Molecular Imaging of Neuroendocrine Prostate Cancer by Targeting Delta-Like Ligand 3
Joshua A. Korsen, Teja M. Kalidindi, Samantha Khitrov, Zachary V. Samuels, Goutam Chakraborty, Julia A. Gutierrez, John T. Poirier, Charles M. Rudin, Yu Chen, Michael J. Morris, Nagavarakishore Pillarsetty, Jason S. Lewis
Abstract
Treatment-induced neuroendocrine prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer (CRPC). Using the zirconium-89 (<sup>89</sup>Zr)-labeled DLL3 targeting antibody SC16 (<sup>89</sup>Zr-DFO-SC16), we have developed a positron emission tomography (PET) agent to non-invasively identify the presence of DLL3-positive NEPC lesions. <b>Methods:</b> 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 <sup>89</sup>Zr-DFO-SC16, <sup>68</sup>Ga-PSMA-11, and <sup>68</sup>Ga-DOTA-TATE was performed in H660 NEPC xenografted male nude mice. <sup>89</sup>Zr-DFO-SC16 uptake was corroborated by biodistribution studies. <b>Results:</b> 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 <sup>89</sup>Zr-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 (<sup>68</sup>Ga-PSMA-11) or somatostatin receptor subtype 2 (SSTR2) (<sup>68</sup>Ga-DOTA-TATE). <b>Conclusion:</b> These studies demonstrate H660 NEPC cells selectively express DLL3 on their cell surface and can be non-invasively identified with <sup>89</sup>Zr-DFO-SC16.