Oncotarget

Research Papers:

MEK inhibitors cobimetinib and trametinib, regressed a gemcitabine-resistant pancreatic-cancer patient-derived orthotopic xenograft (PDOX)

Kei Kawaguchi, Kentaro Igarashi, Takashi Murakami, Tasuku Kiyuna, Thinzar M. Lwin, Ho Kyoung Hwang, Jonathan C. Delong, Bryan M. Clary, Michael Bouvet, Michiaki Unno and Robert M. Hoffman _

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Oncotarget. 2017; 8:47490-47496. https://doi.org/10.18632/oncotarget.17667

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Abstract

Kei Kawaguchi1,2,3, Kentaro Igarashi1,2, Takashi Murakami1,2, Tasuku Kiyuna1,2, Thinzar M. Lwin2, Ho Kyoung Hwang1,2, Jonathan C. Delong2, Bryan M. Clary2, Michael Bouvet2, Michiaki Unno3 and Robert M. Hoffman1,2

1AntiCancer, Inc., San Diego, CA, USA

2Department of Surgery, University of California, San Diego, CA, USA

3Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan

Correspondence to:

Robert M. Hoffman, email: all @anticancer.com

Michael Bouvet, email: mbouvet@ucsd.edu

Bryan M. Clary, email: bclary@ucsd.edu

Keywords: pancreatic cancer, PDOX, nude mice, orthotopic, drug-response

Received: April 15, 2017     Accepted: April 20, 2017     Published: May 07, 2017

ABSTRACT

A pancreatic ductal adenocarcinoma (PDAC), obtained from a patient, was grown orthotopically in the pancreatic tail of nude mice to establish a patient-derived orthotopic (PDOX) model. Seven weeks after implantation, PDOX nude mice were divided into the following groups: untreated control (n = 7); gemcitabine (100 mg/kg, i.p., once a week for 2 weeks, n = 7); cobimetinib (5 mg/kg, p.o., 14 consecutive days, n = 7); trametinib (0.3 mg/kg, p.o., 14 consecutive days, n = 7); trabectedin (0.15 mg/kg, i.v., once a week for 2 weeks, n = 7); temozolomide (25 mg/kg, p.o., 14 consecutive days, n = 7); carfilzomib (2 mg/kg, i.v., twice a week for 2 weeks, n = 7); bortezomib (1 mg/kg, i.v., twice a week for 2 weeks, n = 7); MK-1775 (20 mg/kg, p.o., 14 consecutive days, n = 7); BEZ-235 (45 mg/kg, p.o., 14 consecutive days, n = 7); vorinostat (50 mg/kg, i.p., 14 consecutive days, n = 7). Only the MEK inhibitors, cobimetinib and trametinib, regressed tumor growth, and they were more significantly effective than other therapies (p < 0.0001, respectively), thereby demonstrating the precision of the PDOX models of PDAC and its potential for individualizing pancreatic-cancer therapy.


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