Using patient-derived xenograft models of colorectal liver metastases to predict chemosensitivity

Kai M Brown; Aiqun Xue; Sohel M Julovi; Anthony J Gill; Nick Pavlakis; Jaswinder S Samra; Ross C Smith; Thomas J Hugh

doi:10.1016/j.jss.2018.02.018

Using patient-derived xenograft models of colorectal liver metastases to predict chemosensitivity

J Surg Res. 2018 Jul:227:158-167. doi: 10.1016/j.jss.2018.02.018. Epub 2018 Mar 15.

Authors

Kai M Brown¹, Aiqun Xue², Sohel M Julovi³, Anthony J Gill⁴, Nick Pavlakis⁵, Jaswinder S Samra⁶, Ross C Smith³, Thomas J Hugh²

Affiliations

¹ Cancer Surgery and Metabolism Research Group, University of Sydney, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, New South Wales, Australia; Northern Clinical School, University of Sydney, Upper GI Surgical Unit, Royal North Shore Hospital and North Shore Private Hospital, St Leonards, New South Wales, Australia. Electronic address: kkai6773@uni.sydney.edu.au.
² Cancer Surgery and Metabolism Research Group, University of Sydney, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, New South Wales, Australia; Northern Clinical School, University of Sydney, Upper GI Surgical Unit, Royal North Shore Hospital and North Shore Private Hospital, St Leonards, New South Wales, Australia.
³ Cancer Surgery and Metabolism Research Group, University of Sydney, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
⁴ Cancer Diagnosis and Pathology Group, University of Sydney, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
⁵ Northern Sydney Cancer Centre, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
⁶ Northern Clinical School, University of Sydney, Upper GI Surgical Unit, Royal North Shore Hospital and North Shore Private Hospital, St Leonards, New South Wales, Australia.

PMID: 29804848
DOI: 10.1016/j.jss.2018.02.018

Abstract

Background: Few in vivo models for colorectal cancer have been demonstrated to show external validity by accurately predicting clinical patient outcomes. Patient-derived xenograft (PDX) models of cancer have characteristics that might provide a form of translational research leading to personalized cancer care. The aim of this pilot study was to assess the feasibility of using PDXs as a platform for predicting patient colorectal liver metastases responses, in this case by correlating PDX and patient tumor responses to either folinic acid, fluorouracil plus oxaliplatin or folinic acid, fluorouracil plus irinotecan-based regimens.

Methods: Sixteen patients underwent potentially curative resection of colorectal liver metastases, and tumors were grafted into NOD.CB17-Prkdc^scid/Arc mice. Mice were divided into groups to determine relative tumor growth in response to treatment. Tumors were analyzed by immunohistochemistry for Ki67 and Excision repair cross-complementation group 1.

Results: An engraftment rate of 81% was achieved. Overall, there was a 67% positive match rate between eligible patient and PDX chemosensitivity profiles. There was a significant difference in relative decrease in Ki67 expression between sensitive/stable versus resistant PDXs for both treatment regimens. There was no statistically significant correlation between baseline ERCC1 expression and response to Oxaliplatin + 5-Fluorouracil in the PDXs.

Conclusions: This pilot study supports the feasibility of using PDX models of advanced colorectal cancer in larger studies to potentially predict patient chemosensitivity profiles.

Keywords: Chemosensitivity; Colorectal cancer; Colorectal liver metastases; Mouse model; Patient-derived xenograft; Translational research.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
Chemotherapy, Adjuvant / methods
Colorectal Neoplasms / pathology
Colorectal Neoplasms / therapy*
DNA-Binding Proteins / metabolism
Drug Resistance, Neoplasm*
Endonucleases / metabolism
Feasibility Studies
Female
Humans
Ki-67 Antigen / metabolism
Liver / pathology
Liver / surgery
Liver Neoplasms / pathology
Liver Neoplasms / secondary
Liver Neoplasms / surgery*
Male
Mice
Mice, Inbred NOD
Mice, SCID
Middle Aged
Pilot Projects
Treatment Outcome
Xenograft Model Antitumor Assays*

Substances

DNA-Binding Proteins
Ki-67 Antigen
MKI67 protein, human
ERCC1 protein, human
Endonucleases