Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut, USA.
Curr Opin Oncol. 2012 Sep;24(5):564-71. doi: 10.1097/CCO.0b013e3283564230.
Management of the epithelial ovarian cancer (EOC) remains a therapeutic challenge, with continued poor overall survival (OS). Given low chemotherapy response rates for recurrent disease and short survival times, new treatment options with improved therapeutic indices for targeting cancer's vulnerability are urgently needed in this patient population.
In this review, we summarize the recent development and clinical evaluations of inhibitors of poly (ADP-ribose) polymerase (PARP) as novel targeting agents for EOC. PARP inhibitors exploit synthetic lethality to target DNA repair defects in hereditary breast and ovarian cancer.In recent clinical trials, EOC patients with BRCA mutations exhibited favorable responses to the PARP inhibitor olaparib compared with patients without BRCA mutations. Additionally, olaparib has been reported to augment the effects of cisplatin and carboplatin on recurrence-free survival and OS in mice bearing BRCA1/2-deficient tumors.Given that hereditary EOC with deleterious BRCA1/2 mutations and BRCAness sporadic EOC are profoundly susceptible to synthetic lethality with PARP inhibition, it is imperative to identify a population of EOC patients that is likely to respond to PARP inhibitors. Recent studies have identified the gene expression profiles of DNA repair defects and BRCAness that predict clinical outcomes and response to platinum-based chemotherapy in EOC patients.
Ovarian cancer continues to carry the highest mortality among gynecologic cancers in the western world. Clinical development of PARP inhibitors that target DNA repair defects in cancer is a novel and imperative stride in individualized identification of molecular characteristics in management of ovarian cancer.
上皮性卵巢癌（EOC）的治疗仍然是一个挑战，总生存率（OS）持续较差。鉴于复发性疾病的化疗反应率低和生存时间短，对于这类患者群体，迫切需要具有改善治疗指数的靶向癌症脆弱性的新治疗选择。
在这篇综述中，我们总结了聚（ADP-核糖）聚合酶（PARP）抑制剂作为 EOC 新型靶向药物的最新进展和临床评估。PARP 抑制剂利用合成致死性来靶向遗传性乳腺癌和卵巢癌的 DNA 修复缺陷。最近的临床试验表明，与没有 BRCA 突变的患者相比，BRCA 突变的 EOC 患者对 PARP 抑制剂奥拉帕尼有更好的反应。此外，奥拉帕尼已被报道在携带 BRCA1/2 缺陷肿瘤的小鼠中增强顺铂和卡铂对无复发生存和 OS 的作用。鉴于具有有害 BRCA1/2 突变和 BRCA 样的遗传性 EOC 以及 BRCA 样散发性 EOC 对 PARP 抑制的合成致死性非常敏感，因此必须确定可能对 PARP 抑制剂有反应的 EOC 患者人群。最近的研究已经确定了 DNA 修复缺陷和 BRCA 样的基因表达谱，这些预测了 EOC 患者的临床结局和对铂类化疗的反应。
在西方世界，卵巢癌仍然是妇科癌症中死亡率最高的癌症。针对癌症中 DNA 修复缺陷的 PARP 抑制剂的临床开发是在卵巢癌管理中对分子特征进行个体化识别的一项新颖且必要的进展。
