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

Descripción del proyecto

Cómo bloquear la resistencia intrínseca y adaptativa en el tratamiento contra el cáncer

La resistencia al tratamiento contra el cáncer es un fenómeno polifacético y dinámico. Los estados celulares preexistentes permiten tanto la selección natural como los procesos de adaptación. En un estudio reciente se reveló que las células con estados asociados al estrés presentan resistencia al tratamiento en tumores metastásicos de cáncer de ovario serosos de evolución rápida. Este hallazgo sugiere que el estrés preexistentes puede reforzar la resistencia de las células cancerosas durante la quimioterapia neoadyuvante. El equipo del proyecto STRONGER, financiado por el Consejo Europeo de Investigación, integra el control dinámico del estrés con la identificación de estados resistentes preexistentes mediante la metodología ReSisTrace. En el proyecto se aplicará esta metodología en organoides derivados de pacientes para determinar cómo influye la señalización de estrés pasada de células individuales en sus respuestas adaptativas al estrés y en su supervivencia. El objetivo principal del proyecto es definir los mecanismos de resistencia principal y adaptativa e idear métodos terapéuticos innovadores y secuenciales.

Objetivo

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.