Boussios Stergios, Moschetta Michele, Karihtala Peeter, Samartzis Eleftherios P, Sheriff Matin, Pappas-Gogos George, Ozturk Mehmet Akif, Uccello Mario, Karathanasi Afroditi, Tringos Michail, Rassy Elie, Pavlidis Nicholas
Department of Medical Oncology, Medway NHS Foundation Trust, Gillingham, Kent, UK.
AELIA Organization, 9th Km Thessaloniki-Thermi, Thessaloniki, Greece.
Ann Transl Med. 2020 Dec;8(24):1706. doi: 10.21037/atm.2020.03.156.
Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality among women, potentially due to ineffectiveness of screening tests for early detection. Patients typically present with advanced disease at diagnosis, whereas, up to 80% relapse and the estimated median progression-free survival (PFS) is approximately 12-18 months. Increased knowledge on the molecular biology of EOC resulted in the development of several targeted therapies, including poly(ADP-ribose) polymerase (PARP) inhibitors. These agents have changed the therapeutic approach of the EOC and exploit homologous recombination (HR) deficiency through synthetic lethality, especially in breast cancer genes 1 and 2 () mutation carriers. Furthermore, wild-type patients with other defects in the HR repair pathway, or those with platinum-resistant tumors may obtain benefit from this treatment. While PARP inhibitors as a class display many similarities, several differences in structure can translate into differences in tolerability and antitumor activity. Currently, olaparib, rucaparib, and niraparib have been approved by Food and Drug Administration (FDA) and/or European Medicines Agency (EMA) for the treatment of EOC, while veliparib is in the late stage of clinical development. Finally, since October 2018 talazoparib is FDA and EMA approved for carriers with metastatic breast cancers. In this article, we explore the mechanisms of DNA repair, synthetic lethality, efficiency of PARP inhibition, and provide an overview of early and ongoing clinical investigations of the novel PARP inhibitors veliparib and talazoparib.
上皮性卵巢癌（EOC）是女性癌症死亡的第五大主要原因，这可能是由于早期检测的筛查试验无效所致。患者在诊断时通常表现为晚期疾病，然而，高达80%的患者会复发，估计无进展生存期（PFS）的中位数约为12 - 18个月。对EOC分子生物学认识的增加导致了几种靶向治疗的发展，包括聚（ADP - 核糖）聚合酶（PARP）抑制剂。这些药物改变了EOC的治疗方法，并通过合成致死性利用同源重组（HR）缺陷，特别是在乳腺癌基因1和2（）突变携带者中。此外，HR修复途径存在其他缺陷的野生型患者，或患有铂耐药肿瘤的患者可能从这种治疗中获益。虽然PARP抑制剂作为一类药物有许多相似之处，但结构上的一些差异可能转化为耐受性和抗肿瘤活性的差异。目前，奥拉帕利、鲁卡帕利和尼拉帕利已被美国食品药品监督管理局（FDA）和/或欧洲药品管理局（EMA）批准用于治疗EOC，而维利帕利正处于临床开发后期。最后，自2018年10月以来，他拉唑帕利已获得FDA和EMA批准用于治疗转移性乳腺癌的携带者。在本文中，我们探讨了DNA修复机制、合成致死性、PARP抑制效率，并概述了新型PARP抑制剂维利帕利和他拉唑帕利的早期及正在进行的临床研究情况。
