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89Zr-anti-gH2AX-TAT but not 18F-FDG allows early monitoring of response to chemotherapy in a mouse model of pancreatic ductal adenocarcinoma

Lookup NU author(s): Dr James Knight

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Association for Cancer Research Inc., 2017.

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Abstract

©2017 AACR. Purpose: Late-stage, unresectable pancreatic ductal adenocarcinoma (PDAC) is largely resistant to chemotherapy and consequently has a very poor 5-year survival rate of <5%. The ability to assess the efficacy of a treatment soon after its initiation would enable rapid switching to potentially more effective therapies if the current treatment is found to be futile. We have evaluated the ability of the PET imaging agent, 89Zr-anti-gH2AX-TAT, to monitor DNA damage in response to fluorouracil (5-FU), gemcitabine, or capecitabine treatment in a mouse model of pancreatic cancer. We have also compared the utility of this approach against the standard clinical PET radiotracer, 18F-FDG. Experimental Design: C57BL/6 mice bearing subcutaneous pancreatic cancer (KPC; B8484) allografts were treated with 5-FU, gemcitabine, or capecitabine. Therapeutic response was monitored by PET and ex vivo biodistribution experiments using either 89Zr-anti-gH2AX-TAT or 18F-FDG as imaging agents. To further examine the effect of therapeutic response upon uptake of these imaging agents, IHC analysis of harvested tumor allograft tissue was also performed. Results: Accumulation of 89Zr-anti-gH2AX-TAT in the tumors of mice that received chemotherapy was higher compared with vehicle-treated mice and was shown to be specifically mediated by gH2AX. In contrast, 18F-FDG did not provide useful indications of therapeutic response. Conclusions:89Zr-anti-gH2AX-TAT has shown a superior ability to monitor early therapeutic responses to chemotherapy by PET imaging compared with 18F-FDG in an allograft model of PDAC in mice.


Publication metadata

Author(s): Knight JC, Mosley MJ, Bravo LC, Kersemans V, Allen PD, Mukherjee S, O'Neill E, Cornelissen B

Publication type: Article

Publication status: Published

Journal: Clinical Cancer Research

Year: 2017

Volume: 23

Issue: 21

Pages: 6498-6504

Print publication date: 01/11/2017

Online publication date: 03/08/2017

Acceptance date: 24/07/2017

Date deposited: 30/08/2018

ISSN (print): 1078-0432

ISSN (electronic): 1557-3265

Publisher: American Association for Cancer Research Inc.

URL: https://doi.org/10.1158/1078-0432.CCR-17-0664

DOI: 10.1158/1078-0432.CCR-17-0664

PubMed id: 28774899


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