PARP抑制剂用于肿瘤治疗的研究进展

聚腺苷酸二磷酸核糖转移酶(poly(ADP-ribose)polymerase,PARP)是当今癌症治疗的一个新靶点,其能够催化ADP-核糖单元从烟酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucleotide,NAD+)转移至各种受体蛋白。PARP参与DNA修复和转录调控,不但在调节细胞存活和死亡过程中具有关键作用,同时也是肿瘤发展和炎症发生过程中的主要转录因子。PARP在碱基切除修复的DNA单链缺口(SSBs)修复中具有关键作用,抑制其活性能够增强放疗和DNA损伤类化疗药物的效果。目前已有至少8个PARP抑制剂进入临床,最新的体内外实验表明PARP抑制剂不但能够作为放化疗增敏剂,单独使用也能选择性杀伤DNA修复缺陷的肿瘤细胞,如BRCA1和BRCA2缺陷的乳腺癌细胞。大量的临床试验证明:该类药物毒副作用小、效果明确且短期耐受性良好,对于癌症治疗前景广阔。本文主要对PARP抑制剂的原理及其研究进展进行综述。     

尼拉帕尼：聚腺苷二磷酸-核糖聚合酶抑制剂

尼拉帕尼（Niraparib,商品名Zejula^TM）是聚腺苷二磷酸-核糖聚合酶（PARP）的口服小分子抑制剂,PARP抑制是治疗由DNA修复基因（如BRCA1和BRCA2）特异性畸变引起的DNA修复机制缺陷的癌症的有效策略。尼拉帕尼于2017年3月在美国获批,维持治疗复发性上皮性卵巢癌、输卵管癌、原发性腹膜癌的成年患者,这些患者对铂类化疗有完全或部分反应,推荐剂量为口服300 mg/d,直到疾病发生恶化或产生无法接受的不良反应。临床研究结果表明该药可以延长患者的无恶化生存期,为治疗卵巢癌提供了有效和可靠的治疗手段。     

FAMOUS研究：法莫替丁对阿司匹林所致胃肠粘膜损害的预防作用

背景及目的：抑制聚腺苷二磷酸酯核糖聚合酶（PARP）可致某些肿瘤细胞DNA修复障碍,促进肿瘤细胞凋亡,是治疗肿瘤的潜在方法,特别是对于BRCA1或BRCA2基因突变患者。Olaparib（AZD2281）为一种新型的口服PARP抑制剂,本研究对olaparib的有效性及安全性进行了临床评价。     

聚腺苷二磷酸-核糖聚合酶抑制剂在胰腺癌中的研究进展

胰腺癌是一种高度恶性的肿瘤,聚腺苷二磷酸-核糖聚合酶(PARP)抑制剂(PARPI)是首类基于合成致死概念开发合成的抗肿瘤药物,并被临床批准用于卵巢癌和乳腺癌的治疗。由于特定的DNA修复缺陷,研究发现具有BRCA1/2种系突变的肿瘤对PARPI敏感,但具体的作用机制仍不十分清楚。目前针对胰腺癌的多项临床试验已经开展,Ⅲ期POLO研究表明Olaparib在种系BRCA1/2突变患者和铂类诱导化疗后转移性胰腺癌患者中作为维持治疗有效且耐受性良好。联合治疗的相关临床研究表明添加PARPI的益处很可能来自维持治疗阶段。总的来说,PARPI在胰腺癌治疗领域有广阔的前景。     

PARP-1抑制剂和BRCA基因在乳腺癌治疗中的研究进展

多腺苷二磷酸核糖聚合酶-1[poly(ADP-ribose)polymerases-1,PARP-1]和BRCA在DNA单链和双链修复途径中起着至关重要的作用。研究表明,根据"合成致死"机制,通过抑制PARP-1活性,可以导致BRCA-1/2缺陷细胞DNA损伤修复的障碍,最终增强肿瘤细胞对放化疗的敏感性,因此以PARP-1和BRCA为靶点联合用药,或者在BRCA1和BRCA2基因突变的乳腺癌中使用PARP-1抑制剂,选择性杀死DNA修复缺陷的癌细胞,均显示出惊人的抗肿瘤效果。综述了联合PARP-1抑制剂和BRCA基因在乳腺癌放射治疗中的作用机制和临床研究结果,提出了临床策略中可能存在的问题以及未来发展方向。     

PARP抑制剂在肿瘤治疗中的研究进展

肿瘤是威胁人类生存与健康的重要原因之一。在肿瘤的药物治疗中,化疗是常用手段之一,但由于其特异性低、不良反应大、长期使用易产生耐药性等问题,应用受到较大限制。基于DNA损伤修复机制开发的新型抗肿瘤药物聚腺苷酸二磷酸核糖聚合酶(poly-ADP ribose polymerase,PARP)抑制剂可能是解决这一问题的关键。PARP抑制剂是一类靶向抑制PARP-1蛋白,诱导BRCA基因突变的肿瘤细胞发生“合成致死”现象的新型抗肿瘤药物,已成功应用于卵巢癌、乳腺癌等肿瘤的治疗。近年来PARP抑制剂更是与各类一线化疗药、靶向制剂及免疫检查点抑制剂等进行联合治疗,扩大了临床适用范围。本文将对PARP抑制剂的药理作用与作用机制、在肿瘤治疗中的应用及其耐药机制等研究进展进行总结,以期为PARP抑制剂的临床应用提供合理指导。     

新型PARP抑制剂veliparib

肿瘤细胞能够激活自身DNA的损伤修复机制进行修复,从而导致其对抗肿瘤药物和放疗产生耐药性,而聚腺苷酸二磷酸核糖转移酶(poly ADP-ribose polymerase,PARP)是一种DNA修复酶,在DNA修复通路中起关键作用.veliparib 是一种新型高选择抑制PARP的苯并咪唑类化合物,体内外实验表明本品具有显著的抑制PARP活性的作用.在治疗转移性乳腺癌、结肠癌、转移性黑色素瘤和脑肿瘤方面已取得显著的效果,其与替莫唑胺联用治疗乳腺癌的研究即将进入Ⅲ期临床.     

DNA修复抑制剂有望用于治疗癌症

目前 ,英国的ＫｕＤｏｓ制药公司在研究ＤＮＡ修复抑制剂方面获得了重大进展。ＤＮＡ修复抑制剂有望发展成为一种新型的抗癌药物。在正常情况下 ,ＤＮＡ的修复过程对机体来说是一种有利的行为 ,但是当癌症患者在接受化疗或放疗时 ,这种修复过程则会影响治疗效果 ,这是因为化疗或放疗的作用机制就是通过引起ＤＮＡ损伤来杀死癌细胞的。研究表明 ,ＤＮＡ修复抑制剂和传统的抗癌疗法结合起来可以明显提高后者的治疗效果 ,且对正常细胞影响很小。化疗或放疗可以引起特定的ＤＮＡ修复机制出现 ,这种机制并不是正常细胞所表现的低水平的ＤＮＡ修复…     

AKT抑制剂NTQ1062与Olaparib在卵巢癌细胞中的联用研究

目的： 探讨AKT抑制剂NTQ1062和PARP抑制剂Olaparib的对卵巢癌细胞的联用增效可行性及作用机制。方法：研究NTQ1062和Olaparib联用对三种人卵巢癌细胞系（OVCAR-3、TOV-21G、A2780）增殖的影响,并通过Western blot技术检测PI3K/AKT信号通路及同源重组修复、DNA损伤修复相关蛋白的表达,最后使用Annexin V-FITC双染法检测细胞凋亡。结果：实验结果显示,NTQ1062对TOV-21G、A2780细胞株具有较强的增殖抑制作用,对OVCAR-3细胞增殖的抑制作用较弱,并且联合处理会增加三株卵巢癌细胞的增殖抑制作用;Western blot实验中NTQ1062增加卵巢癌细胞中AKT的磷酸化、抑制S6RP的磷酸化、增加γH2AX蛋白表达、降低RAD51蛋白表达,并发现联合处理具有协同作用;进一步研究发现,联合用药会降低TOV-21G细胞中BRCA1蛋白的表达,但对A2780细胞影响不显著;细胞凋亡实验中,NTQ1062增加细胞凋亡群,并且联合处理显著增加了细胞凋亡效果。结论：NTQ1062可抑制OVCAR-3、TOV-21G、A2780细胞增殖,与Olaparib联用具有协同作用,通过抑制PI3K/AKT通路、DNA损伤、减少同源重组修复、降低BRCA1蛋白表达、增加凋亡来发挥作用。本研究可为临床制订AKT抑制剂NTQ1062与PARP抑制剂联合应用于卵巢癌治疗策略提供理论和技术依据。     

复发性上皮性卵巢癌的药物治疗及进展

卵巢癌是妇科恶性肿瘤中预后最差的肿瘤,80%的上皮性卵巢癌患者会复发。根据卵巢癌对铂类的敏感性不同将复发性卵巢癌分为:铂类敏感、铂类部分敏感、铂类耐药及难治性,对铂类敏感性的不同是影响复发性卵巢癌(ROC)治疗选择的重要特征。以贝伐单抗(Bevacizumab)为代表药物的抗血管生成药物是在复发性卵巢癌治疗中研究最多的靶向药物,而对于存在生殖系或体系BRCA突变的卵巢癌患者,可通过使用PARP抑制剂作为维持治疗直到进展来优化化疗效果并延长无进展生存期(PFS)。复发性卵巢癌患者可通过二次减瘤术、常用化疗药物联合抗血管生成剂或PARP抑制剂的"个性化"方法整合,延长复发性卵巢癌患者的PFS。     

PARP inhibitors in cancer therapy: Two modes of attack on the cancer cell widening the clinical applications

The abundant nuclear enzyme poly(ADP-ribose)polymerase-1 (PARP-1) represents an important novel target in cancer therapy. PARP-1 is essential to the repair of single strand DNA breaks via the base excision repair pathway. Inhibitors of PARP-1 have been shown to enhance the cytotoxic effects of ionising radiation and DNA damaging chemotherapy agents such as the methylating agents and topoisomerase-I inhibitors. There are currently at least eight PARP inhibitors in clinical trial development. In vitro data, in vivo preclinical data and most recently early clinical trial data suggests that PARP inhibitors could be used not only as chemo/radiotherapy sensitizers but also as single agents to selectively kill cancers defective in DNA repair, specifically cancers with mutations in the breast cancer associated (BRCA)1 and BRCA2 genes. This theory of selectively exploiting cells defective in one DNA repair pathway by inhibiting another is a major breakthrough in the treatment of cancer. The current clinical data are discussed within this review with reference to the preclinical models which predicted activity and also future directions and the possible dangers/pitfalls of this clinical strategy are explored.     

The emerging role of poly(ADP-Ribose) polymerase inhibitors in cancer treatment

Poly(ADP-ribose) polymerase (PARP) is a critical DNA repair enzyme involved in DNA single-strand break repair via the base excision repair pathway. PARP inhibitors have been shown to sensitize tumors to DNA-damaging agents and to also selectively kill homologous recombination repair-defective cancers, such as those arising in BRCA1 and BRCA2 mutation carriers. Recent proof-of-concept clinical studies have demonstrated the safety and substantial antitumor activity of the PARP inhibitor, olaparib in BRCA1/2 mutation carriers, highlighting the wide therapeutic window that can be achieved with this synthetic lethal strategy. Likewise, the PARP inhibitor, BSI-201, in combination with carboplatin and gemcitabine have produced promising results in "triple-negative" breast cancers. There are also currently numerous other PARP inhibitors in clinical development. The potential broader therapeutic application of these approaches to a wide range of sporadic tumors harboring specific defects in the homologous recombination repair pathway has generated a great deal of excitement within the oncology community. This review discusses the rationale for targeting PARP and details the strategies and challenges involved in the clinical development of such inhibitors and their future potential applications in cancer medicine.     

The role of PARP inhibitors in the treatment of ovarian carcinomas

Homologous recombination (HR), a key mechanism of DNA double strand break (DSB) repair, is commonly defective in high grade serous carcinomas (HGSC) of the ovary. BRCA1/2 mutations, as well as many other molecular and genetic defects, can lead to impaired HR. Treatment of HR-defective tumours with poly-ADP ribose polymerase (PARP) inhibitors, which block the key mechanism of single strand DNA breaks (SSB), exploits a therapeutic concept called "synthetic lethality". Early experiences with PARP inhibitors in germline BRCA mutation carriers and sporadic HGSCs of the ovary have been promising. The development of PARP inhibitors for ovarian cancer is an area of active research. This article provides an overview of the molecular rationale for the use of PARP inhibitors and summarizes some of the key early clinical data of their use in ovarian cancer.     

Triple-negative breast cancer and poly(ADP-ribose) polymerase inhibitors

Recent gene profiling studies have identified at least 5 major subtypes of breast cancer, including normal type, luminal A type, luminal B type, human epidermal growth factor receptor (HER)-2 positive type, and basal-like type. Triple-negative breast cancer (TNBC), showing no or low expressions of estrogen receptor (ER), progesterone receptor (PgR), and HER2, considered important clinical biomarkers, accounts for 10% to 20% of all breast cancers. Hormonal therapy and molecular targeted therapy are not indicated for the management of TNBC, resulting in poor outcomes. Because TNBC lacks clear-cut therapeutic targets, effective treatment strategies remain to be established. However, TNBC is known to share similar biologic characteristics with basal-like type breast cancer and is often accompanied by loss of functional BRCA, a gene-modifying enzyme. Breast cancer with BRCA1 or BRCA2 mutations is accompanied by activation of the enzyme poly(ADP-ribose) polymerase (PARP). PARP, a DNA base-excision repair enzyme, is known to play a central role in gene repair, along with BRCA. Because some breast cancers with BRCA1 or BRCA2 mutations are TNBC, the suppression of PARP has attracted attention as a new treatment strategy for TNBC. In this article, we review the clinical characteristics of TNBC, discuss problems in treatment, and briefly summarize the international development status of PARP inhibitors.     

Advances in PARP inhibitors for the treatment of breast cancer

Introduction: Poly(ADP-Ribose) polymerases (PARPs) are one of the important components of base excision repair pathway for single strand DNA breaks. Currently accepted hypothesis for the mechanism of action for PARP inhibitors in tumors with homologous recombination deficiency is synthetic lethality, as the simultaneous blockage of both pathways prevents the tumor cells from repairing DNA damage. Other proposed mechanisms include PARP trapping, defective BRCA1 and POLQ recruitment to sites of DNA repair. Breast cancer subgroups with germline BRCA mutations or non-mutational functional defects in BRCA proteins exemplify potential targets for PARP inhibitors.

Areas covered: Promising results have been achieved with PARP inhibitors in BRCA associated cancers, particularly in ovarian and breast cancer. Olaparib is the only PARP inhibitor approved by FDA in the treatment of patients with germline BRCA mutated advanced ovarian cancer pretreated with ≥3 prior lines of chemotherapy. In this article, we reviewed the current status of PARP inhibitors, completed and ongoing trials, safety and resistance issues in patients with breast cancer.

Expert opinion: PARP inhibitors show promise in cancers with BRCA mutation and in the treatment of sporadic cancers with defective homologous recombination. Predictors of response, strategies to overcome resistance, combination with other chemotherapies and targeted agents, optimum dose and schedule of administration should be investigated in future trials.     

治疗遗传性卵巢癌的新药——奥拉帕尼

奥拉帕尼(olaparib)是英国阿斯利康公司研发的一种多聚腺苷二磷酸酯核糖聚合酶强抑制剂,通过抑制基因同源重组缺陷,合成杀灭突变的癌细胞,可用于治疗有特异性DNA修复缺陷的癌症,是治疗2种易感基因BRCA1和BRCA2缺损的晚期卵巢癌药物。奥拉帕尼可以选择性杀死癌细胞而又不损害正常细胞,较之传统的化疗手段,其不良反应小得多。     

Emerging PARP inhibitors for treating breast cancer

ABSTRACT

Introduction: Some breast cancers harbor defects in DNA repair pathways, including BRCA1 and BRCA2 mutations, leading to a genomic instability. Compromised DNA-damage repair response is found in 11 to 42% of triple negative breast cancers, with a frequency varying according to family history and ethnicity. The oral PARP inhibitors are a promising strategy in breast cancer exploiting Homologous Deficient Recombination deficiency (HRD) by a synthetic lethal approach. Several PARP inhibitors have currently reached early phase trials with studies on going in the adjuvant, neoadjuvant and metastatic setting.

Area covered: Here, we review completed and ongoing trials with PARP inhibitors as well as their mechanisms of activity and acquired resistance.

Expert opinion: PARP inhibitors show promising results in breast cancer. However, several issues are raised including the identification of biomarkers to predict treatment response and strategies to counteract emerging resistance.     

Therapeutic targeting and patient selection for cancers with homologous recombination defects

Introduction: DNA double-strand breaks (DSBs) are toxic DNA lesions that can be repaired by non-homologous end-joining (NHEJ) or homologous recombination (HR). Mutations in HR genes elicit a predisposition to cancer; yet, they also result in increased sensitivity to certain DNA damaging agents and poly (ADP-ribose) polymerase (PARP) inhibitors. To optimally implement PARP inhibitor treatment, it is important that patients with HR-deficient tumors are adequately selected.

Areas covered: Herein, the authors describe the HR pathway mechanistically and review the treatment of HR-deficient cancers, with a specific focus on PARP inhibition for BRCA1/2-mutated breast and ovarian cancer. In addition, mechanisms of acquired PARP inhibitor resistance are discussed. Furthermore, combination therapies with PARP inhibitors are reviewed, in the context of both HR-deficient and HR-proficient tumors and methods for proper patient selection are also discussed.

Expert opinion: Currently, only patients with germline or somatic BRCA1/2 mutations are eligible for PARP inhibitor treatment and only a proportion of patients respond. Patients with HR-deficient tumors caused by other (epi)genetic events may also benefit from PARP inhibitor treatment. Ideally, selection of eligible patients for PARP inhibitor treatment include a functional HR read-out, in which cancer cells are interrogated for their ability to perform HR repair and maintain replication fork stability.