The OVAREX study: Establishment of ex vivo ovarian cancer models to validate innovative therapies and to identify predictive biomarkers.
Explants
Ovarian cancer
Patient-derived tumor organoids
Patient-derived tumor xenografts
Predictive functional assays.
Spheroids
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
07 Jun 2024
07 Jun 2024
Historique:
received:
24
04
2024
accepted:
24
05
2024
medline:
8
6
2024
pubmed:
8
6
2024
entrez:
7
6
2024
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND
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
METHODS
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
CONCLUSIONS
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
BACKGROUND
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.
Identifiants
pubmed: 38849726
doi: 10.1186/s12885-024-12429-w
pii: 10.1186/s12885-024-12429-w
doi:
Substances chimiques
Biomarkers, Tumor
0
Banques de données
ClinicalTrials.gov
['NCT03831230']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
701Subventions
Organisme : Région Normandie
ID : ORGATHEREX
Organisme : Canceropole Nord-Ouest, France
ID : ORGRAFT
Organisme : Fondation de l'Avenir
ID : AP-RM-19-020
Organisme : Fondation ARC pour la Recherche sur le Cancer
ID : PJA20191209649
Informations de copyright
© 2024. The Author(s).
Références
Cabasag CJ, Butler J, Arnold M, Rutherford M, Bardot A, Ferlay J, et al. Exploring variations in ovarian cancer survival by age and stage (ICBP SurvMark-2): a population-based study. Gynecol Oncol avr. 2020;157(1):234–44.
doi: 10.1016/j.ygyno.2019.12.047
Torres D, Wang C, Kumar A, Bakkum-Gamez JN, Weaver AL, McGree ME, et al. Factors that influence survival in high-grade serous ovarian cancer: a complex relationship between molecular subtype, disease dissemination, and operability. Gynecol Oncol août. 2018;150(2):227–32.
doi: 10.1016/j.ygyno.2018.06.002
Lheureux S, Braunstein M, Oza AM. Epithelial ovarian cancer: evolution of management in the era of precision medicine. CA Cancer J Clin. 2019;69(4):280–304.
doi: 10.3322/caac.21559
pubmed: 31099893
Marth C, Abreu MH, Andersen KK, Aro KM, de Lurdes Batarda M, Boll D, et al. Real-life data on treatment and outcomes in advanced ovarian cancer: an observational, multinational cohort study (RESPONSE trial). Cancer 15 août. 2022;128(16):3080–9.
Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 29 déc. 2011;365(26):2484–96.
Rossi L, Verrico M, Zaccarelli E, Papa A, Colonna M, Strudel M, et al. Bevacizumab in ovarian cancer: a critical review of phase III studies. Oncotarget 14 févr. 2017;8(7):12389–405.
doi: 10.18632/oncotarget.13310
Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 29 déc. 2011;365(26):2473–83.
Mateo J, Lord CJ, Serra V, Tutt A, Balmaña J, Castroviejo-Bermejo M, et al. A decade of clinical development of PARP inhibitors in perspective. Ann Oncol Sept. 2019;30(9):1437–47.
doi: 10.1093/annonc/mdz192
Ray-Coquard I, Pautier P, Pignata S, Pérol D, González-Martín A, Berger R, et al. Olaparib plus Bevacizumab as First-Line maintenance in Ovarian Cancer. N Engl J Med 19 déc. 2019;381(25):2416–28.
doi: 10.1056/NEJMoa1911361
Leman R, Muller E, Legros A, Goardon N, Chentli I, Atkinson A, et al. Validation of the clinical use of GIScar, an academic-developed genomic instability score Predicting sensitivity to maintenance Olaparib for Ovarian Cancer. Clin Cancer Res 1 nov. 2023;29(21):4419–29.
doi: 10.1158/1078-0432.CCR-23-0898
Morice PM, Coquan E, Weiswald LB, Lambert B, Vaur D, Poulain L. Identifying patients eligible for PARP inhibitor treatment: from NGS-based tests to 3D functional assays. Br J Cancer Juill. 2021;125(1):7–14.
doi: 10.1038/s41416-021-01295-z
Letai A, Bhola P, Welm AL. Functional precision oncology: testing tumors with drugs to identify vulnerabilities and novel combinations. Cancer Cell 10 janv. 2022;40(1):26–35.
doi: 10.1016/j.ccell.2021.12.004
Alkema NG, Wisman GBA, van der Zee AGJ, van Vugt MATM, de Jong S. Studying platinum sensitivity and resistance in high-grade serous ovarian cancer: different models for different questions. Drug Resist Updat janv. 2016;24:55–69.
doi: 10.1016/j.drup.2015.11.005
Thorel L, Florent R, Perréard M, Vincent A, Poulain L, Weiswald LB. [Patient-derived tumor organoids (or tumoroid), a growing preclinical model for oncology]. Med Sci (Paris) Nov. 2022;38(11):880–7.
doi: 10.1051/medsci/2022148
Weiswald LB, Bellet D, Dangles-Marie V. Spherical cancer models in tumor biology. Neoplasia janv. 2015;17(1):1–15.
doi: 10.1016/j.neo.2014.12.004
Lheureux S, N’Diaye M, Blanc-Fournier C, Dugué AE, Clarisse B, Dutoit S, et al. Identification of predictive factors of response to the BH3-mimetic molecule ABT-737: an ex vivo experiment in human serous ovarian carcinoma. Int J Cancer 1 mars. 2015;136(5):E340–350.
Majumder B, Baraneedharan U, Thiyagarajan S, Radhakrishnan P, Narasimhan H, Dhandapani M, et al. Predicting clinical response to anticancer drugs using an ex vivo platform that captures tumour heterogeneity. Nat Commun 27 févr. 2015;6:6169.
doi: 10.1038/ncomms7169
Vaira V, Fedele G, Pyne S, Fasoli E, Zadra G, Bailey D, et al. Preclinical model of organotypic culture for pharmacodynamic profiling of human tumors. Proc Natl Acad Sci U S 4 mai. 2010;107(18):8352–6.
doi: 10.1073/pnas.0907676107
Zanella ER, Grassi E, Trusolino L. Towards precision oncology with patient-derived xenografts. Nat Rev Clin Oncol Nov. 2022;19(11):719–32.
doi: 10.1038/s41571-022-00682-6
Izumchenko E, Paz K, Ciznadija D, Sloma I, Katz A, Vasquez-Dunddel D, et al. Patient-derived xenografts effectively capture responses to oncology therapy in a heterogeneous cohort of patients with solid tumors. Ann Oncol 1 oct. 2017;28(10):2595–605.
doi: 10.1093/annonc/mdx416
Sachs N, Clevers H. Organoid cultures for the analysis of cancer phenotypes. Curr Opin Genet Dev févr. 2014;24:68–73.
doi: 10.1016/j.gde.2013.11.012
Pampaloni F, Reynaud EG, Stelzer EHK. The third dimension bridges the gap between cell culture and live tissue. Nat Rev Mol Cell Biol oct. 2007;8(10):839–45.
doi: 10.1038/nrm2236
Ford CE, Werner B, Hacker NF, Warton K. The untapped potential of ascites in ovarian cancer research and treatment. Br J Cancer Juill. 2020;123(1):9–16.
doi: 10.1038/s41416-020-0875-x
Latifi A, Luwor RB, Bilandzic M, Nazaretian S, Stenvers K, Pyman J, et al. Isolation and characterization of tumor cells from the ascites of ovarian cancer patients: molecular phenotype of chemoresistant ovarian tumors. PLoS ONE. 2012;7(10):e46858.
doi: 10.1371/journal.pone.0046858
pubmed: 23056490
pmcid: 3466197
Veninga V, Voest EE. Tumor organoids: opportunities and challenges to guide precision medicine. Cancer Cell 13 sept. 2021;39(9):1190–201.
doi: 10.1016/j.ccell.2021.07.020
Thorel L, Morice PM, Paysant H, Florent R, Babin G, Thomine C, et al. 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. J Exp Clin Cancer Res. oct 2023;7(1):260.
Florent R, Weiswald LB, Lambert B, Brotin E, Abeilard E, Louis MH, et al. Bim, Puma and Noxa upregulation by Naftopidil sensitizes ovarian cancer to the BH3-mimetic ABT-737 and the MEK inhibitor Trametinib. Cell Death Dis 18 mai. 2020;11(5):1–16.
Dijkstra KK, Cattaneo CM, Weeber F, Chalabi M, van de Haar J, Fanchi LF, et al. Generation of Tumor-reactive T cells by co-culture of Peripheral Blood lymphocytes and Tumor Organoids. Cell. sept 2018;6(6):1586–e159812.
Perréard M, Florent R, Divoux J, Grellard JM, Lequesne J, Briand M, et al. ORGAVADS: establishment of tumor organoids from head and neck squamous cell carcinoma to assess their response to innovative therapies. BMC Cancer déc. 2023;23(1):1–9.
de Witte CJ, Espejo Valle-Inclan J, Hami N, Lõhmussaar K, Kopper O, Vreuls CPH et al. Patient-Derived Ovarian Cancer Organoids Mimic Clinical Response and Exhibit Heterogeneous Inter- and Intrapatient Drug Responses. Cell Reports. 16 juin. 2020;31(11):107762.