PT  - JOURNAL ARTICLE
AU  - Knight, James C.
AU  - Torres, Julia Baguña
AU  - Goldin, Robert
AU  - Mosley, Michael
AU  - Dias, Gemma M.
AU  - Bravo, Luisa Contreras
AU  - Kersemans, Veerle
AU  - Allen, P. Danny
AU  - Mukherjee, Somnath
AU  - Smart, Sean
AU  - Cornelissen, Bart
TI  - Early Detection in a Mouse Model of Pancreatic Cancer by Imaging DNA Damage Response Signaling
AID  - 10.2967/jnumed.119.234708
DP  - 2020 Jul 01
TA  - Journal of Nuclear Medicine
PG  - 1006--1013
VI  - 61
IP  - 7
4099  - http://jnm.snmjournals.org/content/61/7/1006.short
4100  - http://jnm.snmjournals.org/content/61/7/1006.full
SO  - J Nucl Med2020 Jul 01; 61
AB  - 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 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 111In-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 (KRasLSL.G12D/+; p53LSL.R172H/+; PdxCre) mice were imaged with 18F-FDG and 111In-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 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 correlated positively with the age of KPC mice, which correlated with the number of high-grade PanINs. 111In-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 111In-anti-γH2AX-TAT in the pancreas survive for a significantly shorter time than mice with physiologic 111In-anti-γH2AX-TAT uptake. Conclusion: 111In-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.