title: Cediranib combined with chemotherapy reduces tumor dissemination and prolongs the survival of mice bearing patient-derived ovarian cancer xenografts with different responsiveness to cisplatin.
abstract: Cediranib is a pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor that affects tumor angiogenesis and is under investigation in clinical studies on ovarian cancer. Using a panel of eleven patient-derived ovarian cancer xenografts (EOC-PDX) growing orthotopically in the peritoneal cavity of nude mice we investigated the effect of cediranib as monotherapy or in combination with chemotherapy on overall survival (primary endpoint, at euthanasia), and tumor dissemination and metastasis in the peritoneal cavity (secondary endpoint, interim analysis). The response of EOC-PDX to cediranib varied (increment of lifespan, ILS between 12 and 85 %) in the different EOC-PDX, independently from tumor responsiveness to cisplatin (DDP). Cediranib combined with DDP and in maintenance regimen prolonged the survival of mice bearing EOC-PDX with different responsiveness to DDP (ILS between 34 and 224 % with only DDP and between 135 and 337 % with DDP plus Cediranib); survival was extended with the addition of paclitaxel to chemotherapy (50-77 % complete remissions). Cediranib reduced ascites of advanced EOC-PDX, but had limited effect on tumor dissemination; only combined with chemotherapy, ascites and metastases were both reduced. The reduction of tumor dissemination was associated to the increase of overall survival. In conclusion, the response to cediranib differs in the various EOC-PDX, reproducing the heterogeneous response of cancer patients to angiogenesis inhibitors. Cediranib potentiated chemotherapy, significantly inhibiting tumor progression and dissemination to metastatic organs, even in tumors poorly responsive to DDP. EOC-PDX preclinical models with different responsiveness to Cediranib may help in identifying determinants of response to cediranib and mechanisms of adaptation to antiangiogenic treatments.
authors.affiliation: Laboratory of Biology and Treatment of Metastasis, Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Via Stezzano 87, 24126 Bergamo and Via Giuseppe La Masa 19, 20156, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Decio
authors.affiliation: Laboratory of Biology and Treatment of Metastasis, Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Via Stezzano 87, 24126 Bergamo and Via Giuseppe La Masa 19, 20156, Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Cesca
authors.affiliation: Laboratory of Biology and Treatment of Metastasis, Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Via Stezzano 87, 24126 Bergamo and Via Giuseppe La Masa 19, 20156, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bizzaro
authors.affiliation: Laboratory of Methodology for Biomedical Research, Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Via Giuseppe La Masa 19, 20156, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Porcu
authors.affiliation: Laboratory of Biology and Treatment of Metastasis, Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Via Stezzano 87, 24126 Bergamo and Via Giuseppe La Masa 19, 20156, Milan, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Bettolini
authors.affiliation: Laboratory of Cancer Pharmacology, Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Via Giuseppe La Masa 19, 20156, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ubezio
authors.affiliation: Laboratory of Biology and Treatment of Metastasis, Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Via Stezzano 87, 24126 Bergamo and Via Giuseppe La Masa 19, 20156, Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Taraboletti
authors.affiliation: Laboratory of Biology and Treatment of Metastasis, Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Via Stezzano 87, 24126 Bergamo and Via Giuseppe La Masa 19, 20156, Milan, Italy. dorina.belotti@marionegri.it.
authors.forename: Dorina
authors.initials: D
authors.lastname: Belotti
authors.affiliation: Laboratory of Biology and Treatment of Metastasis, Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Via Stezzano 87, 24126 Bergamo and Via Giuseppe La Masa 19, 20156, Milan, Italy. raffaella.giavazzi@marionegri.it.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Giavazzi
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D007211:Indoles
chemical_list: D020533:Angiogenesis Inhibitors; D002945:Cisplatin; D017239:Paclitaxel; D011799:Quinazolines; C500926:cediranib; D007211:Indoles
keywords: Angiogenesis; Cediranib; Combination therapy; Metastasis; Ovarian cancer; Platinum