Prédicteurs moléculaires et nouvelles cibles en oncologie

Over the past 5 years, antibody drug conjugates (ADCs) have shown impressive improvements in survival outcomes of solid tumors and hematological malignancies. With 14 ADCs already approved across different countries and more than 140 that entered the clinical development, they are intended to replace standard chemotherapies across multiple tumor types over the next decade. Although ADCs show great clinical efficacy, resistance eventually occurs, and it becomes critical to understand resistance mechanisms to guide the choice of the following lines of therapy for patients who progress on a given ADC. Given the complex nature of ADCs, immunocompromised mouse models (nude mice, NOD-SCID or NOG mice) and currently used clinical assays (standard radiology, IHC, WES etc) are not the optimal preclinical and clinical tools, to identify the multiple causes of resistance. The OASIS project aims to generate a biobank of different patient-derived organoids (PDOs), which better recapitulate ADCs resistance and integrate different assays, spanning from whole-body molecular imaging (Ab-radiolabeled PET scan or immunoPET), circulating tumor cells (CTC), plasma proteomics, to multiplex immunofluorescence (MIF) and machine-learning enhanced digital pathology (AI-digital pathology) to capture most of the parallel mechanisms of resistance to ADCs. Such tools will enable to define biomarkers of ADC resistance that can inform further therapeutic decisions.

Worldwide, ~7 million women live with or beyond Breast Cancer (BC), as 10-year survival rates exceeding 80% for early-stage (I-III) BC. Premenopausal BC accounts for 25% in the EU and 55% in low/middle income countries. Most premenopausal women with BC have high risk of recurrence, therefore standard treatment includes adjuvant chemo- (CT) and endocrine therapy (ET). However, treatment has substantial physical, emotional and social burden, which is often more pressing for younger compared to older patients. Gene-expression assays are used for post-menopausal patients to identify women who can safely forego CT without detriment on clinical outcomes, preserving Quality of Life (QOL). However, a definitive study has yet to be conducted among premenopausal women with high-risk HR+HER2-BC. The primary objective of PATH-FOR-YOUNG is to conduct a pragmatic randomized controlled trial (RCT) with 5000 patients validating the use of a gene-expression assay to drive adjuvant treatment decisions in this target population. PATH-FOR-YOUNG aims to achieve its objective in 7 years. The project (i) builds on and complements an ongoing twin RCT to ensure timely recruitment, (ii) leverages on a large international consortium of oncologists, pathologists, patient representatives, psychologists, sociologists, ethics and communication experts, biostatisticians, health economists, and technology providers, to assure complementary and multidisciplinary expertise, and (iii) highlights patient-engagement, participatory care, and early involvement of end users. PATH-FOR-YOUNG will also study implementation of digital self-management to support patients throughout the cancer journey and particularly while on ET to improve QOL and medication adherence. A full HTA will ensure a path towards cross-country implementation. PATH-FOR-YOUNG has the ambition to improve BC care, fully integrating the predictive, personalized, preventive, and participatory principles of health management.

Les pratiques dites complémentaires, traditionnelles, naturelles ou intégratives connaissent un regain d’intérêt dans les pays développés., en particulier pour le traitement de symptômes en lien avec le cancer ou ses traitements. Si ces pratiques font appel à des prises de substances ou des changements d’alimentation, elles peuvent modifier le profil de toxicité des traitements conventionnels, et ainsi modifier la balance bénéfice-risque de ces pratiques. La réponse actuellement privilégiée par les tutelles et l’académie est une position de prudence et d’alerte, légitime, mais qui laisse le patient seul face à ses choix, et aux multiples informations circulantes. Il semble donc important aujourd’hui de nous interroger dans le cadre d’une recherche participative réunissant patients, professionnels de santé et chercheurs sur les moyens d’intégrer ces pratiques de manière efficace, sécurisée et éclairée dans le parcours de soins en oncologie. Une première étape fera un état des lieux de l’existant en termes de connaissances attitudes et pratiques des patients et professionnels et de ressource d’information, éducation et communication existantes. Puis l’étape de recherche participative permettra la production de recommandations des ressources nécessaires à l’intégration de ces pratiques dans le parcours de soins conventionnels des patients de manière sécurisée et efficace.

Recent large-scale genomic profiling studies have uncovered mutations in the SWI/SNF (SWItch / Sucrose Non-Fermentable) chromatin remodelling complex subunits in 20% of solid tumours. Most of these tumours resist to current therapies. To address this highly unmet medical need, it is crucial to determine how to harness vulnerabilities induced by SWI/SNF defects. Recent evidence shows that SWI/SNF influences the DNA damage response and is involved in shaping tumour immunogenicity. Though, whether there is a link between these observations, and whether the latter may be therapeutically exploited is unknown. Further, the impact of SWI/SNF defects on tumour heterogeneity, a major determinant of resistance to treatment, remains unaddressed. I therefore propose to identify and understand synthetic lethal vulnerabilities associated with two selected SWI/SNF defects of unmet need (PBRM1 and SMARCB1), and to further study how the latter can be exploited to stimulate the anti-tumour immune response. By using hypothesis-testing and -generating approaches including high-throughput screening on in-house developed isogenic and non-isogenic models, I will identify and decipher novel synthetic lethal vulnerabilities associated with PBRM1 and SMARCB1 defects. Molecular biology, high-content imaging and in vivo experiments will be performed to study the effects of drugs that cause synthetic lethality, both on intra-cellular signalling and on anti-tumour immune response. I will further characterise the impact of SMARCB1 defects on tumour heterogeneity using single cell sequencing on preclinical models and human tumour samples. Preclinical data will be integrated with tumour profiling and clinical data, and will guide the development of proof-of-concept clinical studies, as I previously did. The overall research program will identify, decipher mechanistically and evaluate clinically novel immuno-oncology therapeutic strategies for selected SWI/SNF-deficient tumours of unmet need.

EUonQoL aims to develop, pilot and validate the EUonQoL-Kit, a patient-driven, unified system for the assessment of quality of life (QoL) based on evaluations and preferences of cancer patients and survivors. The EUonQoL-Kit will be developed from a patient perspective, administered digitally, available in the EU27 and Associated countries languages, and applicable in future, periodic surveys to contribute to the EU’s mission on cancer. At the core of the EUonQoL there is the adoption of a multistakeholder, co-design methodology, engaging patient representatives, healthcare professionals, administrators, policymakers, and citizens in all project related activities. Existing QoL tools will be reviewed, scoping all relevant sources. This review will be used in the context of the codesign consensus with stakeholders’ and patients’ preferences to identify gaps and establish all QoL dimensions that are relevant from the perspectives of patients, clinicians, and society. A multidisciplinary panel of leading experts will develop the EUonQoL-Kit to be validated in a digital pilot survey of 4,000 patients and survivors enrolled through a network of EU cancer centres. An analysis of factors potentially impacting QoL, will also be performed. EUonQoL will explore strategies for the implementation and exploitation of the EUonQoL-Kit, while coordinating a QoL-Patient-Centred Care (PCC) cluster across Cancer Mission projects to develop a system-wide PCC policy, built on sustained stakeholder engagement and targeted outreach, as the basis for routine QoL data collection. EUonQoL is composed of research institutions, cancer centres, as well as scientific, professional, and patient representative organizations involved in cancer research, all with extensive experience and robust scientific background in developing self-reported QoL measures. This partnership fuels the ambition of EUonQoL to translate QoL data into future changes in cancer care policy and clinical practice.

The 15-month coordination and support action “4.UNCAN.eu” will generate a strategic agenda to launch UNCAN.eu, a European initiative to UNderstand CANcer proposed by the Mission Board and the European Beating Cancer Plan. This research agenda will be built with the final aim of achieving a new breakthrough in cancer prevention and treatment that will contribute to saving European citizens’ lives and help ensuring an optimal quality of life to disease survivors. To reach a new level of understanding, UNCAN.eu will take advantage of recent advances in research data generation and data sciences. Reliable, high-quality cancer research data generated by experimental model analysis and collected from longitudinal follow-up of cancer patients will be shared and integrated at an unprecedented scale within a Federated Cancer Research data hub, in the context of the General Data Protection Regulation. This information will be used by relevant players in Europe and beyond to address urgent and essential scientific and medical challenges in cancer prevention, early diagnosis, treatment and survivorship, in males and females of various ages. These challenges, identified in close interaction with European patients and citizens, will be tackled through competitive, ambitious and innovative, cross-border and trans-disciplinary research programmes built in a problem-solving manner. The definition of challenges will integrate inequalities in cancer research across regions and member states in order to boost the research potential of less-developed regions in Europe. Players will be committed to open science principles, including FAIR (findable, accessible, interoperable, and reusable) guiding principles for scientific data collection, management and stewardship. The new understanding gained from the collection and analysis of this wealth of data will apply secondarily to other diseases.

Les récentes études de séquençage à haut débit ont mis en évidence des mutations des gènes codant pour les sous-unités du complexe de remodelage de la chromatine SWI/SNF (Switch / Sucrose Non-Fermentable) dans 20% des tumeurs solides. La majorité de ces tumeurs résiste actuellement aux traitements anticancéreux. Afin d’adresser ce besoin médical urgent et non couvert, il est essentiel d’identifier et comprendre les vulnérabilités génétiques conférées par la perte de SWI/SNF, dans le but de développer de nouvelles stratégies thérapeutiques pour les cancers déficients en SWI/SNF. Les récentes données de la littérature suggèrent que SWI/SNF joue un rôle dans la réparation de l’ADN et l’immunité anti-tumorale. Je propose ainsi : (i) d’identifier et comprendre les relations de létalité synthétique (ou vulnérabilités génétiques) associées à la perte de SWI/SNF ; et (ii) d’étudier comment celles-ci peuvent être exploitées pour stimuler la réponse immunitaire anti-tumorale, afin de développer de nouvelles approches thérapeutiques ciblées de médecine de précision en immuno-oncologie, que j’évaluerai ensuite au cours d’un protocole clinique « preuve-de-concept ». Des approches complémentaires « génératrices d’hypothèses » et basées sur nos données préliminaires seront utilisées en parallèle pour identifier et comprendre au plan mécanistique les vulnérabilités génétiques associées aux défauts de SWI/SNF. Pour cela, j’utiliserai des modèles isogéniques et non-isogéniques développés au laboratoire, ainsi que des échantillons tumoraux. Des études utilisant la biologie moléculaire, l’imagerie à haut-débit, et des expériences in vivo sur des xénogreffes ou modèles syngéniques, seront réalisées pour étudier l’effet des molécules identifiées comme étant synthétiques létales avec les défauts de SWI/SNF, à la fois sur la signalisation intra-cellulaire et sur l’immunité anti-tumorale. J’associerai également des approches de criblage à haut-débit et de protéomique pour caractériser précisément la stoechiométrie et l’interactome de SWI/SNF. L’impact des défauts de SWI/SNF sur l’hétérogénéité tumorale sera également exploré. Les résultats de nos travaux au laboratoire seront intégrés avec des données cliniques. Mon programme permettra ainsi l’identification, la compréhension mécanistique et l’évaluation clinique de nouvelles stratégies thérapeutiques ciblées d’immuno-oncologie pour les tumeurs déficientes en SWI/SNF.