(18)F-fluoromisonidazole predicts evofosfamide uptake in pancreatic tumor model

BACKGROUND: Quantitative imaging can facilitate patient stratification in clinical trials. The hypoxia-activated prodrug evofosfamide recently failed a phase III trial in pancreatic cancer. However, the study did not attempt to select for patients with hypoxic tumors. We tested the ability of (18)F-fluoromisonidazole to predict evofosfamide uptake in an orthotopic xenograft model (BxPC3). METHODS: Two forms of evofosfamide were used: (1) labeled on the active moiety ((3)H) and (2) on the hypoxia targeting nitroimidazole group ((14)C). Tumor uptake of evofosfamide and (18)F-fluoromisonidazole was counted ex vivo. Autoradiography of (14)C and (18)F coupled with pimonidazole immunohistochemistry revealed the spatial distributions of prodrug, radiotracer, and hypoxia. RESULTS: There was significant individual variation in (18)F-fluoromisonidazole uptake, and a significant correlation between normalized (18)F-fluoromisonidazole and both (3)H-labeled and (14)C-labeled evofosfamide. (18)F-fluoromisonidazole and (14)C-evofosfamide both localized in hypoxic regions as identified by pimonidazole. CONCLUSION: (18)F-fluoromisonidazole predicts evofosfamide uptake in a preclinical pancreatic tumor model.