Early Detection in a Mouse Model of Pancreatic Cancer by Imaging DNA Damage Response Signaling.

Autor:	Knight JC; Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom.; School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; and., Torres JB; Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom., Goldin R; Department of Histopathology, Imperial College London, St. Mary's Hospital Campus, London, United Kingdom., Mosley M; Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom., Dias GM; Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom., Bravo LC; Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom., Kersemans V; Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom., Allen PD; Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom., Mukherjee S; Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom., Smart S; Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom., Cornelissen B; Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom bart.cornelissen@oncology.ox.ac.uk.
Jazyk:	angličtina
Zdroj:	Journal of nuclear medicine : official publication, Society of Nuclear Medicine [J Nucl Med] 2020 Jul; Vol. 61 (7), pp. 1006-1013. Date of Electronic Publication: 2019 Dec 20.
DOI:	10.2967/jnumed.119.234708
Abstrakt:	Despite its widespread use in oncology, the PET radiotracer 18 F-FDG is ineffective for improving early detection of pancreatic ductal adenocarcinoma (PDAC). An alternative strategy for early detection of pancreatic cancer involves visualization of high-grade pancreatic intraepithelial neoplasias (PanIN-3s), generally regarded as the noninvasive precursors of PDAC. The DNA damage response is known to be hyperactivated in late-stage PanINs. Therefore, we investigated whether the SPECT imaging agent 111 In-anti-γH2AX-TAT allows visualization 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 (KRas LSL.G12D/+ ; p53 LSL.R172H/+ ; PdxCre) mice were imaged with 18 F-FDG and 111 In-anti-γH2AX-TAT. The presence of PanIN/PDAC as visualized by histologic examination was compared with autoradiography and immunofluorescence. Separately, the survival of KPC mice imaged with 111 In-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 111 In-anti-γH2AX-TAT, but not 111 In-IgG-TAT or 18 F-FDG, within the pancreas correlated positively with the age of KPC mice, which correlated with the number of high-grade PanINs. 111 In-anti-γH2AX-TAT localizes preferentially in high-grade PanIN lesions but not in established PDAC. Younger, non-tumor-bearing KPC mice that show uptake of 111 In-anti-γH2AX-TAT in the pancreas survive for a significantly shorter time than mice with physiologic 111 In-anti-γH2AX-TAT uptake. Conclusion: 111 In-anti-γH2AX-TAT imaging allows noninvasive detection of DNA damage repair signaling upregulation in preinvasive PanIN lesions and is a promising new tool to aid in the early detection and staging of pancreatic cancer. (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)
Databáze:	MEDLINE
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