Xenopatients show the need for precision medicine approach to chemotherapy in ovarian cancer

// Jessica Erriquez 2, * , Martina Olivero 1, 2, * , Gloria Mittica 1, 2 , Maria Stella Scalzo 3 , Marco Vaira 2 , Michele De Simone 2 , Riccardo Ponzone 2 , Dionyssios Katsaros 4 , Massimo Aglietta 1, 2 , Raffaele Calogero 5 , Maria Flavia Di Renzo 1, 2 , Giorgio Valabrega 1, 2 1 Department of Oncology, University of Torino, Candiolo, Torino, Italy 2 Candiolo Cancer Institute, FPO-IRCCS Candiolo, Torino, Italy 3 Department of Medical Sciences, University of Torino, Torino, Italy 4 Department of Surgical Sciences, Gynecologic Oncology, AO-Universitaria Citta della Salute, Torino, Italy 5 Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy * These authors have contributed equally to this work Correspondence to: Maria Flavia Di Renzo, e-mail: mariaflavia.direnzo@unito.it Keywords: ovarian cancer, chemotherapy, patient derived xenograft Received: December 14, 2015     Accepted: March 14, 2016     Published: March 24, 2016 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-naive 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 naive 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 naive 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-naive HGS-EOC might display susceptibility to agents not used commonly as first line treatment. Data suggest the importance of personalizing also chemotherapy.