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

• Published in: Journal of Nuclear Medicine Vol. 63; no. 9; pp. 1401 - 1407
• Main Authors: Korsen, Joshua A, Kalidindi, Teja M, Khitrov, Samantha, Samuels, Zachary V, Chakraborty, Goutam, Gutierrez, Julia A, Poirier, John T, Rudin, Charles M, Chen, Yu, Morris, Michael J, Pillarsetty, Nagavarakishore, Lewis, Jason S
• Format: Journal Article
• Language: English
• Published: United States Society of Nuclear Medicine 01.09.2022
• Subjects: Androgen receptors; Animals; Antibodies; Antigens; Basic Science Investigation; Biodistribution; Carcinoma, Neuroendocrine - metabolism; Castration; Cell Line, Tumor; Cell surface; Deferoxamine; Deferoxamine - chemistry; Gallium Isotopes; Gallium Radioisotopes; Humans; Imaging; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Lesions; Ligands; Male; Markers; Membrane Proteins; Mice; Mice, Nude; Molecular Imaging; Polymerase chain reaction; Positron emission; Positron emission tomography; Prostate - pathology; Prostate cancer; Prostate-specific antigen; Prostate-Specific Antigen - metabolism; Prostatic Neoplasms - pathology; Radionuclide Imaging; Radiopharmaceuticals - metabolism; Receptors; Receptors, Androgen - metabolism; Receptors, Somatostatin - metabolism; Somatostatin; Tissue Distribution; Tomography; Tumor cell lines; Xenografts; Xenotransplantation; Zirconium isotopes; molecular imaging; neuroendocrine prostate cancer; immuno-PET; DLL3
• ISSN: 0161-5505; 1535-5667; 2159-662X
• DOI: 10.2967/jnumed.121.263221

Treatment-induced neuroendocrine prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer. Using the Zr-labeled delta-like ligand 3 (DLL3) targeting antibody SC16 ( Zr-desferrioxamine [DFO]-SC16), we have developed a PET agent to noninvasively identify the presence of DLL3-positive NEPC lesions. 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 Zr-DFO-SC16, Ga-PSMA-11, and Ga-DOTATATE was performed on H660 NEPC-xenografted male nude mice. Zr-DFO-SC16 uptake was corroborated by biodistribution studies. 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 Zr-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 ( Ga-PSMA-11) or somatostatin receptor subtype 2 ( Ga-DOTATATE). These studies demonstrated that H660 NEPC cells selectively express DLL3 on their cell surface and can be noninvasively identified with Zr-DFO-SC16.