Rucaparib in the landscape of PARP inhibition in ovarian cancer

Introduction: The landscape of poly (ADP-ribose) polymerase (PARP) inhibition in ovarian cancer is rapidly evolving and becoming increasingly complex. Ovarian cancer is leading therapeutic innovation by providing the proof of concept for DNA repair as a target. Three different PARP inhibitors have now received approvals in the US and Europe in different indications. Subtle but crucial differences can be found among the licensed indications for each PARP inhibitor in terms of histology, type of BRCA mutation (germline and/or somatic), number of prior lines of chemotherapy and whether the indication is in the treatment or maintenance settings.

Areas covered: We review the latest clinical data regarding the PARP inhibitor rucaparib in ovarian cancer, provide an update on the evolving landscape of PARP inhibition in ovarian cancer, and summarize avenues of ongoing and future research.

Expert opinion: All eligible patients should be offered a PARP inhibitor. SOLO1 trial results demonstrated an unprecedented benefit maintenance with PARP inhibitors in first line. Results from trials evaluating PARP inhibitors as maintenance in first line regardless of BRCA status and from trials evaluating combinatorial strategies are eagerly awaited.     

聚腺苷二磷酸核糖聚合酶抑制剂在肿瘤放射治疗中的应用研究进展

聚腺苷二磷酸核糖聚合酶（PARP）是一类在真核细胞中高表达的核酶，在DNA损伤修复中起关键作用。近年来，PARP抑制剂在肿瘤治疗中显示出巨大的潜力，几种小分子PARP抑制剂已被美国食品药品管理局（FDA）批准用于多种肿瘤的维持治疗。PARP抑制剂主要通过抑制PARP酶促作用和PARP捕获作用，导致DNA单链断裂的持续存在，在DNA复制的过程中，转变为双链断裂。研究证明，PARP抑制剂不仅具有显著的抗肿瘤效应，而且与放射治疗联合具有一定的协同作用。本文将阐述PARP抑制剂联合放疗的潜在理论基础，总结近年来PARP抑制剂在肿瘤放射治疗中的临床前和临床研究进展，梳理该领域目前亟待解决的问题，并对其在抗肿瘤治疗中的应用前景进行展望。     

Targeting DNA Repair in Ovarian Cancer Treatment Resistance

Most patients with advanced high-grade serous ovarian cancer (HGSOC) develop recurrent disease within 3 years and succumb to the disease within 5 years. Standard treatment for HGSOC is cytoreductive surgery followed by a combination of platinum (carboplatin or cisplatin) and taxol (paclitaxel) chemotherapies. Although initial recurrences are usually platinum-sensitive, patients eventually develop resistance to platinum-based chemotherapy. Accordingly, one of the major problems in the treatment of HGSOC and disease recurrence is the development of chemotherapy resistance. One of the causes of chemoresistance may be redundancies in the repair pathways involved in the response to DNA damage caused by chemotherapy. These pathways may be acting in parallel, where if the repair pathway that is responsible for triggering cell death after platinum chemotherapy therapy is deficient, an alternative repair pathway compensates and drives cancer cells to repair the damage, leading to chemotherapy resistance. In addition, if the repair pathways are epigenetically inactivated by DNA methylation, cell death may not be triggered, resulting in accumulation of mutations and DNA damage. There are novel and existing therapies that can drive DNA repair pathways towards sensitivity to platinum chemotherapy or targeted therapy, thus enabling treatment-resistant ovarian cancer to overcome chemotherapy resistance.     

PARP1对黑素瘤细胞克隆形成的影响及其作用机制

目的:探究聚二磷酸腺苷核糖多聚酶1［poly (ADP-ribose) polymerase 1,PARP1］对黑素瘤细胞克隆形成的影响及可能的作用机制。方法:在黑素瘤A2058细胞系中利用小干扰RNA干涉PARP1表达水平，利用平板克隆形成实验观察干涉PARP1对黑素瘤细胞克隆形成的影响。提取PARP1干涉片段及对照片段转染细胞的总RNA进行全基因组表达谱芯片检测。Realtime RT-PCR对部分差异性基因进行验证。应用DAVID数据库对差异性基因进行GO及KEGG通路富集分析。Realtime RT-PCR对富集分析结果中可疑靶基因进行验证。结果:干涉PARP1表达可显著抑制黑素瘤细胞克隆形成。全基因组芯片结果显示干涉PARP1表达可引起128个基因表达上调，77个基因表达下调。通过Realtime RT-PCR对部分差异表达基因进行验证，结果表明与芯片筛选结果一致。GO和KEGG富集分析结果显示PARP1调控的差异性表达基因在生物学功能及参与的信号通路中存在部分交集，即MAPK信号通路及其正向调控机制。双特异性磷酸酶5（DUSP5）作为MAPK通路中的抑制分子，Realtime RT-PCR证实干涉PARP1可促进其表达水平升高。结论:干涉PARP1可能通过促进DUSP5表达从而抑制MAPK信号通路活性，进而发挥抑制黑素瘤细胞克隆形成的作用。     

放疗联合安罗替尼对小细胞肺癌患者胱天蛋白酶3、多腺苷二磷酸核糖聚合酶表达的影响研究

目的探讨放疗联合安罗替尼对小细胞肺癌(SCLC)患者胱天蛋白酶3(caspase 3)、多腺苷二磷酸核糖聚合酶(PARP)表达的影响。方法将86例SCLC患者随机分为放疗组(n=42)和联合组(放疗联合安罗替尼,n=44),探索两组1年生存率、不良反应发生情况及对caspase 3、PARP表达的影响。结果治疗前两组患者血清caspase 3、PARP水平比较,差异均无统计学意义(P﹥0.05);治疗后联合组患者血清caspase 3水平明显高于放疗组,PARP水平明显低于放疗组,差异均有统计学意义(P﹤0.01)。两组患者白细胞减少、中性粒细胞减少发生率比较,差异均无统计学意义(P﹥0.05)。联合组患者1年生存率高于放疗组,差异有统计学意义(P﹤0.05)。结论放疗联合安罗替尼可以有效提高SCLC患者血清内caspase 3水平,降低PARP水平,延长患者的生存时间,值得临床进一步研究。     

PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity

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Parp inhibitors as maintenance treatment in platinum sensitive recurrent ovarian cancer: An updated meta-analysis of randomized clinical trials according to BRCA mutational status

ObjectiveThis meta-analysis investigated the effectiveness of PARP inhibitors (PARPis) as maintenance treatment in platinum sensitive recurrent ovarian cancer (ROC), stratifying results based on BRCA mutational status into five different categories: whole population, germ-line BRCA mutated patients, somatic BRCA mutated patients, HRD patients and wild type population.MethodsPubMed, Medline, Scopus, EMBASE and clinicaltrials.gov, as well as meeting proceedings were searched for eligible studies that described RCTs testing the efficacy of PARPis as maintenance treatment in platinum sensitive ROC. Data were extracted independently and analysed using RevMan statistical software version 5.3. Primary end-point was progression free survival (PFS).ResultsThe analysis confirmed the positive effect of PARPis in patients with platinum sensitive ROC in case of germinal or somatic BRCA mutations. Specifically, HR for PFS was 0.26, 95% CI 0.21–0.31, p < 0.00001 for the mutation of BRCA gene and 0.24, 95%, CI 0.12–0.48, p < 0.0001 for the somatic alteration. In addition, in the HRD population, studies that analysed the efficacy of PARPis  reported a PFS improvement with HR 0.34, 95% CI 0.26–0.43, p < 0.00001. Finally, our analysis confirms the role of these drugs in prolonging PFS in the whole population with HR 0.36, 95% CI 0.32–0.42, p < 0.00001, although to a lesser extent, with a significant improvement even in wild type cancers with HR 0.49, 95%, CI 0.41–0.59, p < 0.00001).ConclusionsPARPis are effective regardless of BRCA mutational status. Future investigations are necessary to explore the use of different PARPis as monotherapy, comparing them among each other in terms of efficacy and toxicity, and exploring their potential re-use.     

《PARP抑制剂在卵巢癌中的应用：ASCO指南》解读

        2014年，美国食品和药物监督管理局（FDA）批准了第一个多聚ADP核糖多聚酶（PARP抑制剂）奥拉帕利（Olaparib）治疗已接受≥3线化疗的胚系BRCA突变（gBRCA）卵巢上皮性癌患者；2016年批准卢卡帕利（Rucaparib）用于治疗胚系和体细胞BRCA突变（g/sBRCA）的复发性卵巢癌患者；2017年批准了尼拉帕利（Niraparib）和Olaparib用于对含铂化疗完全或部分缓解患者的维持治疗。 浏览更多请关注本刊微信公众号及当期杂志。