Project description
Tackling drug resistance in AML
Acute myeloid leukaemia (AML) is a deadly cancer with poor survival rates, largely due to drug resistance. Despite advances in targeted therapies, many patients experience relapse. A key challenge lies in understanding how AML’s epigenetic alterations enable cancer cells to develop resistance under drug pressure. In this context, the ERC-funded SC-Plasticity project will use innovative single-cell sequencing techniques, like scRaCH-seq, to analyse how mutations in epigenetic regulators affect therapy responses. By studying how epigenetic modifications influence drug sensitivity, this research could pave the way for new strategies to overcome drug resistance and improve treatment outcomes in AML.
Objective
Novel targeted therapies are increasingly applied against a wide range of cancers. Although such agents can induce cures, most patients suffer from relapsed disease.
Acute myeloid leukaemia (AML) is a prime example of a deadly disease, but we have a chance to dramatically improve outcomes if we can better understand resistance mechanisms against targeted agents that are transforming AML treatment, such as the BCL2 inhibitor venetoclax. AML is characterised by profound alterations in the epigenome that are correlated with poor survival. I therefore hypothesise that targeted drug pressure induces epigenetic plasticity that allows cancer cells to sample alternate chromatin or transcriptional states, a subset of which confer drug resistance. A major challenge is to define how mutations of epigenetic regulators in AML affect therapy responses due to clonal heterogeneity. To address this challenge, I will use and further develop my recently published single-cell Rapid Capture Hybridization sequencing (scRaCH-seq) method to link the genotype of expressed genes to transcription and methylation profiles of thousands of single cells. In this research proposal, I aim to (1) develop a new method linking epigenetic landscape, genotype and transcriptome at a single-cell level and define the impact of treatment on these interactions. (2) Analyse the genome-wide impact of epigenetic therapies. (3) Define the association between drug sensitivity and epigenetic modifications regulating pro-survival genes. To achieve my goals, I will apply my novel single-cell multiomics to samples from AML patients treated with venetoclax alone or in combination with epigenetic therapies and apply state-of-the-art technologies to established laboratory models.
Our new approaches to fully understand the relationship between the genome, epigenome and transcriptome will advance fundamental biology. This has the potential to yield new therapeutic strategies to prevent and overcome resistance.
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 leukemia
- natural sciences biological sciences genetics genomes
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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)
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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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(opens in new window) ERC-2023-STG
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1081 HV Amsterdam
Netherlands
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