title: Patient-derived mouse models of cancer need to be orthotopic in order to evaluate targeted anti-metastatic therapy.
abstract: Patient-derived xenograft (PDX) mouse models of cancer are emerging as an important component of personalized precision cancer therapy. However, most models currently offered to patients have their tumors subcutaneously-transplanted in immunodeficient mice, which rarely metastasize. In contrast, orthotopic-transplant patient-derived models, termed patient-derived orthotopic xenografts (PDOX), usually metastasize as in the patient. We demonstrate in the present report why orthotopic models are so important for the patient, since primary and metastatic tumors developed in an orthotopic model can have differential chemosensitivity, not detectable in standard subcutaneous tumor models. A subcutaneous nude mouse model of HER-2 expressing cervical carcinoma was not sensitive to entinostat (a benzamide histone deactylase inhibitor), which also did not inhibit primary tumor growth in a PDOX model of the same tumor. However, in the PDOX model, entinostat alone significantly reduced the metastatic tumor burden, compared to the control. Thus, only the PDOX model could be used to discover the anti-metastatic activity of entinostat for this patient. The results of the present report indicate the importance of using mouse models that can recapitulate metastatic cancer for precisely individualizing cancer therapy.
authors.affiliation: AntiCancer, Inc., San Diego, CA, USA.|Department of Surgery, University of California San Diego, San Diego, CA, USA.|Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Hiroshima
authors.affiliation: Department of Surgery, University of California San Diego, San Diego, CA, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Maawy
authors.affiliation: AntiCancer, Inc., San Diego, CA, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: AntiCancer, Inc., San Diego, CA, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Murakami
authors.affiliation: Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Chishima
authors.affiliation: Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Kuniya
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ichikawa
authors.affiliation: Department of Surgery, University of California San Diego, San Diego, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bouvet
authors.affiliation: Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Itaru
authors.initials: I
authors.lastname: Endo
authors.affiliation: AntiCancer, Inc., San Diego, CA, USA.|Department of Surgery, University of California San Diego, San Diego, CA, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis / Q000517:prevention & control; D057285:Precision Medicine; D011725:Pyridines / Q000627:therapeutic use*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D011725:Pyridines; C118739:entinostat
keywords: PDOX; cervical cancer; nude mouse; primary tumor; patient-derived orthotopic xenograft