Project description
Targeting hard-to-treat KRAS-driven cancers
Mutations of the KRAS gene result in some of the most aggressive cancers by hijacking cell growth signals, causing tumours to grow uncontrollably. These mutations are difficult to target because they act inside cells and often develop resistance to treatments. Supported by the Marie Skłodowska-Curie Actions programme, the ModProtease project aims to engineer protease-antibody combinations that precisely cut cancer-specific proteins to improve treatment effectiveness, while reducing side effects. Using a screening platform with glowing microbeads, researchers will identify the most promising protease variants. A clever molecular ‘tag-and-catch’ system links these proteases to antibodies, creating powerful targeted therapies. ModProtease offers new hope against KRAS-driven cancers.
Objective
The integration of ModProtease with antibody-based systems represents a promising strategy for targeted cancer therapy, particularly in addressing the challenges posed by KRAS mutations. These mutations are notoriously difficult to target directly with antibodies due to their involvement in intracellular signalling pathways and the development of resistance mechanisms. Strategies to overcome these limitations could include the development of protease-antibody conjugates and these conjugates might be directed to cleave specific substrates within tumour microenvironment, thereby enhancing the therapeutic effect of the antibody while minimizing off-target effects. However, engineered proteases remain underrepresented amongst protein-based biopharmaceuticals. This situation is due to fundamental challenges that exist in redirecting the substrate specificity of proteases. We propose a high-throughput screening platform that employs monoclonal hydrogel microbeads containing target substrates with FRET-based detection systems allowing for the precise identification of protease activity. This enables the rapid evaluation of various ModProtease variants and their effectiveness when conjugated to antibodies. The interplay of the SpyCatcher-SpyTag system enables the efficient and specific conjugation of ModProteases to antibodies, facilitating the creation of potent antibody-protease. Following high-throughput screening using fluorescence-activated bead sorting (FABS), the platform facilitates the recovery and analysis of protease genotypes from the microbeads. The group of Prof. Hollfelder (University of Cambridge) has substantial expertise in high-throughput methods and regarding the biology of proteases and protein binders. These conditions make the Host laboratory ideal for this project and will provide critical insights and technical support. This project will also collaborate with AstraZeneca, and targeted proteolysis against cancer cells will be assessed.
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
- medical and health sciences clinical medicine oncology
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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)
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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
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) HORIZON-MSCA-2024-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.
CB2 1TN CAMBRIDGE
United Kingdom
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.