease progression from presymptomatic to later stages of the disease.
NeuroTRACK will apply emerging network science tools to longitudinal, structural and functional brain connectivity 3T magnetic resonance imaging data from patients with frontotemporal lobar degeneration (FTLD) – a devastating, relentlessly progressive, young onset, neurodegenerative disorder. The study will involve both sporadic and familial cases, including presymptomatic gene mutation carriers. The proposal addresses the following fundamental questions: i) How and where does pathological protein propagation occur in the FTLD phenotypes? ii) Can pathological spreading be predicted from brain connectome fingerprinting? iii) How do different protein abnormalities translate into large-scale network degeneration? iv) How early are brain network changes detectable in the (even presymptomatic) course of the disease?
The ground-breaking nature of the experiments planned in this proposal will pave the way to the development of novel tools for understanding the biological underpinnings of other CNS proteinopathies such as Alzheimer’s disease and Parkinson’s disease, and to identifying individualized, early interventions to modify disease progression.
Summary
Current knowledge of neurodegenerative diseases is limited by poor understanding of how they progress through the central nervous system (CNS). It has recently been hypothesized that clinical progression in these conditions involves the systematic spreading of protein misfolding along neuronal pathways. Protein aggregates would trigger misfolding of adjacent homologue proteins in newly-affected regions, and this would propagate in a “prion-like” fashion across anatomical connections. This proposal seeks to decipher the mechanisms of network-based neurodegeneration by understanding how the complex architecture of brain networks (the connectome) shapes the evolving pathology of neurodegenerative diseases, and to develop tools for monitoring disease progression from presymptomatic to later stages of the disease.
NeuroTRACK will apply emerging network science tools to longitudinal, structural and functional brain connectivity 3T magnetic resonance imaging data from patients with frontotemporal lobar degeneration (FTLD) – a devastating, relentlessly progressive, young onset, neurodegenerative disorder. The study will involve both sporadic and familial cases, including presymptomatic gene mutation carriers. The proposal addresses the following fundamental questions: i) How and where does pathological protein propagation occur in the FTLD phenotypes? ii) Can pathological spreading be predicted from brain connectome fingerprinting? iii) How do different protein abnormalities translate into large-scale network degeneration? iv) How early are brain network changes detectable in the (even presymptomatic) course of the disease?
The ground-breaking nature of the experiments planned in this proposal will pave the way to the development of novel tools for understanding the biological underpinnings of other CNS proteinopathies such as Alzheimer’s disease and Parkinson’s disease, and to identifying individualized, early interventions to modify disease progression.
Max ERC Funding
1 496 994 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
Project acronym TREAT-NPM1-AML
Project Improving therapy of NPM1-mutated AML
Researcher (PI) Brunangelo FALINI
Host Institution (HI) UNIVERSITA DEGLI STUDI DI PERUGIA
Call Details Advanced Grant (AdG), LS7, ERC-2016-ADG
Summary Acute myeloid leukemia (AML) is the most common acute leukemia in adults accounting for approximately 15,000 new cases/year in Europe and 20,000 new cases/year in US. Currently, 40-50% of AML patients (age 18-60 years) and only 5-10% of older patients (who are usually more frequently affected by the disease) can be cured using conventional chemotherapy +/- allogeneic hematopoietic stem cell transplantation. Thus, AML still remains an urgent medical need which calls for new forms of molecular targeted therapies (similarly to those available for acute promyelocytic leukemia). The P.I. previously discovered the nucleophosmin (NPM1) mutations, the most common genetic lesion in AML (about one-third of cases) and gave fundamental contributions in the translation of this seminal discovery into the clinic (improved classification of myeloid neoplasms according to WHO, genetic-based risk- stratification of AML patients, monitoring of minimal residual disease and first demonstration of the anti-leukemic activity of actinomycin D). The present research proposal is focused on improving therapy of NPM1-mutated AML. Specifically, it is aimed to: i) identify novel chemical tools interfering with NPM1 functions by interacting with the N-terminal portion of the protein (objective 1); ii) conduct a clinical trial (AML-PG02; Eudract 2014-003490-41) with actinomycin D in older untreated and/or unfit patients with NPM1-mutated AML and to better understand in vitro and in mice models the mechanisms of action of this drug, used alone or in combination with other agents (objective 2); iii) develop compound mouse models aimed to investigate how NPM1 mutations cooperate with FLT3-ITD or DNMT3A mutations in promoting AML with the goal to better understand the characteristics of relapsed cases and to design new therapeutic strategies (objectives 3 and 4): and iv) generate a murine model for testing the feasibility of “in situ” vaccination in AML, especially in NPM1-mutated AML (objective 5).
Summary
Acute myeloid leukemia (AML) is the most common acute leukemia in adults accounting for approximately 15,000 new cases/year in Europe and 20,000 new cases/year in US. Currently, 40-50% of AML patients (age 18-60 years) and only 5-10% of older patients (who are usually more frequently affected by the disease) can be cured using conventional chemotherapy +/- allogeneic hematopoietic stem cell transplantation. Thus, AML still remains an urgent medical need which calls for new forms of molecular targeted therapies (similarly to those available for acute promyelocytic leukemia). The P.I. previously discovered the nucleophosmin (NPM1) mutations, the most common genetic lesion in AML (about one-third of cases) and gave fundamental contributions in the translation of this seminal discovery into the clinic (improved classification of myeloid neoplasms according to WHO, genetic-based risk- stratification of AML patients, monitoring of minimal residual disease and first demonstration of the anti-leukemic activity of actinomycin D). The present research proposal is focused on improving therapy of NPM1-mutated AML. Specifically, it is aimed to: i) identify novel chemical tools interfering with NPM1 functions by interacting with the N-terminal portion of the protein (objective 1); ii) conduct a clinical trial (AML-PG02; Eudract 2014-003490-41) with actinomycin D in older untreated and/or unfit patients with NPM1-mutated AML and to better understand in vitro and in mice models the mechanisms of action of this drug, used alone or in combination with other agents (objective 2); iii) develop compound mouse models aimed to investigate how NPM1 mutations cooperate with FLT3-ITD or DNMT3A mutations in promoting AML with the goal to better understand the characteristics of relapsed cases and to design new therapeutic strategies (objectives 3 and 4): and iv) generate a murine model for testing the feasibility of “in situ” vaccination in AML, especially in NPM1-mutated AML (objective 5).
Max ERC Funding
2 895 836 €
Duration
Start date: 2017-11-01, End date: 2022-10-31
