Objective
Introduction
Coupled oxido-reductive (redox) reactions drive hydrogen peroxide fluctuations, mediating key cellular processes. Alterations in redox homeostasis support cancer cell survival and therapy resistance but simultaneously increase their reliance on antioxidant enzymes containing selenocysteine (Sec). Non-small cell lung cancer (NSCLC) is among the cancer types most highly dependent on available antioxidant capacity, and therapy-resistant NSCLC represents a vastly unmet clinical need. Inhibiting Sec metabolism is an underexplored anticancer strategy due to the complexity of the enzyme cascades and the challenges associated with selectively targeting their active sites. Since peroxiredoxin 6 (PRDX6) has a direct role in Sec metabolism and its loss selectively sensitizes resistant NSCLC cells to the oxidative stress cell death, ferroptosis, it represents an attractive target.
Objectives
This project aims to develop and characterize the mechanisms of action of novel selective inhibitors of PRDX6 in resistant, persister and mesenchymal NSCLC cells. The compounds host a reactive element selective for the oxidized sulfenic acid form of cysteine, constituting a first-in-class selective covalent inhibitor with this target profile. Mechanistic studies will utilize functional proteomics to delineate the effects on selenoprotein homeostasis, cellular redox signaling pathways and cell cycle. The cell-based models for resistance, recurrence and metastatic NSCLC used here closely replicate the signaling cascades involved in patients on second- and third-line therapy.
Significance
SelenoResist combines the strengths of myself and my host laboratory to achieve a breakthrough in redox signaling research by developing a state-dependent PRDX6 inhibitor engaging only the oxidized form of its active site. This precision pharmacology tool will be leveraged to better understand selenium utilization pathways and break treatment resistance in lung cancer.
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 proteomics
- medical and health sciences clinical medicine oncology lung cancer
- medical and health sciences basic medicine physiology homeostasis
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
- medical and health sciences basic medicine pharmacology and pharmacy
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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-2025-PF
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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.
1010 WIEN
Austria
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.