BMC Medicine | |
Chemotherapy reduces PARP1 in cancers of the ovary: implications for future clinical trials involving PARP inhibitors | |
Michael Witcher1  Walter H. Gotlieb3  Anne-Marie Mes-Masson5  Diane Provencher5  Manuela Pelmus4  Sun Qiang1  Ido Laskov3  Hubert Fleury2  Marie-Claude Beauchamp1  Maud Marques1  | |
[1] Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Côte Ste, Catherine Road, Montréal H3T 1E2, QC, Canada;Centre de recherche du Centre hospitalier de l’Université de Montréal/Institut du cancer de Montréal, Montréal, Canada;Division of Gynecologic Oncology, Jewish General Hospital, McGill University, Montréal, Canada;Division of Pathology, Jewish General Hospital, Montréal, Canada;Department of Medicine, Université de Montréal, Montreal, Canada | |
关键词: ovarian cancer; PARP1; PARP inhibitors; Chemotherapy; | |
Others : 1224790 DOI : 10.1186/s12916-015-0454-9 |
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received in 2015-06-03, accepted in 2015-08-14, 发布年份 2015 | |
【 摘 要 】
Background
PARP inhibitors have shown promising clinical results in cancer patients carrying BRCA1/2 mutations. Their clinical efficacy could logically be influenced by PARP1 protein levels in patient tumors.
Methods
We screened three cohorts of patients with ovarian cancer, totaling 313 samples, and evaluated PARP1 protein expression by immunohistochemistry with further validation by western blotting.
Results
We observed that up to 60 % of tumors showed little PARP1 protein expression. In serous ovarian tumors, comparing intratumoral PARP1 expression between chemo-naïve and post-chemotherapy patients revealed a decrease in intratumoral PARP1 following chemotherapy in all three cohorts (immunohistochemistry: p < 0.001, n = 239; western blot: p = 0.012, n = 74). The findings were further confirmed in a selection of matched samples from the same patients before and after chemotherapy.
Conclusion
Our data suggest that patients should be screened for PARP1 expression prior to therapy with PARP inhibitors. Further, the observed reduction of intratumoral PARP1 post-chemotherapy suggests that treating chemo-naïve patients with PARP inhibitors prior to the administration of chemotherapy, or concurrently, might increase the responsiveness to PARP1 inhibition. Thus, a change in the timing of PARP inhibitor administration may be warranted for future clinical trials.
【 授权许可】
2015 Marques et al.
【 预 览 】
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Fig. 1. | 59KB | Image | download |
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