HORIZON EUROPE
Europeo
Specific Challenge:The last decade has seen tremendous advances in the development of effective targeted therapies as well as in immuno-oncology to more effectively treat cancer. Despite this, cures are still rare in the metastatic setting. In most cases, an initial response to treatment is followed by the eventual emergence of drug resistance . Drug resistance in cancer is one of the greatest causes of mortality and despite increasing success with targeted therapies in the clinic (including immunotherapy), the mechanisms by which cancer cells evade cell death are still not well understood. Drug combinations are likely to be critical to overcoming drug resistance but are dependent on identifying the cellular programmes that cancer cells use to resist therapeutic agents.
In tumours that initially respond to treatment, rare cancer cells can survive and withstand therapy (‘Drug Tolerant Persister’ cells, DTPs) and can act as a reservoir for the eventual emergence of drug resistance. Furthermore, these studies have shown that these cells are able to survive drug treatment by altering the transcriptional state of specific signalling pathways, and that in the early stages s...
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Specific Challenge:The last decade has seen tremendous advances in the development of effective targeted therapies as well as in immuno-oncology to more effectively treat cancer. Despite this, cures are still rare in the metastatic setting. In most cases, an initial response to treatment is followed by the eventual emergence of drug resistance . Drug resistance in cancer is one of the greatest causes of mortality and despite increasing success with targeted therapies in the clinic (including immunotherapy), the mechanisms by which cancer cells evade cell death are still not well understood. Drug combinations are likely to be critical to overcoming drug resistance but are dependent on identifying the cellular programmes that cancer cells use to resist therapeutic agents.
In tumours that initially respond to treatment, rare cancer cells can survive and withstand therapy (‘Drug Tolerant Persister’ cells, DTPs) and can act as a reservoir for the eventual emergence of drug resistance. Furthermore, these studies have shown that these cells are able to survive drug treatment by altering the transcriptional state of specific signalling pathways, and that in the early stages such changes are plastic and reversible but that over time these changes become stable and fixed.
Recent technological advances in single-cell sequencing have revolutionised the study of individual cells within cancer populations and, importantly, would allow the characterisation of DTPs, something previously impossible with bulk sequencing technologies . Single-cell sequencing provides information that is not confounded by genotypic or phenotypic heterogeneity of bulk samples. Importantly, it has confirmed the existence of DTPs in patients following treatment response and, more importantly, the characterisation of the transcriptionally altered pathways in DTPs. Characterising the transcriptionally altered pathways in persister cells, the biological processes they regulate and their druggability will be critical to future drug combination strategies, with the goal of preventing or significantly delaying the development of drug resistance.
There are numerous challenges in applying single cell sequencing to arguably one of the most important barriers to curing in cancer today – drug resistance, and specifically:
Defining best sequencing protocols – single-cell RNA-sequencing (scRNA-seq) is a fast-moving field with a recent benchmarking paper comparing 13 different methods.Computational approaches to big data – as with sequencing methods, the analysis framework is constantly evolving and there are challenges in integrating data across studies and platformsStandardisation of data formatsBest practice single cell collection from in vitro and in vivo model systemsApplication of single-cell sequencing to clinical samplesSpatial imaging technologiesBiological interpretation of data, including novel target identification This topic proposes to apply state-of-the-art single-cell sequencing technologies to characterise cancer cell populations pre-treatment, at minimal residual disease (for DTPs) and upon the acquisition of drug resistance and from a variety of pre-clinical human and mouse models as well as clinical samples.
Scope:The overall objective of the call topic is to use state-of-the-art single-cell sequencing to understand and overcome drug resistance in cancer by characterising the biology of drug tolerant persister cells, building the capability for such studies across Europe.
The call topic will address primarily adult tumours, with the provision to include childhood tumours where appropriate models are available at a later stage of the program. To optimise our ability to determine the role of tissue lineage on the biological processes observed in single-cells, we propose that the majority (>80%) of the single-cells should be provided from drug treatments in 3 adult cancers:
non-small cell lung cancer (NSCLC) breast cancercolorectal cancer The goals of the call topic are:
To characterise the biology of drug tolerant persister cells - defining the signalling pathways and cellular processes that enable DTPs to survive drug treatment and thereby identify novel drug targets to overcome this – using state-of-the-art single-cell sequencing and spatial transcriptomics in a range of cancer models.To better understand the tumour microenvironment – to avoid solely focusing on cell intrinsic drug resistance programmes, a key element of the work packages should be to use spatial imaging techniques to explore the interaction between cancer cells and the microenvironment.Generation of single cell RNAseq data from adult and childhood cancers – although the pre-clinical models used to explore the biology of drug treatment in cancer are predominantly based on adult cancers, drug resistance is equally a major problem in childhood tumours. The applicants should anticipate that from year 3 of the funded project, specific childhood cancers could be considered for inclusion where the appropriate models are accessible and where there is a hypothesis relationship with drugs or tumours being investigated by the consortium.To develop best practice in clinical validation and single-cell sequencing – clinical validation will be key to translation of any findings and a change in clinical practice. To include informed patient consent forms that cover all intended uses, including clinical outcome data and sharing of data inside the consortium and with 3rd parties. GDPR-compliant tracking of patient data, samples and PDXs.To create gold standard protocols for single cell collection – across a range of models and to include differing methods for isolating single cells from human (organoids, clinical biopsies) and mouse (PDX, genetically engineered mouse models (GEMM) and syngeneic mice) model systems.To develop core analytical methods – use pre-treatment, on-treatment and post-treatment single-cell sequencing data to develop novel computational approaches to identify the different subtypes of cancer cells present and the biological processes that are complicit in maintaining their survival following drug treatment. To build EU capability in single-cell sequencing – in the process of developing the protocols for single cell collection, sequencing and analysis, the funded project will put in place infrastructure to enable other groups in the EU to carry out similar single-cell sequencing studies in both cancer and non-cancer models.
Expected Impact:A comprehensive database, profiling DTPs across a range of cancers and therapies would enable a deeper understanding of the biology of DTPs and allow cross-tumour studies.
Impact for Patients
Identification of novel drug targets in DTPs and resulting drug combinations that delay or prevent the emergence of drug resistance in cancerBetter understanding of the contribution of tumour heterogeneity and plasticity to disease outcome, progression and relapse Impact for Academia and SMEs
Harmonisation of protocols for single cell experimentsEnhanced infrastructure in the EU for single cell sequencingDevelopment of gold standards for the analysis of single-cell sequencing dataAccess to comparative data on different pre-clinical and clinical models and better understanding of the biology of DTPs in cancer with a high likelihood of spin-off projectsImprovements in single cell sequencing and spatial imaging with potential for commercial developmentBetter understanding of drug development post-novel target identification Impact for Industry
Access to a data source for further functional studies (e.g. KO, knock-out, knock-in, target perturbation) that will lead to opportunities for identification of novel targets in DTP space - pointing to new targets or rational drug combinations that alter the drug resistance paradigmAccess to single cell measurement data combined with outcome data (models) and clinical outcome dataDevelopment of expertise in the analysis of single-cell sequencing data Gold standard methods for the delivery of single cell projects
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Características del consorcio
:
La ayuda es de ámbito europeo, puede aplicar a esta linea cualquier empresa que forme parte de la Comunidad Europea.
Características del Proyecto
Los costes de personal subvencionables cubren las horas de trabajo efectivo de las personas directamente dedicadas a la ejecución de la acción. Los propietarios de pequeñas y medianas empresas que no perciban salario y otras personas físicas que no perciban salario podrán imputar los costes de personal sobre la base de una escala de costes unitarios
Los otros costes directos se dividen en los siguientes apartados: Viajes, amortizaciones, equipamiento y otros bienes y servicios. Se financia la amortización de equipos, permitiendo incluir la amortización de equipos adquiridos antes del proyecto si se registra durante su ejecución. En el apartado de otros bienes y servicios se incluyen los diferentes bienes y servicios comprados por los beneficiarios a proveedores externos para poder llevar a cabo sus tareas
La subcontratación en ayudas europeas no debe tratarse del core de actividades de I+D del proyecto. El contratista debe ser seleccionado por el beneficiario de acuerdo con el principio de mejor relación calidad-precio bajo las condiciones de transparencia e igualdad (en ningún caso consistirá en solicitar menos de 3 ofertas). En el caso de entidades públicas, para la subcontratación se deberán de seguir las leyes que rijan en el país al que pertenezca el contratante
Características de la financiación
Please read carefully all provisions below before the preparation of your application.
The IMI2 JU 20th Call for proposals topics text as well as the Call Conditions are available here.
The budget breakdown for this Call, along with the information below, are given at the end of the Call topics text, in the Call Conditions section.
1. Eligible countries: described in article 10(2) of the Rules for participation in Horizon 2020 and in article 1 of the Commission Delegated Regulation related to IMI JU.
2. Eligibility and admissibility conditions: described in the IMI2 Manual for submission, evaluation and grant award. See also the Commission Delegated Regulation related to IMI JU.
Proposal page limits and layout: Please refer to Part B of the proposal template in the submission tool below.
3. Evaluation:
Submission and evaluation process, including evaluation criteria and procedure, scoring and threshold are described in the IMI2 Manual for submission, evaluation and grant award. See also the proposal templates for your specific action in section 5, below.
4. Indicative time for evaluation and grant agreement:
Notification of outcomes of stage 1 evaluations: maximum 5 months from deadline for submitting proposals.
Notification of outcomes of stage 2 evaluations: maximum 5 months from deadline for submitting full proposals.
Signature o...
Please read carefully all provisions below before the preparation of your application.
The IMI2 JU 20th Call for proposals topics text as well as the Call Conditions are available here.
The budget breakdown for this Call, along with the information below, are given at the end of the Call topics text, in the Call Conditions section.
1. Eligible countries: described in article 10(2) of the Rules for participation in Horizon 2020 and in article 1 of the Commission Delegated Regulation related to IMI JU.
2. Eligibility and admissibility conditions: described in the IMI2 Manual for submission, evaluation and grant award. See also the Commission Delegated Regulation related to IMI JU.
Proposal page limits and layout: Please refer to Part B of the proposal template in the submission tool below.
3. Evaluation:
Submission and evaluation process, including evaluation criteria and procedure, scoring and threshold are described in the IMI2 Manual for submission, evaluation and grant award. See also the proposal templates for your specific action in section 5, below.
4. Indicative time for evaluation and grant agreement:
Notification of outcomes of stage 1 evaluations: maximum 5 months from deadline for submitting proposals.
Notification of outcomes of stage 2 evaluations: maximum 5 months from deadline for submitting full proposals.
Signature of grant agreements: maximum 3 months from the date of informing successful applicants.
5. Proposal templates, evaluation forms and model grant agreements (MGA):
IMI2 Research and Innovation Action (IMI2-RIA) and Innovation Action (IMI2-IA):
Standard Evaluation Form
Proposal templates are available after entering the submission tool
Proposal template stage 1
Proposal template stage 2
IMI2 Model Grant Agreement
Clinical trial template – the Clinical Trial template is compulsory at stage 2 only!
6. Open access must be granted to all scientific publications resulting from Horizon 2020 actions.
Where relevant, proposals should also provide information on how the participants will manage the research data generated and/or collected during the project, such as details on what types of data the project will generate, whether and how this data will be exploited or made accessible for verification and re-use, and how it will be curated and preserved.
Open access to research data
The Open Research Data Pilot has been extended to cover all Horizon 2020 topics for which the submission is opened on 26 July 2016 or later. Projects funded under this topic will therefore by default provide open access to the research data they generate, except if they decide to opt-out under the conditions described in Annex L of the H2020 main Work Programme. Projects can opt-out at any stage, that is both before and after the grant signature.
Note that the evaluation phase proposals will not be evaluated more favourably because they plan to open or share their data, and will not be penalised for opting out.
Open research data sharing applies to the data needed to validate the results presented in scientific publications. Additionally, projects can choose to make other data available open access and need to describe their approach in a Data Management Plan.
Projects need to create a Data Management Plan (DMP), except if they opt-out of making their research data open access. A first version of the DMP must be provided as an early deliverable within six months of the project and should be updated during the project as appropriate. The Commission already provides guidance documents, including a template for DMPs. See the Online Manual.
Eligibility of costs: costs related to data management and data sharing are eligible for reimbursement during the project duration.
The legal requirements for projects participating in this pilot are in the article 29.3 of the Model Grant Agreement.
Members of consortium are required to conclude a consortium agreement prior to the signature of the grant agreement.
7. Additional documents:
Summary of the most relevant provisions for participating in IMI2 actions
IMI2 JU Annual Work Plan 2020
IMI2 JU derogation to H2020 Rules for Participation
Horizon 2020 Rules for Participation
Horizon 2020 Regulation of Establishment
Horizon 2020 Specific Programme
Información adicional de la convocatoria
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