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

Despite its widespread use in oncology, the PET radiotracer F-18-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 In-111-anti-gamma H2AX-TAT allows visualization of the DNA damage repair marker gamma H2AX in PanIN-3s in an engineered mouse model of PDAC, to facilitate early detection of PDAC. Methods: Genetically engineered KPC (KRas(LSL.G12D/)(+); p53(LSLR172H/)(+); PdxCre) mice were imaged with F-18-FDG and In-111-anti-gamma H2AX-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 In-111-anti-gamma H2AX-TAT was evaluated. Results: In KPC mouse pancreata, yH2AX expression was increased in high-grade PanINs but not in PDAC, corroborating earlier results obtained from human pancreas sections. Uptake of In-111-anti-gamma H2AX-TAT, but not In-111-IgG-TAT or F-18-FDG, within the pancreas correlated positively with the age of KPC mice, which correlated with the number of high-grade PanINs. In-111-anti-gamma H2AX-TAT localizes preferentially in high-grade PanIN lesions but not in established PDAC. Younger, non-tumorbearing KPC mice that show uptake of In-111-anti-gamma H2AX-TAT in the pancreas survive for a significantly shorter time than mice with physiologic In-anti-gamma H2AX-TAT uptake. Conclusion: In-111-anti-gamma H2AX-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.