Clinical Implications of DNA Repair Defects in High-Grade Serous Ovarian Carcinomas
Despite significant improvements in surgical and medical management, high grade serous ovarian cancer (HGSOC) still represents the deadliest gynecologic malignancy and the fifth most frequent cause of cancer-related mortality in women in the USA. Since DNA repair alterations are regarded as the “the...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-05-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/5/1315 |
| _version_ | 1797567289410715648 |
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| author | Michela Camilla Milanesio Silvia Giordano Giorgio Valabrega |
| author_facet | Michela Camilla Milanesio Silvia Giordano Giorgio Valabrega |
| author_sort | Michela Camilla Milanesio |
| collection | DOAJ |
| description | Despite significant improvements in surgical and medical management, high grade serous ovarian cancer (HGSOC) still represents the deadliest gynecologic malignancy and the fifth most frequent cause of cancer-related mortality in women in the USA. Since DNA repair alterations are regarded as the “the Achille’s heel” of HGSOC, both DNA homologous recombination and DNA mismatch repair deficiencies have been explored and targeted in epithelial ovarian cancers in the latest years. In this review, we aim at focusing on the therapeutic issues deriving from a faulty DNA repair machinery in epithelial ovarian cancers, starting from existing and well-established treatments and investigating new therapeutic approaches which could possibly improve ovarian cancer patients’ survival outcomes in the near future. In particular, we concentrate on the role of both Poly (ADP-ribose) Polymerase (PARP) inhibitors (PARPis) and immune checkpoint inhibitors in HGSOC, highlighting their activity in relation to BRCA1/2 mutational status and homologous recombination deficiency (HRD). We investigate the biological rationale supporting their use in the clinical setting, pointing at tracking their route from the laboratory bench to the patient’s bedside. Finally, we deal with the onset of mechanisms of primary and acquired resistance to PARPis, reporting the pioneering strategies aimed at converting homologous-recombination (HR) proficient tumors into homologous recombination (HR)-deficient HGSOC. |
| first_indexed | 2024-03-10T19:39:40Z |
| format | Article |
| id | doaj.art-5c84d0e8a4bd49ceb6cfb65e331bc050 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T19:39:40Z |
| publishDate | 2020-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-5c84d0e8a4bd49ceb6cfb65e331bc0502023-11-20T01:19:57ZengMDPI AGCancers2072-66942020-05-01125131510.3390/cancers12051315Clinical Implications of DNA Repair Defects in High-Grade Serous Ovarian CarcinomasMichela Camilla Milanesio0Silvia Giordano1Giorgio Valabrega2Department of Oncology, University of Torino, Candiolo, 10060 Torino, ItalyDepartment of Oncology, University of Torino, Candiolo, 10060 Torino, ItalyDepartment of Oncology, University of Torino, Candiolo, 10060 Torino, ItalyDespite significant improvements in surgical and medical management, high grade serous ovarian cancer (HGSOC) still represents the deadliest gynecologic malignancy and the fifth most frequent cause of cancer-related mortality in women in the USA. Since DNA repair alterations are regarded as the “the Achille’s heel” of HGSOC, both DNA homologous recombination and DNA mismatch repair deficiencies have been explored and targeted in epithelial ovarian cancers in the latest years. In this review, we aim at focusing on the therapeutic issues deriving from a faulty DNA repair machinery in epithelial ovarian cancers, starting from existing and well-established treatments and investigating new therapeutic approaches which could possibly improve ovarian cancer patients’ survival outcomes in the near future. In particular, we concentrate on the role of both Poly (ADP-ribose) Polymerase (PARP) inhibitors (PARPis) and immune checkpoint inhibitors in HGSOC, highlighting their activity in relation to BRCA1/2 mutational status and homologous recombination deficiency (HRD). We investigate the biological rationale supporting their use in the clinical setting, pointing at tracking their route from the laboratory bench to the patient’s bedside. Finally, we deal with the onset of mechanisms of primary and acquired resistance to PARPis, reporting the pioneering strategies aimed at converting homologous-recombination (HR) proficient tumors into homologous recombination (HR)-deficient HGSOC.https://www.mdpi.com/2072-6694/12/5/1315epithelial ovarian cancerDNA repair deficiencyDNA homologous recombinationDNA mismatch repairPARP inhibitorsBRCA reversion mutations |
| spellingShingle | Michela Camilla Milanesio Silvia Giordano Giorgio Valabrega Clinical Implications of DNA Repair Defects in High-Grade Serous Ovarian Carcinomas Cancers epithelial ovarian cancer DNA repair deficiency DNA homologous recombination DNA mismatch repair PARP inhibitors BRCA reversion mutations |
| title | Clinical Implications of DNA Repair Defects in High-Grade Serous Ovarian Carcinomas |
| title_full | Clinical Implications of DNA Repair Defects in High-Grade Serous Ovarian Carcinomas |
| title_fullStr | Clinical Implications of DNA Repair Defects in High-Grade Serous Ovarian Carcinomas |
| title_full_unstemmed | Clinical Implications of DNA Repair Defects in High-Grade Serous Ovarian Carcinomas |
| title_short | Clinical Implications of DNA Repair Defects in High-Grade Serous Ovarian Carcinomas |
| title_sort | clinical implications of dna repair defects in high grade serous ovarian carcinomas |
| topic | epithelial ovarian cancer DNA repair deficiency DNA homologous recombination DNA mismatch repair PARP inhibitors BRCA reversion mutations |
| url | https://www.mdpi.com/2072-6694/12/5/1315 |
| work_keys_str_mv | AT michelacamillamilanesio clinicalimplicationsofdnarepairdefectsinhighgradeserousovariancarcinomas AT silviagiordano clinicalimplicationsofdnarepairdefectsinhighgradeserousovariancarcinomas AT giorgiovalabrega clinicalimplicationsofdnarepairdefectsinhighgradeserousovariancarcinomas |