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      Targeted treatment of advanced ovarian cancer: spotlight on rucaparib

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          Abstract

          The last 2 years have ushered in a new era in ovarian cancer therapy with the US Food and Drug Administration’s (FDA) approval of poly-ADP ribose polymerase (PARP) inhibitors (PARPi). One of the deadliest cancers that women experience, ovarian cancer, is most often diagnosed in advanced stages. Although cytoreductive surgery and (platinum/taxane-based) chemotherapy can place the majority of patients into remission, most will experience a relapse of their disease in their lifetime. This has led to studies exploring the benefits and efficacy of maintenance treatment. This review will briefly discuss the history of maintenance therapy as well as focus on the FDA’s approval of rucaparib and its companion tumor profiling test, in the US. It will describe how women with deleterious mutations in the BRCA gene, through their inherent deficiency in homologous recombination, presented scientists with a target to exploit through a concept known as synthetic lethality. Not only did this lead to a targeted treatment for BRCA mutation carriers but for other patients with deficiencies in homologous recombination and, more broadly, also in platinum-sensitive patients. The focus of this review will be on rucaparib in the US, approved for both maintenance of platinum-sensitive recurrent ovarian cancer and treatment in the third-line setting and beyond. It has the broadest indication amongst the three PARPi in ovarian cancer. Furthermore, the ongoing trials using rucaparib in ovarian cancer and other disease types will be discussed.

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          Most cited references 27

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          Linkage of early-onset familial breast cancer to chromosome 17q21.

          Human breast cancer is usually caused by genetic alterations of somatic cells of the breast, but occasionally, susceptibility to the disease is inherited. Mapping the genes responsible for inherited breast cancer may also allow the identification of early lesions that are critical for the development of breast cancer in the general population. Chromosome 17q21 appears to be the locale of a gene for inherited susceptibility to breast cancer in families with early-onset disease. Genetic analysis yields a lod score (logarithm of the likelihood ratio for linkage) of 5.98 for linkage of breast cancer susceptibility to D17S74 in early-onset families and negative lod scores in families with late-onset disease. Likelihood ratios in favor of linkage heterogeneity among families ranged between 2000:1 and greater than 10(6):1 on the basis of multipoint analysis of four loci in the region.
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            A mechanism for gene conversion in fungi

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              Therapeutic potential of poly(ADP-ribose) polymerase inhibitor AG014699 in human cancers with mutated or methylated BRCA1 or BRCA2.

              Mutations in BRCA1 and BRCA2 (BRCA1/2), components of the homologous recombination DNA repair (HRR) pathway, are associated with hereditary breast and ovarian cancers. Poly(ADP-ribose) polymerase (PARP) inhibitors are selectively cytotoxic to animal cells with defective HRR, but results in human cancer cells have been contradictory. We undertook, to our knowledge, the first comprehensive in vitro and in vivo investigations of the antitumor activity of the PARP inhibitor AG014699 in human cancer cells carrying mutated or epigenetically silenced BRCA1/2. We used nine human cell lines, four with nonmutated BRCA1/2 (MCF7, MDA-MB-231, and HCC1937-BRCA1 [breast cancer] and OSEC-2 [ovarian surface epithelial]), two with mutated BRCA1 (MDA-MB-436 and HCC1937 [breast cancer]), one with mutated BRCA2 (CAPAN-1 [pancreatic cancer]), one that was heterozygous for BRCA2 (OSEC-1 [ovarian surface epithelial]), and one with epigenetically silenced BRCA1 (UACC3199 [breast cancer]), and two Chinese hamster ovary cell lines, parental AA8 and XRCC3 mutated IRS 1SF. We assessed cytotoxicity, DNA damage, and HRR function. Antitumor activity of AG014699 was determined by growth of xenograft tumors (five mice per treatment group). Long-term safety of AG014699 was assessed. AG014699 (≤10 μM) was cytotoxic to cells with mutated BRCA1/2 or XRCC3 and to UACC3199 cells with epigenetically silenced BRCA1 but not to cells without BRCA1/2 or XRCC3 mutations or that were heterozygous for BRCA2 mutation. AG014699 induced DNA double-strand breaks in all nine cell lines studied. HRR was observed only in cells with functional BRCA1/2 proteins. Growth of xenograft tumors with BRCA1/2 mutations or with epigenetically silenced BRCA1 was reduced by AG014699 treatment, and combination treatment with AG014699 plus carboplatin was more effective than either drug alone. AG014699 was not toxic in mice with nonmutated or heterozygous BRCA2. Human cancer cells or xenograft tumors with mutated or epigenetically silenced BRCA1/2 were sensitive to AG014699 monotherapy, indicating a potential role for PARP inhibitors in sporadic human cancers.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                2018
                02 November 2018
                : 14
                : 2189-2201
                Affiliations
                Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of California, Irvine Medical Center, Orange, CA, USA, ktewari@ 123456uci.edu
                Author notes
                Correspondence: Krishnansu S Tewari, Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of California, Irvine Medical Center, 333 The City Boulevard West, Orange, CA 92868, USA, Tel +1 714 456 8020, Fax +1 714 456 6632, Email ktewari@ 123456uci.edu
                Article
                tcrm-14-2189
                10.2147/TCRM.S149248
                6223341
                © 2018 Pearre and Tewari. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Review

                Medicine

                ovarian cancer, rucaparib, targeted therapy, parp inhibitor, brca

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