Project description
How to block intrinsic and adaptive resistance in cancer treatment
Cancer therapy resistance is a multifaceted and dynamic phenomenon. Pre-existing cell states enable both natural selection and adaptation processes. A recent study revealed that cells with stress-associated states exhibit therapy resistance in high-grade serous ovarian cancer metastatic tumours. This finding suggests that pre-existing stress may bolster the resilience of cancer cells during neoadjuvant chemotherapy. The ERC-funded STRONGER project integrates dynamic stress monitoring with the identification of pre-existing resistant states using the ReSisTrace methodology. The project will apply this methodology on patient-derived organoids to ascertain how past stress signalling of individual cells influences their adaptive stress responses and survival. The primary goal of the project is to delineate primed and adaptive resistance mechanisms and devise innovative, sequential therapeutic approaches.
Objective
Cancer therapy resistance is a complex, dynamic process. Pre-existing heterogeneity in cell states provides substance for evolutionary selection, and their plasticity enables adaptation during the therapy. Recently, we discovered a stress-related, immunocompromised cell state underpinning both intrinsic and adaptive resistance in high-grade serous ovarian cancer (HGSC) metastatic tumours, suggesting that pre-existing stress improves the resilience of cancer cells during neoadjuvant chemotherapy.
To unveil how past stress responses prime cancer cells adaptation during therapies, I suggest a novel approach that combines dynamic stress recording with the identification of pre-existing resistant states via my novel methodology, ReSisTrace. We will apply this ground-breaking approach in patient-derived organoids to reveal how past stress signalling of a single cell is reflected in its adaptive stress responses and survival upon chemotherapy or cytotoxic immune attack. We will further characterise subclonal and spatial enrichment of the identified resistant phenotypes in longitudinal clinical specimens to incorporate the effect of tumour microenvironment in discovered mechanisms.
Importantly, simultaneous characterisation of primed and adaptive resistance enables us to overcome both of them by a sequential combination of drugs where the first will drive cells to identified sensitive states prior the treatment, and the second will block identified adaptive responses during the treatment. After finding the most effective pre-sensitisers and anti-adaptive drugs in the organoids, we will validate most promising combinations in patient-derived xenograft models to pave the way for clinical translation. By targeting both pre-existing cell states and their plasticity, my novel approach will lead to a paradigm shift by providing novel, sequential therapeutic strategies to mutually overcome intrinsic and adaptive resistance in the treatment of cancer.
Fields of science (EuroSciVoc)
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CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
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Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
00014 HELSINGIN YLIOPISTO
Finland