Assays Of Conventional Chemotherapeutics And Targeted Drugs For Ovarian Cancer Using Patient Derived Models

Patients with advanced ovarian cancers have experienced little improvement in overall survival with standard treatments. We used patient derived models to accelerate the discovery of treatment options. We developed a platform of Patient Derived Xenografts (PDX), by implanting and propagating patient9s tumor samples collected at surgery in severely immunocompromised mice. From each PDX line we derived short term cultures of PDX Derived Tumor Cells (PDTCs). We envisioned that the weakness of PDXs and PDTCs, i.e. lack of human stromal and immune cells, might be instrumental to link tumor biomarkers to treatments. We have successfully propagated 49 PDX lines from metastatic EOC, which were fully characterized as far as histology, immunohistochemistry of epithelial and tissue specific markers and presence of TP53 and BRCA1/2 mutations. On PDTCs cultures we first assessed sensitivity to Carboplatin, currently used as first-line drug in ovarian cancer treatment. Of PDX lines derived from naive metastatic HGS-EOC copy number variations and whole exome sequencing analyses were carried out, in order to identify putative and actionable cancer genes. Thus, on PDTCs we assayed also approved or experimental targeted drugs as monotherapy or in combinations. In one PDX line we identified a possibly loss-of-function mutation (W624R) of the PIK3R1 gene (encoding the p85alpha regulatory subunit of PI3K) with an allele frequency of 0.9, which could result in activation of the PI3K pathway. Several PI3K inhibitors were assayed on PDTCs of this PDX line harboring the PIK3R1W624R. Buparlisib (a Pan Class I PI3Ki) showed the ability to block proliferation of the PDTCs and the growth of the relevant PDXs in vivo. Altogether these data show that Patient Derived models are invaluable tools to unveil actionable pathways for the treatment of advanced/metastatic HGS-EOC. Citation Format: Concetta D9Ambrosio, Jessica Erriquez, Maddalena Arigoni, Sonia Capellero, Gloria Mittica, Eleonora Ghisoni, Fulvio Borella, Dionyssios Katsaros, Silvana Privitera, Marisa Ribotta, Elena Maldi, Giovanna Di Nardo, Enrico Berrino, Tiziana Venesio, Riccardo Ponzone, Marco Vaira, Douglas Hall, Mercedes Jimenez-Linan, Anna Paterson, Giorgio Valabrega, Raffaele Calogero, James Brenton, Mariaflavia Di Renzo, Martina Olivero. Assays of conventional chemotherapeutics and targeted drugs for ovarian cancer using patient derived models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1677.