What doesn’t kill you: primed and adaptive mechanisms of treatment resistance in ovarian cancer

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.

Novel 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 where:

1. The first drug will drive cells to identified sensitive states prior to the treatment.
2. The second drug will block identified adaptive responses during the treatment.

Validation in Patient-Derived Xenograft Models

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.