MEK inhibitor trametinib in combination with gemcitabine regresses a patient-derived orthotopic xenograft (PDOX) pancreatic cancer nude mouse model

Kei Kawaguchi; Kentaro Igarashi; Kentaro Miyake; Thinzar M Lwin; Masuyo Miyake; Tasuku Kiyuna; Ho Kyoung Hwang; Takashi Murakami; Jonathan C Delong; Shree Ram Singh; Bryan Clary; Michael Bouvet; Michiaki Unno; Robert M Hoffman

doi:10.1016/j.tice.2018.05.003

MEK inhibitor trametinib in combination with gemcitabine regresses a patient-derived orthotopic xenograft (PDOX) pancreatic cancer nude mouse model

Tissue Cell. 2018 Jun:52:124-128. doi: 10.1016/j.tice.2018.05.003. Epub 2018 May 5.

Authors

Affiliations

¹ AntiCancer, Inc., 7917 Ostrow Street, San Diego, CA, 92111, USA; Department of Surgery, University of California, San Diego, CA, 92093, USA; Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, 980-8574, Japan.
² AntiCancer, Inc., 7917 Ostrow Street, San Diego, CA, 92111, USA; Department of Surgery, University of California, San Diego, CA, 92093, USA.
³ Department of Surgery, University of California, San Diego, CA, 92093, USA.
⁴ Basic Research Laboratory, National Cancer Institute, Frederick, MD, 21702, USA. Electronic address: [email protected].
⁵ Department of Surgery, University of California, San Diego, CA, 92093, USA. Electronic address: [email protected].
⁶ Department of Surgery, University of California, San Diego, CA, 92093, USA. Electronic address: [email protected].
⁷ Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, 980-8574, Japan. Electronic address: [email protected].
⁸ AntiCancer, Inc., 7917 Ostrow Street, San Diego, CA, 92111, USA; Department of Surgery, University of California, San Diego, CA, 92093, USA. Electronic address: [email protected].

PMID: 29857821
DOI: 10.1016/j.tice.2018.05.003

Abstract

Pancreatic cancer is resistant to treatment and needs precision individualized therapy to improve the outcome of this disease. Previously, we demonstrated that trametinib (TRA), a MEK inhibitor, could inhibit a pancreatic cancer patient-derived orthotopic xenograft (PDOX). In the present study, we show that gemcitabine (GEM) in combination with TRA was more effective than TRA alone. We implanted a patient pancreatic cancer orthotopically in the pancreatic tail of nude mice to establish the PDOX model. After seven weeks of tumor growth, we divided 32 pancreatic-cancer PDOX nude mice into 4 groups of eight: untreated control; GEM (once a week for 2 weeks); TRA (14 consecutive days); GEM + TRA (GEM: once a week for 2 weeks, TRA:14 consecutive days). We found that treated mice on day 14 had significantly reduced tumor volume in comparison to untreated control. TRA and the combination of GEM + TRA therapy significantly inhibited tumor development in comparison to GEM alone. However, GEM + TRA inhibited the PDOX tumor growth significantly greater than TRA alone. These results suggest the clinical potential of the combination of TRA and GEM for pancreatic cancer.

Keywords: Cancer resistance; Combination; Gemcitabine; Indvidualized therapy; PDOX; Pancreatic cancer; Precision medicine; Trametinib.

Published by Elsevier Ltd.

MeSH terms

Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Deoxycytidine / analogs & derivatives
Deoxycytidine / pharmacology
Disease Models, Animal
Gemcitabine
Humans
Mice
Mice, Nude
Pancreatic Neoplasms / pathology*
Pyridones / pharmacology
Pyrimidinones / pharmacology
Xenograft Model Antitumor Assays

Substances

Pyridones
Pyrimidinones
Deoxycytidine
trametinib
Gemcitabine