Data-Gouv-ML/pcri-actions-marie-curie-participations-et-projets-laureats huggingface dataset:
Projet PROTACs (Horizon 2020, appel à projets 2020)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Chemistry
Statut du projet : TERMINATED

Cancer diseases are critical medical problems - according to the International Agency for Research on Cancer and European Commission estimates, globally there were more than 18 million new cases and 9.5 million cancer-related deaths in 2018, what indicates that tumors are among the leading causes of death, worldwide. Traditional anticancer drug design based on small molecules continues to be a powerful strategy for the development of novel chemotherapeutics. However, these anticancer therapies are facing major problems such as drug resistance, especially in advanced cancers. This is mainly due to the alterations in the target, ineffective apoptosis or activation of different pathways, among others. The use of PROteolysis-TArgeting Chimerics (PROTACs) has become a promising approach to overcome resistance since they act degrading instead of inhibiting the target, with the advantage of reducing the systemic drug exposure and to counteract the protein expression that often accompanies inhibition of protein function. This approach uses bivalent molecules that possess a target protein recruiting group linked to an E3 ligase interacting moiety for protein degradation. The main goal of this project is to design, synthesize and evaluate a series of new small-molecule PROTACs, which will be able to degrade enzymes and receptors that are responsible for tumor development and progression. To address this aim, I shall carry out a fellowship at Universidad San Pablo CEU under the supervision of Prof. Beatriz de Pascual-Teresa and Irene Ortín from Faculty of Pharmacy. As part of this research, I shall carry out a secondment in the Department of Molecular Biotechnology and Health Sciences at University of Turin (Italy), and another one at the company CsFlowChem S.L. It is worth noting that the design and synthesis of new PROTACs will be based on our wide experience in the development of compounds responsible for inhibition or regulation of the selected target proteins.

Mots clés : cancer, anticancer agents, protacs

Participants :
- Fundación Universitaria San Pablo CEU (Espagne) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 172932.48 €
Projet PERICYTEStroma (Horizon 2020, appel à projets 2015)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Cancer is a devastating diagnosis since treatments to prevent a lethal outcome are limited. Tumor constitutes a complex tissue consisting of malignant cells and stromal cells. Emerging studies have shown the importance of stroma in tumor growth, invasion, and metastasis highlighting its potential as an attractive target for cancer therapy. However, the source of tumor stroma generating cells remains elusive. Generation of connective tissue is a general feature of scarring and fibrosis. While scarring is part of the wound healing response, fibrosis represents a failure to terminate tissue repair. In this context, tumors can be considered as “wounds that do not heal”. While studying spinal cord injury-induced scarring, a subpopulation of perivascular cells, type A pericytes, has been shown to be a major source of the stromal scar. Type A pericytes are embedded in the vascular wall but proliferate and leave blood vessels upon injury, differentiating into fibroblast-like cells that deposit extracellular matrix and form the stromal scar. Here, I propose to determine whether type A pericytes are a source of tumor stroma and whether blocking type A pericyte-derived stroma formation can impede cancer progression. Single cell studies to determine pericyte heterogeneity within malignant and non-malignant tissue will be performed. This characterization of heterogeneity is important to distinguish stroma-forming pericytes from the non-forming ones and from tumor cell-derived pericytes as described in Glioblastoma multiforme (GBM). Furthermore, by using combinations of pericyte reporter mice with genetic tools to manipulate pathways regulating cell proliferation and recruitment within specific pericyte subpopulations, I aim to investigate underlying mechanisms mediating pericyte-derived stroma generation. Studying stroma formation using the GBM mouse model, the proposed research intends to uncover common mechanisms of tumor stroma formation and identify new targets for therapy.

Mots clés : pericytes, tumor stroma, glioblastoma, pericyte heterogeneity, angiogenesis

Participants :
- Karolinska Institutet (Suède) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 185857.2 €
Projet BlaC E-assay (Horizon 2020, appel à projets 2014)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Information Science and Engineering
Statut du projet : CLOSED

Cancer is a leading cause of death worldwide and the best approaches to improve cancer survival rate is to diagnose it at an early stage. In spite of the rapid explosion of new technology platforms, traditional optical ELISA is used in clinical practice, which is laborious, time-consuming, require large sample volume and suffer from low sensitivity. On the other hand, recently proposed electrochemical sensors which promise easy operation, accuracy, high sensitivity, low cost and compact size mainly suffer from background signals, non-specificity and selectivity in clinical samples. Therefore, there is an urgent need to solve the key issues in the development of clinically relevant and commercially viable technologies that enable screening of high-risk individuals for cancer at an early stage. The proposed program is to develop a reliable point-of-care (POC) diagnostic system based on a multidisciplinary approach of integrated microfluidic and electrochemistry for multiple biomarker detection in clinical samples. The proposal aims at finding solutions for key issues of non-specificity, sensitivity and selectivity in clinical samples for sensitive and multiplexed detection. The proposal will address the above mentioned challenges, via separation of assay chamber and detection chamber with innovative surface chemistry and microfluidic design with electrochemical detection techniques. Work will be focused on bladder cancer as a test model to solve the above mentioned issues. The proposed device will be of bench top size and have capabilities to detect a panel of 3 or more biomarkers simultaneously. The successful outcome of the project will result in high impact publications, technology know-how and IP, which will be used to design and develop a prototype device. A secondment at Applied Enzyme Technology Ltd, Gwent Group (GWENT) will be used to study optimization of sensor shelf life and to ensure the developed system meets industrial standards.

Mots clés : biosensors, cancer diagnosis devices, electrochemical sensors

Participants :
- University of Bath (Royaume-Uni) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 195454.8 €
Projet PlateletLiquidBiopsy (Horizon 2020, appel à projets 2016)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Cancer is one of the major causes of death worldwide. Early detection leads to treatment initiation in earlier cancer stages and therefore increases the chance of survival. However, appropriate diagnosis can be challenging because tissue acquisition of tumor samples for molecular testing often requires invasive procedure. To overcome these challenges researchers have focused on the real-time monitoring of molecules and cells in easily obtainable peripheral blood to gain diagnostic information, termed 'liquid biopsies'. A recent study by Best et al profiled purified platelet gene expression from cancer patients and healthy controls and was able to predict disease status and location of the primary tumor with 96% and 71% accuracy, respectively using a machine learning based algorithm. The pan-cancer nature of their finding is a major advancement compared to other liquid biopsy approaches and highlights the utility of platelets as an all-in-one platform for blood-based cancer diagnostics. We plan to advance the idea of platelet liquid biopsies by studying platelet single-cell RNA sequencing data from cancer patients and healthy controls. The overall goal of the proposed project is to investigate single platelet gene expression to gain insight into the molecular mechanisms underlying tumor driven changes in the platelet RNA profile.

Mots clés : single cell, rna sequencing, platelet, liquid biopsy

Participants :
- Helmholtz Zentrum München (Allemagne) — Coordinator, beneficiary, Recherche, subvention : 159460.8 €
Projet BIOplasma (Horizon 2020, appel à projets 2018)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Chemistry
Statut du projet : CLOSED

Cancer is the leading cause of death in economically developed countries and the second leading cause of death in developing countries. In 2015, over 8.8 million people died of cancer worldwide and the numbers are expected to rise above 13 million in 2030 . As a consequence, development of non-invasive, fast and robust methods to detect different types of cancer in an early stage are timely. BIOplasma addresses the essential need for analytical tools that permit the diagnosis of biological tissues. A novel analytical strategy based on the Liquid Chromatography/Mass Spectrometry (LC-MS) using flexible Tube Micro Plasma (FµTP) as ionization source for the identification and quantification of several lipid biomarkers in body fluids is proposed

Mots clés : lipidomic

Participants :
- Leibniz Association (Allemagne) — Coordinator, beneficiary, Recherche, subvention : 162806.4 €
Projet TARGETOF (Horizon 2020, appel à projets 2019)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Chemistry
Statut du projet : SIGNED

Cancer is the second highest cause of death in Europe and one of the biggest challenges facing humanity. The discovery of multi-kinase inhibitors has emerged as a strong alternative treatment for many cancers. However, the appearance of severe side effects due to their intrinsic target promiscuity limits the dosage and efficiency of these treatments. Therefore the characterisation of this promiscuity is crucial to develop selective and safe treatments. We propose a versatile and efficient approach to detect the binding of a given drug to target proteins. Combining intracellular target engagement devices based on nanotechnology with the state-of-the-art mass cytometry techniques, this approach will allow one-step target engagement profiling, and thus will streamline the discovery of the mode-of-action of a given drug. Furthermore, the development of an intracellular barcoding system in combination with the multiplexing capacities of mass cytometry will allow for the combination of multiple cell types in one single experiment, further accelerating the target deconvolution process. This research will greatly contribute to the development of a straightforward method to detect the most expressed targets in patient biopsies, and to select the best therapy for a given patient. This fellowship will consolidate me as an independent researcher, providing me with the opportunity for many cross-disciplinary collaborations, and to establish myself as an expert in the field of precision medicine.

Mots clés : mass cytometry

Participants :
- University of Granada (Espagne) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 160932.48 €
Projet CancerCOtreat (Horizon 2020, appel à projets 2020)
Action : Postdoctoral Fellowships - Global Fellowships
Panel : Life Sciences
Statut du projet : SIGNED

Cancer patients are of high risk to develop severe COVID-19, which has a negative impact on their clinical management. Cancer therapy and COVID-19 severity can be also affected negatively by preconditions, including obesity, diabetes, hypertension and advanced age, as well as by the gender. To help cancer patients suffering from COVID-19 and the other preconditions as soon as possible, it will be necessary to repurpose existing and well tolerated drugs - alone or in combination. To accelerate this process, we propose to develop an in silico systems biology approach to model the known biology of SARS-CoV-2 infection and the action of approved drugs overlaid on the underlying pathophysiology of cancer patients with different disease states, preconditions and gender. The proposed mathematical framework will mechanistically model the COVID-19 progression in the context of cancer. We will also simulate the effect of COVID-19 in this patient population and explore the efficacy of various treatment regimens to identify synergistic combinations as well as optimal schedules for therapy. Robust model validation will be performed using data from the Massachusetts General Hospital patient database (host of outgoing phase). This is a very timely research because the proposed mechanism-based model will reveal novel strategies to optimally combine current and emerging treatments for COVID-19 in cancer. Importantly, the proposed model will not be limited to COVID-19 but it will set a mathematical framework for the optimal treatment of cancer patients contracted by any infectious diseases. The fellowship will allow the applicant to substantially built upon his previous experience and strengthen his overall scientific abilities. In particular, he will expand his knowledge in tumor/virus biology, cancer research and clinical translation, will enrich his mathematical modelling capabilities and the analysis of complex biological systems that involve more than one medical conditions.

Mots clés : mathematical modeling, cancer research, covid 19, tumor, virus biology

Participants :
- The general hospital corporation (Etats-Unis) — Partner, organization partner, Autres, subvention : 0.0 €
- University of Cyprus (Chypre) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 256236.48 €
Projet MelImmuneOrg (Horizon 2020, appel à projets 2019)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Cancer progression is a complex process that depends on the interplay between tumor cells, tumor microenvironment, and the immune system. Inhibiting immunosuppression is beneficial for cancer patients. Although these therapies are promising they are successful only in part of the patients. Tumors are composed of distinct cell types with different phenotypes, that influence the efficacy of immunotherapies. Therefore, in order to better understand tumor biology and response to treatment, it is necessary to profile protein expression while preserving spatial information. Multiplexed Ion Beam Imaging by Time of Flight (MIBI-TOF) is a method in which antibodies conjugated to metals are used to simultaneously visualize dozens of proteins in intact tissue specimens by secondary ion mass spectrometry. Here we suggest to uncover the immune profile and organization within the tumors of melanoma patients undergoing immunotherapy using MIBI-TOF. My first objective is to characterize the tumor-immune microenvironments to understand how these are structured across patients and discover predictive features of response to immunotherapies. My second objective is to analyze the intratumor heterogeneity (ITH) of melanoma patients by exome sequencing. I will examine whether there are genetic correlates between ITH, immune microenvironment and response to therapy. Finally, my third objective will be the manipulation of individual hits to test their functional significance in tumor-immune architecture in murine models. By joining Dr. Keren’s lab that masters the MIBI-TOF technology, I will acquire this state-of-the art technique, as well as develop lab management and organization skills, and I will meet leader scientists from the immune-oncology field. This proposal will promote my competitiveness to gain an independent researcher position.

Mots clés : multiplex imaging, melanoma, immunology, immunotherapy

Participants :
- Weizmann Institute of Science (Israël) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 185464.32 €
Projet SYNKIT (Horizon 2020, appel à projets 2018)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Cancer remains a leading cause of death worldwide, urging for innovative therapies. Infusion of natural killer (NK) cells, which possess an intrinsic capacity to eliminate cancer cells, is a promising treatment option for various tumours. Genetic engineering of NK cells before transfer allows to specifically tailor and modulate their anti-tumour responses. One particularly attractive strategy for broad implementation of NK cell immunotherapy in an “off-the-shelf” setting is to expand large numbers of NK cells from induced pluripotent stem cells (iPSCs). However, this approach is limited by two main bottlenecks: i) poor persistence of allogeneic iPSC-derived NK (iNK) cells due to rejection by the recipient immune system and ii) impaired functionality due to failure to achieve complete differentiation in vitro. The SYNKIT project seeks to address both of these current limitations through genetic engineering of iNK cells for increased persistence and function. Deletion of human leukocyte antigen (HLA) "self-ligands" allows the transferred cells to escape from host T cells. However, absence of HLA also triggers “missing-self” recognition and rejection by host NK cells. In addition, new insights from the host laboratory into the molecular mechanism underlying NK cell education have unravelled a pathway of functional disarming in NK cells that lack self-ligands, further diminishing the anti-tumour efficacy of HLA-deficient NK cells. In SYNKIT, I will use HLA-deficient iNK cells as a platform to assess how introduction of synthetic self-ligands modulates the allogenicity and functionality of iNK cells. The overall goal of SYNKIT is to identify synthetic self-ligands, which reduce recognition by the host immune system and yet prevent functional disarming of the engineered iNK cells, thereby resulting in optimised anti-tumour function. Successful completion of SYNKIT will pave the way for development of next generation immunotherapy to more effectively combat cancer.

Mots clés : cancer immunotherapy, adoptive cell therapy, synthetic biology, molecular biology

Participants :
- Karolinska Institutet (Suède) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 191852.16 €
Projet BispecificsThatClick (Horizon 2020, appel à projets 2018)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Chemistry
Statut du projet : CLOSED

Cancer represents one of the major challenges for modern medicine as we still lack tools to selectively target malignant over healthy tissues. The main issues with state of the art anti-cancer treatments lie on their inefficiency and their associated side-effects. Improving this treatments has focused a lot of attention of the scientific community and has led to the development of new strategies. Harnessing our own immune system to fight malignant cells is one of the strategies with promising potential to improve cancer treatments, although challenges still remain. An emerging therapeutic modality to trigger our immune system against carcinogenic tissues are bispecific antibodies (bsAbs). bsAbs are the combination of two antigen binding specificities on a common scaffold. The potential of these constructs to bind to two antigens can be used to simultaneously target cancer cells and the immune cell which will effectively kill it. The problem of bsAbs is their slow and tedious production process, which is responsible for their linear development. Herein we propose a methodology to speed up and improve the efficiency of their production. Our approach will consist in using novel site-specific bioorthogonal ligation reactions to tag monoclonal antibodies (mAbs) with linkers that will serve as substrates for an inverse electron demand Diels Alder condensation. By condensation of different combinations of tagged mAbs a library of bsAbs will be assembled. The immunondulatory properties of the bsAbs will be tested in high throughput using a high content imaging platform. We will be able to select potential bsAbs for anticancer treatment from our extense library which will study in more depth using classic immunology methods to determine their mode of action and their anti tumour efficacy. The acceleration of both the synthesis and identification of relevant bsAbs for anticancer treatments would significantly increase the presence and value of this technology.

Mots clés : bispecific antibodies, bioorthogonal, inverse electron diels alder, immunotherapy, immunochemistry

Participants :
- University of Cambridge (Royaume-Uni) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 212933.76 €
Projet BioCapSoft (Horizon 2020, appel à projets 2020)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Physics
Statut du projet : SIGNED

Capturing fluids at small scales is a challenge that nectarivores have solved by developing various type of specialized tongues, which consist of a complex assembly of flexible structures of small size compared to the capillary length. Most of the physicochemical mechanisms allowing some of those animals to quickly feed on nectar are not yet fully understood. This project aims to understand the physical mechanisms underlying the efficient capture of nectar by bees and hummingbirds which results from the dynamical coupling between viscous flows, capillary forces and elasticity in hierarchical soft tongues. To achieve this objective, model experiments are proposed. Mimicking hummingbirds’ tongues, I will first characterise the static closing of soft open tubes in contact with a specific amount of liquid. I will then study the dynamics when the same structure is dipped and removed from a fluid bath. In a second step, I will study the equilibrium shape and the dynamics of soft brushes and hairy surfaces dipped into a fluid bath, mimicking bumblebee’s tongue. The study of these systems will allow us to develop general physical models. The relevance of these models for describing the biological systems will be assessed by the direct comparison between the theoretical predictions and in-vivo measurements by setting the control parameters of the model systems to values compatible with the biological systems. This project will thus provide general models for the capture of viscous fluid through elastocapillary effects in some geometries inspired by biological systems. Based on the insights gained from these model experiments and the comparison with in-vivo data, optimal soft structures will be designed to passively capture precise amount of viscous fluids at a controlled rate. The BioCapSoft project will thus contribute to a better understanding of the dynamical coupling between viscous flows, capillary forces and elasticity in soft impregnated structures.

Mots clés : elastocapillarity, impregnation dynamics, bio inspired slender structures

Participants :
- Université Libre de Bruxelles (Belgique) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 166320.0 €