Project description
Oncogene targeting for cancer suicide
Cancer development and progression is often driven by oncogenic transcription factors (OTFs) which disrupt normal cellular process and cause uncontrolled cell division. OTFs are formed through genetic abnormalities or chromosomal translocations and have served as targets for therapeutic interventions. However, the unique structural and functional characteristics of certain OTFs render them undruggable. Funded by the European Research Council, the Cancer-Harakiri project aims to address this issue by leveraging the unique DNA-binding preferences of OTFs for a novel therapeutic strategy. The idea is to delineate the regulatory landscape of OTFs and identify genes that regulate their activity. The ultimate goal is to induce cancer cell suicide.
Objective
Many aggressive cancers, such as pediatric high-risk Ewing sarcoma and alveolar rhabdomyosarcoma, are fueled by and addicted to chimeric oncogenic transcription factors (OTFs). So far, all attempts to suppress these potent OTFs largely failed, wherefore they are classified as undruggable.
This proposal challenges this dogma with a novel strategy to leverage, rather than to suppress, the exquisite neomorphic DNA-binding preferences of OTFs to express therapeutic genes specifically in cancer cells. In pursuing three ambitious aims, this project goes far beyond an original proof-of-concept study in which we drove pediatric cancer cells in preclinical models into suicide (CANCER-HARAKIRI) via viral transfer of therapeutic genes induced by the specific interaction of an OTF with its neomorphic DNA-binding motif:
In Aim 1, we will genetically engineer and functionally test a conceptionally advanced viral vector in vivo with optimized general design, oncotropism, and therapeutic payload focusing on immuno-oncological aspects.
In Aim 2, we will comprehensively map the regulome of OTFs using novel reporter cell lines, single-cell sequencing, RNAi-screens, and CRISPR interference to identify and validate OTF-inhibiting genes that can be co-targeted in our vector to prevent escape variants with low OTF-activity.
In Aim 3, we will integrate insights from Aims 1&2 into our new vector design, translate our therapeutic approach from our main model entity, Ewing sarcoma, to other OTF-driven cancers, and set the stage for GMP-compliant virus production and initiation of a clinical trial.
This integrative approach combines expertise and technology across disciplines with original experimental tools to afford a comprehensive understanding of the OTF-regulome, and to rationally design and leap ahead an innovative therapeutic concept, which has the potential to revolutionize the therapy of metastatic OTF-driven cancers. Thus, we will exploit the undruggable to promote CANCER-HARAKIRI.
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 microbiology virology
- medical and health sciences clinical medicine oncology
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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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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.
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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-ERC - HORIZON ERC Grants
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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) ERC-2023-COG
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69120 Heidelberg
Germany
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