title: Xenopatients show the need for precision medicine approach to chemotherapy in ovarian cancer.
abstract: Platinum-based chemotherapy is the recommended first-line treatment for high-grade serous (HGS) epithelial ovarian cancer (EOC). However, most patients relapse because of platinum refractory/resistant disease. We aimed at assessing whether other drugs, commonly used to treat relapsed HGS-EOC and poorly active in this clinical setting, might be more effective against chemotherapy-naïve cancers. We collected couples of HGS-EOC samples from the same patients before and after neo-adjuvant platinum-based chemotherapy. Samples were propagated as Patient Derived Xenografts (PDXs) in immunocompromised mice ("xenopatients"). Xenopatients were treated in parallel with carboplatin, gemcitabine, pegylated liposomal doxorubicin (PLD) and trabectedin. PDXs derived from a naïve HSG-EOC showed responsiveness to carboplatin, trabectedin and gemcitabine. The PDXs propagated from a tumor mass of the same patient, grown after carboplatin therapy, did no longer respond to trabectedin and gemcitabine and showed heterogeneous response to carboplatin. In line, the patient experienced clinically platinum-sensitivity first and then discordant responses of different tumor sites to platinum re-challenge. Loss of PDX responsiveness to drugs was associated with 4-fold increase of NR2F2 gene expression. PDXs from another naïve tumor showed complete response to PLD, which was lost in the PDXs derived from a mass grown in the same patient after platinum-based chemotherapy. This patient showed platinum refractoriness and responded poorly to PLD as second-line treatment. PDX response to PLD was associated with high expression of TOP2A protein. PDXs demonstrated that chemotherapy-naïve HGS-EOC might display susceptibility to agents not used commonly as first line treatment. Data suggest the importance of personalizing also chemotherapy.
authors.affiliation: Candiolo Cancer Institute, FPO-IRCCS Candiolo, Torino, Italy.
authors.forename: Jessica
authors.initials: J
authors.lastname: Erriquez
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Torino, Italy.|Candiolo Cancer Institute, FPO-IRCCS Candiolo, Torino, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Olivero
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Torino, Italy.|Candiolo Cancer Institute, FPO-IRCCS Candiolo, Torino, Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Mittica
authors.affiliation: Department of Medical Sciences, University of Torino, Torino, Italy.
authors.forename: Maria Stella
authors.initials: MS
authors.lastname: Scalzo
authors.affiliation: Candiolo Cancer Institute, FPO-IRCCS Candiolo, Torino, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Vaira
authors.affiliation: Candiolo Cancer Institute, FPO-IRCCS Candiolo, Torino, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: De Simone
authors.affiliation: Candiolo Cancer Institute, FPO-IRCCS Candiolo, Torino, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Ponzone
authors.affiliation: Department of Surgical Sciences, Gynecologic Oncology, AO-Universitaria Città della Salute, Torino, Italy.
authors.forename: Dionyssios
authors.initials: D
authors.lastname: Katsaros
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Torino, Italy.|Candiolo Cancer Institute, FPO-IRCCS Candiolo, Torino, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Aglietta
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Calogero
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Torino, Italy.|Candiolo Cancer Institute, FPO-IRCCS Candiolo, Torino, Italy.
authors.forename: Maria Flavia
authors.initials: MF
authors.lastname: Di Renzo
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Torino, Italy.|Candiolo Cancer Institute, FPO-IRCCS Candiolo, Torino, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Valabrega
mesh_terms: D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D016190:Carboplatin / Q000008:administration & dosage; D049109:Cell Proliferation; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004149:Dioxoles / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D006801:Humans; D051379:Mice; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011092:Polyethylene Glycols / Q000008:administration & dosage; D057285:Precision Medicine; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage; D000077606:Trabectedin; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D004149:Dioxoles; D044005:Tetrahydroisoquinolines; C506643:liposomal doxorubicin; D003841:Deoxycytidine; D011092:Polyethylene Glycols; D004317:Doxorubicin; D016190:Carboplatin; D000077606:Trabectedin; D000093542:Gemcitabine
keywords: chemotherapy; ovarian cancer; patient derived xenograft