The OVAREX study: Establishment of ex vivo ovarian cancer models to validate innovative therapies and to identify predictive biomarkers.

BACKGROUND: Ovarian cancer is the first cause of death from gynecological malignancies mainly due to development of chemoresistance. Despite the emergence of PARP inhibitors, which have revolutionized the therapeutic management of some of these ovarian cancers, the 5-year overall survival rate remains around 45%. Therefore, it is crucial to develop new therapeutic strategies, to identify predictive biomarkers and to predict the response to treatments. In this context, functional assays based on patient-derived tumor models could constitute helpful and relevant tools for identifying efficient therapies or to guide clinical decision making. METHOD: The OVAREX study is a single-center non-interventional study which aims at investigating the feasibility of establishing in vivo and ex vivo models and testing ex vivo models to predict clinical response of ovarian cancer patients. Patient-Derived Xenografts (PDX) will be established from tumor fragments engrafted subcutaneously into immunocompromised mice. Explants will be generated by slicing tumor tissues and Ascites-Derived Spheroids (ADS) will be isolated following filtration of ascites. Patient-derived tumor organoids (PDTO) will be established after dissociation of tumor tissues or ADS, cell embedding into extracellular matrix and culture in specific medium. Molecular and histological characterizations will be performed to compare tumor of origin and paired models. Response of ex vivo tumor-derived models to conventional chemotherapy and PARP inhibitors will be assessed and compared to results of companion diagnostic test and/or to the patient's response to evaluate their predictive value. DISCUSSION: This clinical study aims at generating PDX and ex vivo models (PDTO, ADS, and explants) from tumors or ascites of ovarian cancer patients who will undergo surgical procedure or paracentesis. We aim at demonstrating the predictive value of ex vivo models for their potential use in routine clinical practice as part of precision medicine, as well as establishing a collection of relevant ovarian cancer models that will be useful for the evaluation of future innovative therapies. TRIAL REGISTRATION: The clinical trial has been validated by local research ethic committee on January 25th 2019 and registered at ClinicalTrials.gov with the identifier NCT03831230 on January 28th 2019, last amendment v4 accepted on July 18, 2023.

Patient-derived tumor organoids: a new avenue for preclinical research and precision medicine in oncology.

Over the past decade, the emergence of patient-derived tumor organoids (PDTOs) has broadened the repertoire of preclinical models and progressively revolutionized three-dimensional cell culture in oncology. PDTO can be grown from patient tumor samples with high efficiency and faithfully recapitulates the histological and molecular characteristics of the original tumor. Therefore, PDTOs can serve as invaluable tools in oncology research, and their translation to clinical practice is exciting for the future of precision medicine in oncology. In this review, we provide an overview of methods for establishing PDTOs and their various applications in cancer research, starting with basic research and ending with the identification of new targets and preclinical validation of new anticancer compounds and precision medicine. Finally, we highlight the challenges associated with the clinical implementation of PDTO, such as its representativeness, success rate, assay speed, and lack of a tumor microenvironment. Technological developments and autologous cocultures of PDTOs and stromal cells are currently ongoing to meet these challenges and optimally exploit the full potential of these models. The use of PDTOs as standard tools in clinical oncology could lead to a new era of precision oncology in the coming decade.

Comparative analysis of response to treatments and molecular features of tumor-derived organoids versus cell lines and PDX derived from the same ovarian clear cell carcinoma.

BACKGROUND: In the era of personalized medicine, the establishment of preclinical models of cancer that faithfully recapitulate original tumors is essential to potentially guide clinical decisions. METHODS: We established 7 models [4 cell lines, 2 Patient-Derived Tumor Organoids (PDTO) and 1 Patient-Derived Xenograft (PDX)], all derived from the same Ovarian Clear Cell Carcinoma (OCCC). To determine the relevance of each of these models, comprehensive characterization was performed based on morphological, histological, and transcriptomic analyses as well as on the evaluation of their response to the treatments received by the patient. These results were compared to the clinical data. RESULTS: Only the PDX and PDTO models derived from the patient tumor were able to recapitulate the patient tumor heterogeneity. The patient was refractory to carboplatin, doxorubicin and gemcitabine, while tumor cell lines were sensitive to these treatments. In contrast, PDX and PDTO models displayed resistance to the 3 drugs. The transcriptomic analysis was consistent with these results since the models recapitulating faithfully the clinical response grouped together away from the other classical 2D cell culture models. We next investigated the potential of drugs that have not been used in the patient clinical management and we identified the HDAC inhibitor belinostat as a potential effective treatment based on PDTO response. CONCLUSIONS: PDX and PDTO appear to be the most relevant models, but only PDTO seem to present all the necessary prerequisites for predictive purposes and could constitute relevant tools for therapeutic decision support in the context of these particularly aggressive cancers refractory to conventional treatments.

[Patient-derived tumor organoids (or tumoroid), a growing preclinical model for oncology]. / Les tumoroïdes, modèles précliniques en plein essor pour l'oncologie.

The recent emergence of tumor organoid cultures, or tumoroids, has enriched the repertoire of preclinical models in oncology. These microtumors are obtained in vitro by including cells from patient tumor samples in an extracellular matrix and cultured in specific media. Very close to the tumor of origin, tumoroids can be amplified fairly rapidly from a small quantity of tissue, established with high success rate for most tumor types, easily genetically engineered, and stored in biobanks. Tumoroids thus offer numerous possibilities in terms of basic research, such as the study of carcinogenesis or mechanisms of chemoresistance, but also the identification of new targets and preclinical validation of new anti-cancer compounds or personalized medicine. Technological developments and enrichment of tumoroids with other cell types are currently ongoing to optimally exploit the full potential of these models.

Title: Les tumoroïdes, modèles précliniques en plein essor pour l'oncologie. Abstract: La récente émergence des cultures d'organoïdes tumoraux, ou tumoroïdes, a permis d'enrichir le répertoire des modèles précliniques en oncologie. Très proches de la tumeur dont elles dérivent, ces microtumeurs offrent de nombreuses possibilités en termes de recherche fondamentale, telles que l'étude de la carcinogenèse ou de la chimioré-sistance, de validation préclinique de nouvelles molécules à visée anticancéreuse, ou encore de personnalisation des traitements. Divers développements techniques et l'enrichissement des tumoroïdes par l'addition d'autres types cellulaires sont actuellement en cours pour améliorer la pertinence de ces modèles et exploiter de façon optimale leur remarquable potentiel.

[Patient-derived tumor organoids (or tumoroid) as valuable precision medicine tools]. / Les organoïdes dérivés de tumeurs (ou tumoroïdes), des outils de choix pour la médecine de précision en oncologie.

Review of literature shows that it is possible to establish tumor-derived organoids, or tumoroids, from almost any type of tumor, and that these "micro-tumors" could be used to develop functional assays allowing the prediction of the patient response to treatments and/or the identification of predictive molecular signatures associated with the development of these therapies. Although it is still essential to optimize culture conditions to promote and accelerate the establishment of tumoroids, or to recapitulate tumor microenvironment, many applications are now possible in the field of prediction of response to treatments and in guiding therapeutic decision-making. Using tumoroids as standard tools in clinical oncology could make precision oncology enter a new era in the coming decade. Numerous ongoing research and clinical trials conducted throughout the world aim to validate the interest of this approach.

Title: Les organoïdes dérivés de tumeurs (ou tumoroïdes), des outils de choix pour la médecine de précision en oncologie. Abstract: Il est désormais possible d'établir des tumoroïdes à partir de presque tout type de tumeur, notamment en vue de la mise en place de tests fonctionnels prédictifs et/ou de l'identification de signatures moléculaires prédictives. Bien que l'optimisation des conditions de culture ou la complexification du micro-environnement des tumoroïdes soit encore nécessaire, de nombreuses applications sont déjà envisageables dans le domaine de la prédiction de la réponse aux traitements et de l'orientation de la décision thérapeutique. Par l'introduction de leur utilisation en clinique, l'oncologie de précision pourrait bien entrer dans une nouvelle ère dans le courant de la décennie à venir.