Molecular Imaging of Neuroendocrine Prostate Cancer by Targeting Delta-Like Ligand 3

Treatment-induced neuroendocrine prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer (CRPC). Using the zirconium-89 (⁸⁹Zr)-labeled DLL3 targeting antibody SC16 (⁸⁹Zr-DFO-SC16), we have developed a positron emission tomography (PET) agent to non-invasively identify the presence of DLL3-positive NEPC lesions. Methods: qPCR and immunohistochemistry were used to compare relative levels of androgen receptor (AR)-regulated markers and NEPC marker DLL3 in a panel of prostate cancer cell lines. PET imaging with ⁸⁹Zr-DFO-SC16, ⁶⁸Ga-PSMA-11, and ⁶⁸Ga-DOTA-TATE was performed in H660 NEPC xenografted male nude mice. ⁸⁹Zr-DFO-SC16 uptake was corroborated by biodistribution studies. Results: In vitro studies demonstrate H660 are positive for DLL3 and negative for AR, prostate-specific antigen (PSA), and prostate-specific membrane antigen (PSMA) both at the transcriptional and translational levels. PET imaging and biodistribution studies confirm ⁸⁹Zr-DFO-SC16 uptake is restricted to H660 tumor xenografts with background uptake in non-NEPC lesions (both AR-dependent and AR-independent). Conversely, H660 xenografts cannot be detected with imaging agents targeting PSMA (⁶⁸Ga-PSMA-11) or somatostatin receptor subtype 2 (SSTR2) (⁶⁸Ga-DOTA-TATE). Conclusion: These studies demonstrate H660 NEPC cells selectively express DLL3 on their cell surface and can be non-invasively identified with ⁸⁹Zr-DFO-SC16.