聚(ADP-核糖)聚合酶(PARP)抑制剂是第一个临床批准的药物,旨在利用合成杀伤力,并于2005年首次作为癌症靶向策略引入。它们导致了晚期卵巢癌治疗的重大变化,并通过同源重组(HR)途径改变了具有极端遗传复杂性和DNA修复缺陷的疾病的自然史。此外,除乳腺癌相关癌抗原1和2(BRCA1/2)突变外,其他机制也可导致HR通路改变,从而导致PARP抑制剂的临床获益.PARP抑制剂与其他抗癌疗法的新型组合具有挑战性,更好地理解PARP生物学,DNA修复机制,PARP抑制剂的作用机制至关重要。似乎PARP抑制剂和生物剂组合在BRCA突变和野生型癌症中均表现出良好的耐受性和临床有效性。他们针对卵巢癌中不同的异常和可利用的途径,并可能导致更大的DNA损伤和HR缺乏。卵巢癌中免疫疗法的输入是基于免疫抑制微环境可以影响肿瘤生长的观察。转移,甚至治疗抵抗。已经研究了几种生物制剂与PARP抑制剂的组合,包括血管内皮生长因子抑制剂(VEGF;贝伐单抗,塞迪尼布),和PD-1或PD-L1(Durvalumab,pembrolizumab,nivolumab),抗CTLA4单克隆抗体(曲美木单抗),mTOR-(vistusertib),AKT-(capivasertib),和PI3K抑制剂(布帕利布,alpelisib),以及MEK1/2和WEE1抑制剂(司米替尼和阿达沃司替,分别)。Olaparib和veliparib也已与化疗结合,其理由是通过PARP抑制破坏碱基切除修复。奥拉帕尼已经与卡铂和紫杉醇进行了研究,而维利帕里布已经与替莫唑胺联合使用进行了额外的测试聚乙二醇化脂质体阿霉素,以及口服环磷酰胺,和拓扑异构酶抑制剂。然而,PARP抑制剂和化疗联合使用观察到的重叠骨髓抑制需要通过剂量递增研究进行进一步研究.在这次审查中,我们讨论了正在进行的多项临床试验,这些临床试验正在研究此类组合策略的抗肿瘤活性。
Poly (ADP-ribose) polymerase (PARP) inhibitors are the first clinically approved drugs designed to exploit synthetic lethality, and were first introduced as a cancer-targeting strategy in 2005. They have led to a major change in the treatment of advanced ovarian cancer, and altered the natural history of a disease with extreme genetic complexity and defective DNA repair via homologous recombination (HR) pathway. Furthermore, additional mechanisms apart from breast related cancer antigens 1 and 2 (BRCA1/2) mutations can also result in HR pathway alterations and consequently lead to a clinical benefit from PARP inhibitors. Novel combinations of PARP inhibitors with other anticancer therapies are challenging, and better understanding of PARP biology, DNA repair mechanisms, and PARP inhibitor mechanisms of action is crucial. It seems that PARP inhibitor and biologic agent combinations appear well tolerated and clinically effective in both BRCA-mutated and wild-type cancers. They target differing aberrant and exploitable pathways in ovarian cancer, and may induce greater DNA damage and HR deficiency. The input of immunotherapy in ovarian cancer is based on the observation that immunosuppressive microenvironments can affect tumour growth, metastasis, and even treatment resistance. Several biologic agents have been studied in combination with PARP inhibitors, including inhibitors of vascular endothelial growth factor (VEGF; bevacizumab, cediranib), and PD-1 or PD-L1 (durvalumab, pembrolizumab, nivolumab), anti-CTLA4 monoclonal antibodies (tremelimumab), mTOR-(vistusertib), AKT-(capivasertib), and PI3K inhibitors (buparlisib, alpelisib), as well as MEK 1/2, and WEE1 inhibitors (selumetinib and adavosertib, respectively). Olaparib and veliparib have also been combined with chemotherapy with the rationale of disrupting base excision repair via PARP inhibition. Olaparib has been investigated with carboplatin and paclitaxel, whereas veliparib has been tested additionally in combination with temozolomide vs. pegylated liposomal doxorubicin, as well as with oral cyclophosphamide, and topoisomerase inhibitors. However, overlapping myelosuppression observed with PARP inhibitor and chemotherapy combinations requires further investigation with dose escalation studies. In this
review, we discuss multiple clinical trials that are underway examining the antitumor activity of such combination strategies.