Project description
Rewiring transcription for cancer therapy
Transcription regulation controls when and how genes are expressed, ensuring proper cell function. In cancer, this process is frequently disrupted by mutations, leading to uncontrolled growth and survival. However, directly inhibiting transcription has proven largely ineffective as a therapeutic strategy. The ERC-funded geNEOMORPH project introduces a novel approach based on neomorphic transcriptional compounds (NeoTraCs) that chemically rewire transcriptional regulators. NeoTraCs disrupt oncogenic transcriptional circuits in a targeted, sustained way. Utilising an interdisciplinary strategy, researchers will target key cancer regulators currently lacking effective inhibitors. By establishing a new paradigm for modulating transcription, the project aims to pave the way towards transformative cancer therapies.
Objective
Many cancers are driven by mutations affecting transcription regulation. Through cancer genome sequencing studies, we understand that these aberrations are pervasive through many layers of gene control. Yet, with few exceptions, this knowledge has not precipitated in effective treatments since pharmacologic inhibition of transcription is often infeasible or functionally inconsequential.
To address this limitation, I want to innovate chemical strategies that move beyond loss of function (LOF) approaches. Gene control is organized at the level of proximity. Hence, I hypothesize that transcriptional regulators can be chemically rewired by neomorphic small molecules that recruit functionally opposing gene-regulatory effectors, thereby prompting an acute, deep, and sustained disruption of oncogenic transcriptional circuits. The identification, characterization, and translation of such Neomorphic Transcriptional Compounds (NeoTraCs) will be the subject of the GE|NEomorph proposal. We will focus on NeoTraCs to rewire the repressive PRC2 complex, the p400 chromatin regulator complex, and the non-canonical BAF complex. While these targets have established roles in various cancers, inhibitors are not available or have limited functional impact.
To identify NeoTraCs that address these limitations, we will implement a diverse discovery approach that incorporates hypothesis-driven design with phenotypic strategies geared to co-opt undrugged transcriptional effectors via bivalent NeoTraCs, and unligandable effectors via molecular glue-like NeoTraCs. Identified hits will be characterized via multi-omics approaches. Through careful mechanistic investigation, we will deduce general mechanistic principles, understand their impact on oncogenic transcription and investigate associated translational opportunities.
GE|NEomorph will significantly advance our ability to understand and disrupt transcriptional dysregulation in cancer and pave the way for novel innovative therapies.
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 genetics mutation
- medical and health sciences clinical medicine oncology
- natural sciences biological sciences genetics genomes
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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.1.1 - European Research Council (ERC)
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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.
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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.
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Call for proposal
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(opens in new window) ERC-2024-COG
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1030 Vienna
Austria
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