Preclinical Efficacy of a PARP-1 Targeted Auger-Emitting Radionuclide in Prostate Cancer.

Abstract

There is an unmet need for better therapeutic strategies for advanced prostate cancer. Poly (ADP-ribose) polymerase-1 (PARP-1) is a chromatin-binding DNA repair enzyme overexpressed in prostate cancer. This study evaluates whether PARP-1, on account of its proximity to the cell's DNA, would be a good target for delivering high-linear energy transfer Auger radiation to induce lethal DNA damage in prostate cancer cells. We analyzed the correlation between PARP-1 expression and Gleason score in a prostate cancer tissue microarray. A radio-brominated Auger emitting inhibitor ([77Br]Br-WC-DZ) targeting PARP-1 was synthesized. The ability of [77Br]Br-WC-DZ to induce cytotoxicity and DNA damage was assessed in vitro. The antitumor efficacy of [77Br]Br-WC-DZ was investigated in prostate cancer xenograft models. PARP-1 expression was found to be positively correlated with the Gleason score, thus making it an attractive target for Auger therapy in advanced diseases. The Auger emitter, [77Br]Br-WC-DZ, induced DNA damage, G2-M cell cycle phase arrest, and cytotoxicity in PC-3 and IGR-CaP1 prostate cancer cells. A single dose of [77Br]Br-WC-DZ inhibited the growth of prostate cancer xenografts and improved the survival of tumor-bearing mice. Our studies establish the fact that PARP-1 targeting Auger emitters could have therapeutic implications in advanced prostate cancer and provides a strong rationale for future clinical investigation.

• Authors: Sreeja Sreekumar, Dong Zhou, Cedric Mpoy, Elsa Schenk, Jalen Scott, Jeffrey M Arbeit, Jinbin Xu, Buck E Rogers
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 24 Issue 4 (Feb 04 2023) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 36834491 (Publication Type: Journal Article)

Chemical References

• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerase Inhibitors
• Radioisotopes
• PARP1 protein, human

Topics

• Animals
• Humans
• Male
• Mice
• Cell Line, Tumor
• DNA Damage
• Poly (ADP-Ribose) Polymerase-1 (metabolism)
• Poly(ADP-ribose) Polymerase Inhibitors (pharmacology)
• Prostatic Neoplasms (metabolism)
• Radioisotopes (therapeutic use)