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

Abstract

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 (KRas^LSL.G12D/+; p53^LSL.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.

Keywords: DNA damage repair; PET; SPECT; pancreatic ductal adenocarcinoma; γH2AX.