Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : STEPUP (Horizon 2020, appel 2016, Proof of concept grants)
Entité participante : Radboud University Nijmegen — Pays : Pays-Bas — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 150000.0 €

Cancer immunotherapy and adoptive transfer of genetically manipulated T cells in particular has shown promising results for the treatment of cancer. Central in cancer immunotherapy is the activation of tumour-specific T cells. However, the wide-spread clinical use of T cell therapies remains limited due to costly, time-consuming and labour-intensive processes associated with the ex vivo activation and expansion of tumour-specific T cells. Artificial antigen presenting cells (aAPCs) have been developed as an alternative for efficient activation of T cells. In the ERC project ‘PATHFINDER’, Prof. Figdor and his team have developed aAPCs or synthetic dendritic cells (sDCs) based on highly flexible polyisocianide (PIC) polymers, that mimic naturally occurring DCs. The semi-flexible polymer backbone allows for proper arrangement and clustering of antigen and (co-)stimulatory markers, resulting in potent activation and expansion of T cells. With the use of PIC based sDCs, we propose a production platform for tumour specific T cells suitable for cancer immunotherapy. In this ERC PoC project, a team of technological and commercial experts will investigate commercial feasibility of this innovative approach.

Mots-clés : cancer immunotherapy,synthetic,dendritic cells,t cell activation,t cell expansion,production platform
Projet ERC : ReSinAge (Horizon 2020, appel 2020, Consolidator grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : Institut d'Investigació Biomédica de Bellvitge — Pays : Espagne — Rôle : PI
Acronyme de l'entité : IDIBELL;IDIBELL-CERCA
Type d'entité : Recherche
Financement ERC de l'entité : 1997360.0 €

Cancer is a disease of the elderly and chemotherapy remains the mainstay of treatment. The benefits of chemotherapy include increased overall survival, improvement in quality of life, and palliation of symptoms. However, older patients are more susceptible to specific toxicities of chemotherapy, like myelosuppression and life-threatening neutropenia. Among the tissues strongly affected by chemotherapy, the bone marrow sinusoidal endothelial cells constitute the most important supportive niche for aged hematopoietic stem cells function and for myelopoietic recovery in the elderly. Up to now, few data are available about how aged sinusoidal niches regenerate upon chemotherapy damage and whether it is possible to rejuvenate vascular endothelial stem cells and improve the regeneration of the old sinusoidal niche as an effective strategy to improve HSC function and prevent myelosuppression and life-threatening neutropenia in the elderly. Here I hypothesize that the reduced regenerative capacity of aged sinusoidal niches can be improved by rejuvenating vascular endothelial stem cells in vivo via targeting Cdc42 activity and the Notch:Jag2 signaling. The current proposal investigates whether improving the regeneration of the aged sinusoidal niche might represent an important target to enhance the hematopoietic recovery and increase the survival after chemotherapy in the elderly. By combining several ground-breaking approaches ranging from single-cell sequencing, whole-mount bone marrow imaging, deep learning strategies for data analysis and integration, stem cell sorting techniques and specific mouse models, this research project will demonstrate that aging is not irreversible and that targeting the stem cell niche could represent an unprecedented innovative strategy to improve the regenerative capacity not only of hematopoietic stem cells.

Mots-clés : stem cell niche,vascular endothelial stem cell,chemotherapy toxicity,aging,hematopoietic stem cell,cdc42,jag2
Projet ERC : ONCOmetENHANCERS (Horizon 2020, appel 2016, Consolidator grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : Hebrew University of Jerusalem — Pays : Israël — Rôle : PI
Acronyme de l'entité : HUJI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2000000.0 €

Cancer is a growing medical problem which genetic and environmental basis is not clearly understood. Massive efforts over the last decade have identified differences in cancer gene expression that cannot be explained by coding sequences or promoter variations, whereas the effect of transcriptional enhancers remains unclear due to the lack of an effective way to link enhancers with their controlled genes. Recently, we discovered a class of inter-tumor, inter-patient DNA methylation variations in putative enhancers that predict changes in gene expression levels with much greater power than promoter or sequence analyses. The overall goal of this proposal is to determine if changes in enhancer methylation form part of the genomic basis of cancer. Our aim is to elucidate methylation-influenced disease regulatory circuits that affect cancer driver and risk genes and may ultimately serve as markers for disease progression and drug response. Utilizing a new genomic methodology, which allows systematic prediction and verification of gene-enhancer pairing, I will test the above hypothesis in two disease models: breast cancer and glioblastoma. I will methodologically assess numerous potential enhancers across the disease genomes and explore the effects of genetic and epigenetic mutations and variations at these sites. Informative sites will then be evaluated as markers of gene expression level in tumor biopsies. Ultimately, I will apply novel tools to manipulate selected enhancers genetically and epigenetically, thus investigating the causal relationships between enhancer methylation and gene expression, and assessing the potential for tuning gene expression levels by enhancer methylation modification. This study may transform our understanding of the mechanisms underlying disease predisposition, determine the regulatory circuits of key disease genes, lead to improved diagnosis and predictive abilities, and may pave the way for precision epigenetic therapy.

Mots-clés : cancer predisposition,transcriptional enhancers,epimutations,regulatory mutations,epigenetic therapy,precision medicine,cancer methylation,oncotypedx
Projet ERC : BARCODE DIAGNOSTICS (Horizon 2020, appel 2015, Starting grants)
Domaine scientifique : Life Science
Panel : Prevention, Diagnosis and Treatment of Human Diseases
Entité participante : Technion – Israel Institute of Technology — Pays : Israël — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1499250.0 €

Cancer is the leading cause of death in the Western world and the second cause of death worldwide. Despite advances in medical research, 30% of cancer patients are prescribed a medication the tumor does not respond to, or, alternatively, drugs that induce adverse side effects patients' cannot tolerate. Nanotechnologies are becoming impactful therapeutic tools, granting tissue-targeting and cellular precision that cannot be attained using systems of larger scale. In this proposal, I plan to expand far beyond the state-of-the-art and develop a conceptually new approach in which diagnostic nanoparticles are designed to retrieve drug-sensitivity information from malignant tissue inside the body. The ultimate goal of this program is to be able to predict, ahead of time, which treatment will be best for each cancer patient – an emerging field called personalized medicine. This interdisciplinary research program will expand our understandings and capabilities in nanotechnology, cancer biology and medicine. To achieve this goal, I will engineer novel nanotechnologies that autonomously maneuver, target and diagnose the various cells that compose the tumor microenvironment and its disseminated metastasis. Each nanometric system will contain a miniscule amount of a biologically-active agent, and will serve as a nano lab for testing the activity of the agents inside the tumor cells. To distinguish between system to system, and to grant single-cell sensitivity in vivo, nanoparticles will be barcoded with unique DNA fragments. We will enable nanoparticle' deep tissue penetration into primary tumors and metastatic microenvironments using enzyme-loaded particles, and study how different agents, including small-molecule drugs, proteins and RNA, interact with the malignant and stromal cells that compose the cancerous microenvironments. Finally, we will demonstrate the ability of barcoded nanoparticles to predict adverse, life-threatening, side effects, in a personalized manner.

Mots-clés : nanotechnology,drug delivery
Projet ERC : INFRADYNAMICS (Horizon 2020, appel 2019, Starting grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Synthetic Chemistry and Materials
Entité participante : Middle East Technical University — Pays : Turquie — Rôle : PI
Acronyme de l'entité : METU;ODTÜ
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1500000.0 €

Cancer is the second leading cause of death worldwide, accounting for a total of 8.8 million deaths in 2015. Research efforts have resulted in significant increase in 5-year survival rates for some cancer types, however this is not the case in brain cancer. Three fundamental issues are at the core of this reality: 1) High percentage of inoperable brain tumours; 2) Limited number of drugs that can pass through the blood-brain barrier and 3) Absence of effective targeted brain cancer therapies. Photodynamic therapy (PDT) has the potential to be a selective, effective and non-invasive alternative to current treatments, however to date it is only applicable to a small group of cancers. Realization of non-toxic, water-soluble and photostable PDT agents, with strong near infrared absorption for deep tissue penetration, that also realizes high singlet oxygen generation efficiency and effective targeting, is the key for widespread use of PDT for majority of cancers. For brain cancer specifically, low molecular weights (Mws) and controlled lipophilicity is needed as well. The ultimate aim of INFRADYNAMICS is to create and validate the first series of advanced PDT agents that meet all these requirements and to demonstrate that a significant impact on brain cancer survival rates could be achieved. First, a series of advanced fluorophores that combine the two contradicting entities – absorption in NIR region (>700 nm) and low Mws – will be realized using novel design approaches which also allow a synthetically-viable pathway to tune lipophilicity. Then, appropriate heavy atom modifications for sensitization will be pursued. Most importantly, these sensitizers will be decorated with known and novel handles towards specific targeting of glioblastoma cells to attain the final PDT agents. Photophysical properties will be investigated, and finally, in-vitro and in-vivo studies will be performed to determine the effectiveness of our agents on brain cancer treatment.

Mots-clés : photodynamic therapy,nir absorption,m idh1,targeted cancer therapy
Projet ERC : GlycoTherapy (Horizon 2020, appel 2020, Consolidator grants)
Domaine scientifique : Life Science
Panel : Prevention, Diagnosis and Treatment of Human Diseases
Entité participante : Tel Aviv University — Pays : Israël — Rôle : PI
Acronyme de l'entité : TAU
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2150000.0 €

Cancer remains a major cause of death despite phenomenal progress in current immunotherapy, that aims to boost host immune responses of antibodies and T cells, and their ability to distinguish cancer from normal cells. The three main cancer immunotherapies are therapeutic cancer vaccines, cellular therapeutics and immune checkpoint blockade, but those have only limited success mainly due to difficulties in identifying target antigens. Carbohydrate chains (glycans) ubiquitously occupy surface of cells, but on cancer they are aberrantly-expressed, in particular with a wide collection of sialic acid-glycans. Their antigenic complexity arise by sialic acid structure modification, linkages, length, protein/lipid scaffolds, surface organization and density. The presentation mode of glycans and their heterogeneity affect their immune recognition, but the fundamental knowledge of how these factors contribute to efficient cancer therapy in vivo has not been defined systematically. The primary objective of this proposal is to design a comprehensive novel cancer immunotherapy approach targeting glycan-neoantigens. We propose an innovative interdisciplinary approach that integrates glycobiology, immunology and nanotechnology, to design and fully investigate new frontiers in cancer ‘GlycoTherapy’ in vivo. Our discovery line is based on a two-arms modular platform to study both engineered carbohydrate-cancer vaccines and T cells, and their combined effects with checkpoint blockade on therapeutic glycan immune recognition in mouse models. Efficacy will be evaluated in detail by systematic characterization of immune cell and humoral responses with cutting-edge tools, including glycan microarrays, to track response repertoire and kinetics. Successful establishment and in-depth understanding of these therapies will provide a platform to devise and validate potent novel glyco-cancer diagnostic tools and therapeutics, and will instigate their prospective clinical translation in humans

Mots-clés : sialic acid,neu5gc,cancer carbohydrate antigen,neoantigen,antibodies,chimeric antigen receptor  car  t cells,cancer,nanotechnology,cancer vaccine,checkpoint inhibitors,immunotherapy
Projet ERC : BARB (Horizon 2020, appel 2019, Advanced grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Fundamental constituents of matter
Entité participante : GSI Helmholtz Centre for Heavy Ion Research — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : GSI
Type d'entité : Recherche
Financement ERC de l'entité : 2000000.0 €

Cancer remains one of the main causes of death worldwide. In 2018, >50% cancer patients in Europe underwent radiotherapy. While over 80% were treated using high-energy X-rays, the number of patients receiving accelerated protons or heavy ions (charged particle therapy: CPT) is rapidly growing, with nearly 200,000 patients treated up till now. Although CPT offers a better depth-dose distribution compared to common X-ray based techniques, range uncertainty and poor image guidance still limit its application. Improving accuracy is key to broadening the applicability of CPT. In BARB, we will open a new paradigm in the clinical use of CPT by using high-intensity radioactive ion beams (RIB), produced at GSI/FAIR-phase-0 in Darmstadt, for simultaneous treatment and visualization. This will reduce range uncertainty and extend the applicability of CPT to treatment of small lesions (e.g. metastasis and heart ventricles) with unprecedented precision. The Facility for Antiprotons and Ion Research (FAIR) is currently under construction at GSI. RIB are one of the main tools for basic nuclear physics studies in the new facility. As part of the ongoing FAIR-phase-0, an intensity upgrade will increase the light ion currents in the existing SIS18 synchrotron. Within this project BARB, we will study four b+ emitters (10,11C, and 14,15O) and build an innovative hybrid detector for online positron emission tomography (PET) and g-ray imaging. This novel detector will acquire both prompt g-rays during the beam-on phase of the pulsed synchrotron beam delivery, and the delayed emission from b+ annihilation during the pulse intervals. The technique will be further validated in vivo by applying it to treatment of small tumors in a mouse model. BARB will exploit the potential of the Bragg peak in medicine. The project will tweak RIB production in nuclear physics and validate the therapeutic potential of RIB therapy in vivo by empowering simultaneous treatment and visualization.

Mots-clés : nuclear physics,medical physics,radioactive ion beams,particle therapy,radiobiology
Projet ERC : INSITUMUT (Horizon 2020, appel 2016, Proof of concept grants)
Entité participante : University of Birmingham — Pays : Royaume-Uni — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 149688.0 €

Cancers develop because they acquire changes (mutations) in a specific set of genes that promote their growth. Different mutations are associated with cancer aggressiveness, patient prognosis and/or the response to treatment. Although these mutations can usually be detected by extracting DNA from tumour specimens, this provides incomplete information because it is common for mutations not to occur in every cell that makes up the cancer. In a number of research and clinical settings, it is of great use to learn which regions or cells within a cancer carry a particular mutation. To do this, we need to detect mutations in space by examining sections of tissue. There are several potential benefits, including sensitive detection of cancer cells that have been left behind after operation or that will cause relapse after treatment. Here, we shall develop a method to detect mutations in situ in cancer specimens. The INSITUMUT technique uses molecular probes that are specific to mutations in cancer genes and bind to RNA expressed from those genes. We have piloted the method successfully in collaboration with Advanced Cellular Diagnostics Inc., sensitively identifying cancer cells that have acquired specific mutations in the oncogene KRAS and specifically distinguishing them from cells and cancers with normal KRAS. Before making the method available, our workplan in this proposal involves determining probe sensitivity and specificity more accurately, expanding the range of cancer-causing mutations that are detected, developing methods for simultaneous detection of multiple mutations, extending the technique as far as possible to detection of mutations in DNA, and automating the mutation detection process. Subject to technical feasibility and commercial assessments, we shall disseminate the INSITUMUT method to non-profit sectors on a cost recovery basis, and make it generally available as a commercial service in partnership with SME partner Oxford Cancer Biomarkers.

Mots-clés : in situ mutation detection,cancer,histological sections,tumour clonality
Projet ERC : DualRP (Horizon 2020, appel 2017, Starting grants)
Domaine scientifique : Life Science
Panel : Integrative Biology: from Genes and Genomes to Systems
Entité participante : German Cancer Research Center — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : DKFZ
Type d'entité : Recherche
Financement ERC de l'entité : 1499375.0 €

Cancers develop in very heterogeneous tissue environments. They depend on the tumor microenvironment (TME) for sustained growth, metastasis, and therapy resistance. Stromal cells are genetically stable and they have less likelihood to develop resistance than cancer cells. Therefore, targeting the TME represents an attractive approach for treating cancer. In order to develop new therapeutic strategies to reprogram the TME and inhibit tumor growth and resistance, it is essential to understand in detail the molecular mechanisms of the interactions between cancer and stromal cell populations. However, current methods to study these interactions require complete dissociation of the tumor, exposing the cells to severe stress and affecting dramatically gene expression patterns. Here, I propose to use Dual Ribosome Profiling (DualRP), a system that I recently developed, to study cell interactions in the TME. DualRP is an approach that allows not only simultaneous analysis of gene expression in two interacting cell populations in vivo, but also is able to uncover metabolic limitations in tumors. I aim to apply DualRP to mouse xenograft models where cancer cells interact with non-transformed fibroblasts and I’ll explore the combined response of both populations to cancer therapy. Moreover, I’ll utilize mouse genetic models tailored for DualRP to study cancer cell and macrophages/endothelial cells interactions. I will employ a combination of mouse genetic models, biochemical tools, deep sequencing, and bioinformatics. These studies will provide insight into how gene expression and metabolic programs define the interaction between cancer and stromal cells to promote tumor growth and metastasis, identify potential targets for therapeutic intervention, and provide maps of cell interactions in vivo. Therefore, this research has the potential to significantly advance our understanding of the molecular and metabolic mechanisms underlying the complex cell interactions in the TME.
Projet ERC : RECGLYCANMR (Horizon 2020, appel 2017, Advanced grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Synthetic Chemistry and Materials
Entité participante : CIC bioGUNE — Pays : Espagne — Rôle : PI
Type d'entité : Recherche
Financement ERC de l'entité : 2499980.0 €

Carbohydrates (glycans, sugars) play key roles in virtually all biological events. Given their chemical complexity, understanding their roles in nature requires a multidisciplinary approach. Research in the field is growing, since advances in the area could be part of the solution to many health issues. However, we lack full knowledge on the role of most glycan-mediated events especially at the resolution required from a chemical perspective to manipulate them and create new probes and eventually drugs. Understanding sugar recognition remains a major challenge in science. Although X-ray diffraction has been employed to study sugar/protein complexes, a recent report has highlighted that most sugar conformers deposited in the Protein Data Bank are incorrect. Flexible glycans are handled poorly in X-ray: errors reflect incorrect refinement of sugars, with huge implications when interpreted in the biocontext.I propose to address glycan recognition by using a multidisciplinary approach, combining synthesis, molecular biology and biophysics, with a prominent role for NMR. In RECGLYCANMR I will develop new NMR protocols to decipher key glycan recognition aspects beyond current knowledge: the role of presentation and dynamics and understanding the mechanisms behind the exquisite receptor and ligand selectivity. Importantly, till now, sugar recognition NMR studies have been exclusively limited to in vitro. RECGLYCANMR will break the limits of NMR, studying the interactions in-cell, a crowded ambient where viscosity is doubled respect to water. I am in a unique position to approach this project due to my wide expertise in NMR and the network of collaborators I have established for years, enabling me to access a large variety of synthetic sugars. Discovering the molecular bases of in-cell interactions will provide groundbreaking information on sugar chemical biology and will open unexplored avenues for approaching sugar-associated diseases, as inflammation and viral infections

Mots-clés : carbohydrates,molecular recognition