Early detection in a mouse model of pancreatic cancer by imaging DNA damage response signalling
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Rationale: Despite its widespread use in oncology, the PET radiotracer 18F-FDG is ineffective for improving early detection of pancreatic ductal adenocarcinoma (PDAC). An alternative strategy for early detection of pancreatic cancer involves visualisation of high-grade pancreatic intraepithelial neoplasias (PanIN-3), generally regarded as the non-invasive precursors of PDAC. The DNA damage response is known to be hyper-activated in late-stage PanINs. Therefore, we investigated whether the SPECT imaging agent, 111In-anti-γH2AX-TAT, allows visualisation of the DNA damage repair marker γH2AX in PanIN-3s in an engineered mouse model of PDAC, to facilitate early detection of PDAC. Methods: Genetically engineered KPC mice (KRasLSL.G12D/+; p53LSL.R172H/+; PdxCre) were imaged with 18F-FDG and 111In-anti-γH2AX-TAT. PanIN/PDAC presence visualised by histology was compared with autoradiography and immunofluorescence. Separately, the survival of KPC mice imaged with 111In-anti-γH2AX-TAT was evaluated. Results: In KPC mouse pancreata, γH2AX expression was increased in high-grade PanINs, but not in PDAC, corroborating earlier results obtained from human pancreas sections. Uptake of 111In-anti-γH2AX-TAT, but not 111In-IgG-TAT or 18F-FDG, within the pancreas was positively correlated with the age of KPC mice, which was correlated with the number of high-grade PanINs. 111In-anti-γH2AX-TAT localises preferentially in high-grade PanIN lesions, but not in established PDAC. Younger, non-tumour-bearing KPC mice that show uptake of 111In-anti-γH2AX-TAT in the pancreas survive significantly shorter than mice with physiological 111In-anti-γH2AX-TAT uptake. Conclusion:111In-anti-γH2AX-TAT imaging allows non-invasive detection of DNA damage repair signalling upregulation in pre-invasive PanIN lesions and is a promising new tool to aid in the early detection and staging of pancreatic cancer.
Date Issued
2020-07-01
Date Acceptance
2019-11-21
Citation
Journal of Nuclear Medicine, 2020, 61 (7), pp.1006-1013
ISSN
0161-5505
Publisher
Society of Nuclear Medicine
Start Page
1006
End Page
1013
Journal / Book Title
Journal of Nuclear Medicine
Volume
61
Issue
7
Copyright Statement
© 2019 by the Society of Nuclear Medicine and Molecular Imaging, Inc. Creative Commons Attribution 4.0 International License (CC BY) allows users to share and adapt with attribution, excluding materials credited to previous publications. License: https://creativecommons.org/licenses/by/4.0/. Details: http://jnm.snmjournals.org/site/misc/permission.xhtml.
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/31862800
PII: jnumed.119.234708
Subjects
γH2AX
Animal Imaging
DNA damage repair
Gastrointestinal
Oncology: Pancreas
PET
Pancreatic Ductal Adenocarcinoma
Radioimmunoimaging
SPECT
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2019-12-20