Objective
Gastrointestinal stromal tumour (GIST) is the most common subtype of sarcoma in humans and its initiation and progression is predominantly driven by constitutively activating mutations in the receptor tyrosine kinase (RTK) KIT. This dependency on KIT led to the approval of kinase inhibitors for the treatment of GIST. Inhibition of KIT activity is effective at treating GIST in the short-term however, the majority of patients eventually develop resistance. This resistance is predominantly due to the emergence of additional KIT mutations. Therefore, the development of alternative KIT targeting therapies, beyond the current state-of-the-art, is paramount for the effective treatment of GIST in the long-term. One such strategy is targeted protein degradation (TPD). TPD is based on drugs called degraders which are compounds that induce the proximity between a protein of interest (POI) and components of the cellular proteolytic machinery resulting in the destruction of the former. Degradation of KIT offers several benefits over inhibition, that may combat resistance in GIST. Firstly, small molecule inhibitors rely on a strong affinity for the POI to be effective whereas degraders can maintain activity when the affinity for the target is compromised by mutations. Secondly, inhibition of protein function is not a requirement for degrader activity and therefore additional ligandable sites on the POI.
In this project, I will employ a multifaceted drug discovery approach with the overarching aim of designing, identifying, and optimising degraders of KIT and investigate their effectiveness in GIST models. In order to explore the full potential of TPD in the treatment of GIST, I will pursue two different modalities of degraders: (i) bivalent (Objective 1) and (ii) monovalent (Objective 2). With a clear clinical translational goal in mind, the optimised degraders will be evaluated in various preclinical models of GIST (cellular and organoid) (Objective 3).
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences biochemistry biomolecules proteins
- natural sciences biological sciences genetics mutation
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
MAIN PROGRAMME
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Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) HORIZON-MSCA-2023-PF-01
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
08028 BARCELONA
Spain
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.