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

Abstract

Treatment-induced neuroendocrine prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer. Using the ⁸⁹Zr-labeled delta-like ligand 3 (DLL3) targeting antibody SC16 (⁸⁹Zr-desferrioxamine [DFO]-SC16), we have developed a PET agent to noninvasively identify the presence of DLL3-positive NEPC lesions. Methods: Quantitative polymerase chain reaction and immunohistochemistry were used to compare relative levels of androgen receptor (AR)-regulated markers and the NEPC marker DLL3 in a panel of prostate cancer cell lines. PET imaging with ⁸⁹Zr-DFO-SC16, ⁶⁸Ga-PSMA-11, and ⁶⁸Ga-DOTATATE was performed on H660 NEPC-xenografted male nude mice. ⁸⁹Zr-DFO-SC16 uptake was corroborated by biodistribution studies. Results: In vitro studies demonstrated that H660 NEPC cells are positive for DLL3 and negative for AR, prostate-specific antigen, and prostate-specific membrane antigen (PSMA) at both the transcriptional and the translational levels. PET imaging and biodistribution studies confirmed that ⁸⁹Zr-DFO-SC16 uptake is restricted to H660 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 (⁶⁸Ga-DOTATATE). Conclusion: These studies demonstrated that H660 NEPC cells selectively express DLL3 on their cell surface and can be noninvasively identified with ⁸⁹Zr-DFO-SC16.

Keywords: DLL3; immuno-PET; molecular imaging; neuroendocrine prostate cancer.