What doesn’t kill you: primed and adaptive mechanisms of treatment resistance in ovarian cancer
This project aims to develop a novel methodology to identify and target pre-existing resistant cell states in ovarian cancer, enhancing therapy effectiveness through sequential drug combinations.
Projectdetails
Introduction
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.
Proposed Approach
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.
Application in Patient-Derived Organoids
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.
Characterisation of Resistant Phenotypes
We will further characterise subclonal and spatial enrichment of the identified resistant phenotypes in longitudinal clinical specimens to incorporate the effect of the tumour microenvironment in discovered mechanisms.
Overcoming Resistance
Importantly, simultaneous characterisation of primed and adaptive resistance enables us to overcome both of them by a sequential combination of drugs:
- The first drug will drive cells to identified sensitive states prior to treatment.
- The second drug will block identified adaptive responses during the treatment.
Validation of Drug Combinations
After finding the most effective pre-sensitisers and anti-adaptive drugs in the organoids, we will validate the most promising combinations in patient-derived xenograft models to pave the way for clinical translation.
Conclusion
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.
Financiële details & Tijdlijn
Financiële details
Subsidiebedrag | € 1.999.754 |
Totale projectbegroting | € 1.999.754 |
Tijdlijn
Startdatum | 1-4-2024 |
Einddatum | 31-3-2029 |
Subsidiejaar | 2024 |
Partners & Locaties
Projectpartners
- HELSINGIN YLIOPISTOpenvoerder
Land(en)
Vergelijkbare projecten binnen European Research Council
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Paradoxical activation of oncogenic signaling as a cancer treatment strategy.This project aims to selectively kill cancer cells by hyperactivating oncogenic signaling while disrupting stress responses, using multi-omics to identify vulnerabilities and effective combination therapies. | ERC Advanced... | € 2.500.000 | 2024 | Details |
Precision oncology of spatial immune escape mechanisms in ovarian cancerThis project aims to exploit tumor genetic drivers of immune escape in high-grade serous ovarian cancer to develop effective immunotherapies through advanced profiling and functional testing of patient-derived organoids. | ERC Starting... | € 2.368.459 | 2023 | Details |
Dynamics of Adaptation and Resistance in Cancer: MApping and conTrolling Transcriptional and Epigenetic RecurrenceThis project aims to uncover the mechanisms of drug resistance in colorectal cancer through innovative models and computational methods, ultimately improving treatment strategies and patient outcomes. | ERC Consolid... | € 1.995.582 | 2024 | Details |
Understanding and targeting cancer persister cellsThis project aims to develop tools for studying cancer persister cells using single-cell lineage tracing to enhance understanding and treatment of therapy-resistant tumors. | ERC Starting... | € 1.728.750 | 2024 | Details |
Cancer cell plasticity on targeted therapy
This project aims to develop innovative cancer therapies by analyzing tumor heterogeneity and targeting drug-tolerant persister cells to prevent resistance and improve patient outcomes.
Paradoxical activation of oncogenic signaling as a cancer treatment strategy.
This project aims to selectively kill cancer cells by hyperactivating oncogenic signaling while disrupting stress responses, using multi-omics to identify vulnerabilities and effective combination therapies.
Precision oncology of spatial immune escape mechanisms in ovarian cancer
This project aims to exploit tumor genetic drivers of immune escape in high-grade serous ovarian cancer to develop effective immunotherapies through advanced profiling and functional testing of patient-derived organoids.
Dynamics of Adaptation and Resistance in Cancer: MApping and conTrolling Transcriptional and Epigenetic Recurrence
This project aims to uncover the mechanisms of drug resistance in colorectal cancer through innovative models and computational methods, ultimately improving treatment strategies and patient outcomes.
Understanding and targeting cancer persister cells
This project aims to develop tools for studying cancer persister cells using single-cell lineage tracing to enhance understanding and treatment of therapy-resistant tumors.
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Macrophage-based immunotherapy of platinum-resistant ovarian cancerThe MACOV project aims to develop a groundbreaking macrophage-based therapy for platinum-resistant ovarian cancer, preparing it for Phase I clinical trials through comprehensive pre-clinical efficacy and safety studies. | EIC Transition | € 2.499.998 | 2022 | Details |
Functional chemical reprogramming of cancer cells to induce antitumor immunityThe RESYNC consortium aims to revolutionize cancer immunotherapy by reprogramming cancer cells into antigen-presenting dendritic cells using small molecules for personalized and safer treatments. | EIC Pathfinder | € 2.966.695 | 2024 | Details |
Macrophage-based immunotherapy of platinum-resistant ovarian cancer
The MACOV project aims to develop a groundbreaking macrophage-based therapy for platinum-resistant ovarian cancer, preparing it for Phase I clinical trials through comprehensive pre-clinical efficacy and safety studies.
Functional chemical reprogramming of cancer cells to induce antitumor immunity
The RESYNC consortium aims to revolutionize cancer immunotherapy by reprogramming cancer cells into antigen-presenting dendritic cells using small molecules for personalized and safer treatments.