ObjectiveThis study assessed the real-world application, effectiveness, and safety of olaparib and niraparib as maintenance therapies in patients with platinum-sensitive recurrent ovarian cancer (PSROC) in China and investigated clinical factors associated with prolonged benefits of poly ADP-ribose polymerase (PARP) inhibitors to help guide clinician treatment-decision making in daily practice.MethodsThis real-world single-center retrospective cohort study was conducted at the Shandong Cancer Hospital and Institute. Archival data of consecutive patients diagnosed with PSROC who achieved a complete response (CR) or partial response (PR) after the last platinum-based chemotherapy and treated with olaparib or niraparib as maintenance therapy from August 2018 to September 2021 were collected.ResultsOverall, 106 women were included in the cohort. Seventy-two (68%) patients were treated with olaparib, while 34 (32%) received niraparib; 99.1% of the patients were diagnosed with high-grade serous carcinoma, and 73.6% had FIGO stages III–IV. Approximately 71.7% of the patients had received PARP inhibitors after the second platinum-based line and 44.3% of the patients achieved a CR in their last platinum-based therapy. The median platinum-free interval (PFI) after the penultimate platinum-based therapy was 10 (95% CI: 10–13.6) months. The median PFS was 21 (95% CI: 13–24.5) months and the median CFI was 22 (95% CI: 16–26.5) months. Consistent with the univariate analysis, the multivariate analysis identified three independent factors associated with prolonged progression-free survival (PFS) and chemotherapy-free interval (CFI): breast cancer susceptibility gene (BRCA) mutant type (p = 0.005 and p = 0.003); PFI ≥12 months (p = 0.01 and p = 0.006); and CR to last platinum-based therapy (p = 0.016 and p = 0.019). It was found that there was no appreciable difference in any grade 3–4 hematological AE between patients who received olaparib and niraparib.ConclusionMaintenance treatment with olaparib and niraparib is effective and well tolerated for PSROC patients in real-world clinical practice. Three clinical factors were identified that predicted prolonged survival under maintenance therapy with PARP inhibitors: BRCA mutant type, PFI ≥12 months, and CR to last platinum-based therapy. These findings should be further confirmed with an appropriately powered analysis in studies with larger sample sizes.

The protein expression rather than mRNA transcription of Slug should be considered as a potent biomarker for poor prognosis of tumours, particularly head and neck cancer as well as lung and urinary carcinomas.

Human poly(ADP-ribose) polymerase 1 (PARP-1) is involved in DNA strand break repair and has been recognized as a promising druggable target for ovarian cancer. The active site of PARP-1 is π electron-rich, which contains at least 12 aromatic amino aid residues in its first-and second-shell regions, and can form effective π-stacking interactions with its natural substrates and inhibitor ligands. In this study, the intermolecular interactions between the 12 PARP-1 aromatic residues and 16 approved/clinical/preclinical small-molecule inhibitors were systematically profiled using quantum mechanics/molecular mechanics (QM/MM) analyses and dispersion-corrected density functional theory (DFT) calculations. It was found that the aromatic residues contribute ~50% affinity to the global binding energy of PARP-1/inhibitor complexes, in which the four residues (His862, Tyr889, Tyr896 and Tyr907) play a primary role in π-stacking interactions with most inhibitor ligands. Based on the harvested knowledge, we attempted to perform the rational design of aromatic amino acid-rich (AAAr) peptides to target PARP-1 active site by using peptide docking, affinity scoring, and QM/MM analyses. These peptides are only composed of four aromatic amino acids, namely phenylalanine (Phe), tyrosine (Tyr), tryptophan (Trp) and histidine (His), and their π-stacking contribution is improved to ~60% from the ~50% of small-molecule inhibitors, although their global binding energy is moderately lower than these inhibitors. Three designed AAAr peptides (WYHY, WYYH and WFYY) with high-affinity scores were determined as potent PARP-1 targeted agents; they exhibited high inhibitory activities and are roughly comparable with that of the sophisticated PARP-1 inhibitor drug Olaparib, suggesting that these designed peptides, as expected, can effectively target PARP-1 with a satisfactory inhibitory profile.Molecular modeling revealed a number of face-to-face, parallel-displaced, and T-shaped π-stacking interactions at PARP-1/peptide complex interface, which