Patient-derived mouse models of cancer need to be orthotopic in order to evaluate targeted anti-metastatic therapy
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Yukihiko Hiroshima1,2,3, Ali Maawy2, Yong Zhang1, Nan Zhang1, Takashi Murakami3, Takashi Chishima3, Kuniya Tanaka3, Yasushi Ichikawa3, Michael Bouvet2, Itaru Endo3, Robert M. Hoffman1,2
1AntiCancer, Inc., San Diego, CA, USA
2Department of Surgery, University of California San Diego, San Diego, CA, USA
3Yokohama City University Graduate School of Medicine, Yokohama, Japan
Robert M. Hoffman, email: [email protected]
Michael Bouvet, email: [email protected]
Itaru Endo, email: [email protected]
Keywords: patient-derived orthotopic xenograft, PDOX, cervical cancer, nude mouse, primary tumor
Received: August 02, 2016 Accepted: September 22, 2016 Published: September 28, 2016
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.
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