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.

• Authors: 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
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 63 Issue 9 Pg. 1401-1407 (09 2022) ISSN: 1535-5667 [Electronic] United States
• PMID: 35058323 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural)
• Copyright: © 2022 by the Society of Nuclear Medicine and Molecular Imaging.

Chemical References

• DLL3 protein, human
• Gallium Isotopes
• Gallium Radioisotopes
• Intracellular Signaling Peptides and Proteins
• Ligands
• Membrane Proteins
• Radiopharmaceuticals
• Receptors, Androgen
• Receptors, Somatostatin
• copper dotatate CU-64
• gallium 68 PSMA-11
• Prostate-Specific Antigen
• Deferoxamine

Topics

• Animals
• Carcinoma, Neuroendocrine (metabolism)
• Cell Line, Tumor
• Deferoxamine (chemistry)
• Gallium Isotopes
• Gallium Radioisotopes
• Humans
• Intracellular Signaling Peptides and Proteins
• Ligands
• Male
• Membrane Proteins
• Mice
• Mice, Nude
• Molecular Imaging
• Positron-Emission Tomography
• Prostate (pathology)
• Prostate-Specific Antigen (metabolism)
• Prostatic Neoplasms (pathology)
• Radionuclide Imaging
• Radiopharmaceuticals (metabolism)
• Receptors, Androgen (metabolism)
• Receptors, Somatostatin (metabolism)
• Tissue Distribution