4.6 Article

In vivo anti-tumor activity of the PARP inhibitor niraparib in homologous recombination deficient and proficient ovarian carcinoma

期刊

GYNECOLOGIC ONCOLOGY
卷 143, 期 2, 页码 379-388

出版社

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ygyno.2016.08.328

关键词

Ovarian cancer; Xenografts; PARP inhibitors; Niraparib; BRCA; Homologous recombination; DNA repair

资金

  1. Mayo Clinic Ovarian SPORE [P50 CA136393]
  2. Ovarian Cancer Research Fund
  3. Pacific Ovarian Cancer Research Consortium SPORE [P50 CA0836]
  4. Wendy Feuer Ovarian Cancer Research Fund
  5. Cori and Tony Bates Novel Technologies for Cancer Prevention Fund
  6. Fred C. and Katherine B. Andersen Foundation [T32 DK07352, T32 GM65841]

向作者/读者索取更多资源

Objective. Poly(ADP-ribose) polymerase (PARP) inhibitors have yielded encouraging responses in high-grade serous ovarian carcinomas (HGSOCs), but the optimal treatment setting remains unknown. We assessed the effect of niraparib on HGSOC patient-derived xenograft (PDX) modeE as well as the relationship between certain markers of homologous recombination (HR) status, including BRCA1/2 mutations and formation of RAD51 foci after DNA damage, and response of these PDX5 to niraparib in vivo. Methods. Massively parallel sequencing was performed on HGSOCs to identify mutations contributing to HR deficiency. HR pathway integrity was assessed using fluorescence microscopy-based RAD51 focus formation assays. Effects of niraparib (MK-4827) on treatment-naive PDX tumor growth as monotherapy, in combination with carboplatin/paclitaxel, and as maintenance therapy were assessed by transabdominal ultrasound. Niraparib responses were correlated with changes in levels of poly(ADP-ribose), PARP1, and repair proteins by western blotting. Results. Five PDX models were evaluated in vivo. Tumor regressions were induced by single-agent niraparib in one of two PDX models with deleterious BRCA2 mutations and in a PDX with RAD51C promoter methylation. Diminished formation of RAD51 foci failed to predict response, but Artemis loss was associated with resistance. Niraparib generally failed to enhance responses to carboplatin/paclitaxel chemotherapy, but maintenance niraparib therapy delayed progression in a BRCA2-deficient PDX. Conclusions. Mutations in HR genes are neither necessary nor sufficient to predict response to niraparib. Assessment of repair status through multiple complementary assays is needed to guide PARP inhibitor therapy, design future clinical trials and identify ovarian cancer patients most likely to benefit from PARP inhibition. (C) 2016 Elsevier Inc. All rights reserved.

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