Project description
Overcoming drug resistance in gastrointestinal stromal tumours
Gastrointestinal stromal tumour (GIST) is the most common human sarcoma, driven primarily by activating mutations in the receptor tyrosine kinase KIT. Although kinase inhibitors provide initial clinical benefit, most patients relapse due to secondary KIT mutations conferring drug resistance. With the support of the Marie Skłodowska-Curie Actions programme, the Novel GIST Therapies project aims to develop a novel therapeutic strategy based on targeted protein degradation (TPD). This approach works by recruiting a target protein to endogenous clearance machinery, thereby eliminating it from a cell rather than merely inhibiting its activity. Researchers will set up and test the preclinical efficacy of TPD in cellular and organoid GIST models, offering a novel strategy against resistance mechanisms in GIST.
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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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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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)
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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
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(opens in new window) HORIZON-MSCA-2023-PF-01
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08028 BARCELONA
Spain
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