Update on Poly-ADP-ribose polymerase inhibition for ovarian cancer treatment.
Update on Poly-ADP-ribose polymerase inhibition for ovarian cancer treatment.
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DOI：
10.1186/s12967-016-1027-1
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发表时间：
2016-09-15
影响因子：
7.4
通讯作者：
Tomao F
中科院分区：
文献类型：
--
作者：
Papa A;Caruso D;Strudel M;Tomao S;Tomao F
尽管上皮性卵巢癌（EOC）的标准治疗涉及细胞减灭术，随后是基于铂的化疗，以及对这些的初始高应答率，但高达80%的患者经历复发，中位无进展生存期为12-18个月。仍然迫切需要新的靶向治疗来改善卵巢癌的临床结局。在目前正在评估的许多靶向治疗中，迄今为止开发的最有希望的策略是抗血管生成剂和聚（ADP-核糖）聚合酶（PARP）抑制剂。特别地，PARP抑制剂在具有通过同源重组（HR）途径受损的DNA修复的细胞中具有活性。具有突变的乳腺相关癌抗原（BRCA）功能的细胞具有HR缺陷，其也存在于显著比例的非BRCA突变的卵巢癌（“BRCAness”卵巢癌）中。在EOC中，生殖系BRCA突变的患病率历来估计为10- 15%左右。然而，最近的报告表明，这可能是一个严重低估，特别是在高级别浆液性卵巢癌（HGSOC）的妇女。DNA修复途径作为各种癌症的合理靶点的出现导致了PARP抑制剂的发展。肿瘤选择性合成致死性的概念预示着一个多事的十年的开始，最终在欧洲的监管机构批准作为维持治疗，并在美国批准第一种口服PARP抑制剂奥拉帕尼治疗晚期复发性疾病，用于治疗BRCA突变的卵巢癌患者。其他PARP抑制剂在这种疾病中明显有效，在未来几年内，正在进行的随机试验的结果将阐明它们各自的作用。本文将讨论不同的PARP抑制剂的发展和这类药物在未来的潜在用途。此外，涉及PARP抑制剂的组合策略可能会受到越来越多的关注。PARP抑制剂与细胞毒性化疗联合使用的价值值得怀疑，因为这种联合的毒性增强;而更有前途的策略包括与抗血管生成剂或P13 K/AKT通路抑制剂和新一代免疫疗法的联合使用。
Despite standard treatment for epithelial ovarian cancer (EOC), that involves cytoreductive surgery followed by platinum-based chemotherapy, and initial high response rates to these, up to 80 % of patients experience relapses with a median progression-free survival of 12–18 months. There remains an urgent need for novel targeted therapies to improve clinical outcomes in ovarian cancer. Of the many targeted therapies currently under evaluation, the most promising strategies developed thus far are antiangiogenic agents and Poly(ADP-ribose) polymerase (PARP) inhibitors. Particularly, PARP inhibitors are active in cells that have impaired repair of DNA by the homologous recombination (HR) pathway. Cells with mutated breast related cancer antigens (BRCA) function have HR deficiency, which is also present in a significant proportion of non-BRCA-mutated ovarian cancer (“BRCAness” ovarian cancer). The prevalence of germline BRCA mutations in EOC has historically been estimated to be around 10–15 %. However, recent reports suggest that this may be a gross underestimate, especially in women with high-grade serous ovarian cancer (HGSOC). The emergence of the DNA repair pathway as a rational target in various cancers led to the development of the PARP inhibitors. The concept of tumor-selective synthetic lethality heralded the beginning of an eventful decade, culminating in the approval by regulatory authorities both in Europe as a maintenance therapy and in the United States treatment for advanced recurrent disease of the first oral PARP inhibitor, olaparib, for the treatment of BRCA-mutated ovarian cancer patients. Other PARP inhibitors are clearly effective in this disease and, within the next years, the results of ongoing randomized trials will clarify their respective roles. This review will discuss the different PARP inhibitors in development and the potential use of this class of agents in the future. Moreover, combination strategies involving PARP inhibitors are likely to receive increasing attention. The utility of PARP inhibitors combined with cytotoxic chemotherapy is of doubtful value, because of enhanced toxicity of this combination; while, more promising strategies include the combination with antiangiogenic agents, or with inhibitors of the P13K/AKT pathway and new generation of immunotherapy.
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DOI：
10.1097/igc.0b013e31825736b2
发表时间：
2012-07-01
影响因子：
4.8
作者：
Benedetti-Panici, Pierluigi;Perniola, Giorgia;Bellati, Filippo
通讯作者：
Bellati, Filippo
影响因子：
28.2
作者：
Bouwman, Peter;van der Gulden, Hanneke;Jonkers, Jos
通讯作者：
Jonkers, Jos
影响因子：
168.9
作者：
Audeh, M. William;Carmichael, James;Tutt, Andrew
通讯作者：
Tutt, Andrew
DOI：
10.1016/0006-291x(63)90024-x
发表时间：
1963-01-01
影响因子：
3.1
作者：
CHAMBON, P;MANDEL, P;WEILL, JD
通讯作者：
WEILL, JD
BRCA1和BRCA2突变之间的关联以及侵入性上皮卵巢癌女性的生存。
影响因子：
120.7
作者：
Bolton, Kelly L.;Chenevix-Trench, Georgia;Goh, Cindy;Sadetzki, Siegal;Ramus, Susan J.;Karlan, Beth Y.;Lambrechts, Diether;Despierre, Evelyn;Barrowdale, Daniel;McGuffog, Lesley;Healey, Sue;Easton, Douglas F.;Sinilnikova, Olga;Benitez, Javier;Garcia, Maria J.;Neuhausen, Susan;Gail, Mitchell H.;Hartge, Patricia;Peock, Susan;Frost, Debra;Evans, Gareth;Eeles, Rosalind;Godwin, Andrew K.;Daly, Mary B.;Kwong, Ava;Ma, Edmond S. K.;Lazaro, Conxi;Blanco, Ignacio;Montagna, Marco;D'Andrea, Emma;Nicoletto, Maria Ornella;Johnatty, Sharon E.;Krueger, Susanne;Jensen, Allan;Hogdall, Estrid;Goode, Ellen L.;Fridley, Brooke L.;Loud, Jennifer T.;Greene, Mark H.;Mai, Phuong L.;Chetrit, Angela;Lubin, Flora;Hirsh-Yechezkel, Galit;Glendon, Gord;Andrulis, Irene L.;Toland, Amanda E.;Senter, Leigha;Gore, Martin E.;Gourley, Charlie;Michie, Caroline O.;Song, Honglin;Tyrer, Jonathan;Whittemore, Alice S.;McGuire, Valerie;Sieh, Weiva;Kristoffersson, Ulf;Olsson, Hakan;Borg, Ake;Levine, Douglas A.;Steele, Linda;Beattie, Mary S.;Chan, Salina;Nussbaum, Robert L.;Moysich, Kirsten B.;Gross, Jenny;Cass, Ilana;Walsh, Christine;Li, Andrew J.;Leuchter, Ronald;Gordon, Ora;Garcia-Closas, Montserrat;Gayther, Simon A.;Chanock, Stephen J.;Antoniou, Antonis C.;Pharoah, Paul D. P.
通讯作者：
Pharoah, Paul D. P.