Poly (ADP-ribose) polymerase inhibitor: an evolving paradigm in the treatment of prostate cancer

Abstract

Recent phase I studies have reported single-agent activities of poly (ADP-ribose) polymerase (PARP) inhibitor in sporadic and in BRCA-mutant prostate cancers. Two of the most common genetic alterations in prostate cancer, ETS gene rearrangement and loss of PTEN, have been linked to increased sensitivity to PARP inhibitor in preclinical models. Emerging evidence also suggests that PARP1 plays an important role in mediating the transcriptional activities of androgen receptor (AR) and ETS gene rearrangement. In this article, the preclinical work and early-phase clinical trials in developing PARP inhibitor-based therapy as a new treatment paradigm for metastatic prostate cancer are reviewed.

Figure 1

(a) Western blots comparing PARP1 cleavage (apoptosis marker) and levels of Rad51 and rH2AX (marker for double strand DNA breaks) in untreated (Un), ABT888-treated (A) or SN38-treated (SN) PC3 cells grown under 21% or 0.2% oxygen for 4 days. SN38 is the active metabolite of irinotecan. Compared to drug-treated PC3 cells under normoxia, less DNA damage and apoptosis were observed in treated PC3 cells under hypoxia. (b) Immunofluorescence of Rad51 (red) and γ-H2AX (green) foci in untreated or SN38-treated (0.1 μmol l^–1 for 4 h) PC3 cells grown under normoxia (21% O₂) or chronic hypoxia (0.2% O₂ for 72 h). Increased Rad51 nuclear foci formation was observed soon after PC3 cells were challenged with SN38. Compared to SN38-treated cells under normoxia, there was less DNA damage under hypoxia. (c) Blocking Rad51 upregulation with siRNA-resensitized PC3 cells to SN38. Percentage of apoptosis was detected by flow cytometry with propidium iodide and annexin V. PC3 cells grown in 0.2% O2 were transfected with Rad51 siRNA or scrambled siRNA control (siCTRL); inhibiting Rad51 with siRad51 reversed the resistance to SN38 under hypoxic culture. Untreated and SN38-treated PC3 cells grown in 21% O₂(hatched column) and 0.2% O₂ were shown for comparison.

Figure 2

Distribution of the copy numbers of 338 probes covering 24 chromosomes in PC3 cells as detected by nCounter human karotyping. PC3 cells are known to have Y-chromosome deletion. These copy numbers were normalized to human foreskin fibroblasts (user selected lane). Compared to PC3 cells grown under normoxia, no significant alterations in chromosomal copy numbers were observed in PARP inhibitor-treated or untreated PC3 cells grown under 0.2% O₂(hyp) for 3 weeks.