Objective
In Europe, cancer is the leading cause of disease-related deaths in children. Among these, the pediatric brain tumor diffuse midline glioma (DMG) is the most lethal, with a median survival of only 9–11 months. Surgical resection is not possible due to its location, and radiation –the current standard of care– provides only temporary benefit before resistance develops. A hallmark of DMG is loss of the H3K27me3 epigenetic repressive mark, which stalls cancer cells into proliferative, stem-like states driven by transcription factor (TF) dysregulation. My research indicates that these TF-mediated programs not only sustain tumor growth but also influence treatment response, suggesting they represent actionable targets to both impair tumor progression and enhance the efficacy of targeted therapies.
RESET-DMG will investigate how TF-mediated transcriptional states cooperate with genetic alterations to drive treatment resistance in DMG. Aim 1 will establish proof-of-concept that disrupting these transcriptional states enhances the efficacy of TP53 reactivation– a therapeutic strategy with particular promise for the >40% of DMGs retaining wild-type TP53. This will be evaluated in patient-derived neurospheres, brain organoids, and orthotopic mouse xenograft models. Aim 2 will expand this question to eight clinically-relevant targeted therapies in DMG, generating resistant cell line models and profiling emerging cell populations with single-cell barcoding and multiome technologies across treatment modalities. Aim 3 will use predictive modelling to identify the features that contribute the most to treatment resistance in our generated cell line models, validating them in vitro and in a cohort of >70 human DMG samples, with the goal of informing therapeutic strategies for primary and relapsed disease.
Upon completion, I envision this interdisciplinary project will establish a framework for rational therapeutic combinations designed to overcome treatment resistance in DMG.
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Keywords
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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.1.1 - European Research Council (ERC)
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
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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-2026-STG
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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.
751 05 Uppsala
Sweden
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