Guy's and St Thomas's Hospitals and Breakthrough Breast Cancer Research Unit Kings Health Partners AHSC, Research Oncology, 3(rd) Floor Bermondsey Wing, Guys Hospital, Great Maze Pond, London SE1 9RT, UK.
Breast. 2011 Oct;20 Suppl 3:S12-9. doi: 10.1016/S0960-9776(11)70288-0.
Epithelial carcinomas in general arise as a result of the acquisition of and selection for multiple mutations in a parental somatic cell clone within the tissues of the primary organ of origin. In the last two decades genome caretakers, which function in key areas of DNA damage response, have been recognized as important tumour suppressor genes. Inactivating mutations in these genes occur both as germline and/or somatic mutations with increasing evidence of epigenetic silencing as an additional cause of loss of function. In any event, loss of function in a tumour cell pre-cursor clone leads to accelerated mutation acquisition and underpins the aetiology of the tumour. With increasing understanding of the complex network that is the DNA damage response, signaling pathways already recognized to be central to the establishment of the cancer phenotype are gaining additional roles as controllers of DNA repair. This has relevance to identification of wider populations of patients with tumours susceptible to approaches that target DNA repair deficiency. These have classically been with DNA damaging chemotherapy but the recently developed small molecule inhibitors of DNA repair enzymes such as Poly-ADP polymerases PARP-1 and PARP-2 have been shown to target tumour deficiencies in DNA repair as well sensitizing to DNA damaging therapeutics such as radiation and chemotherapy. Early phase trials with efficacy endpoints have been presented for the PARP inhibitors AG014699, olaparib, veliparib, iniparib and MK4827. The results of the first phase II trials exploring monotherapy PARP inhibitor strategies, which are based on revisiting the concept of synthetic lethality, have emerged and are reviewed herein. The clinical trials that have or are exploring combinations with DNA damaging therapy in these contexts are discussed with particular reference to breast cancer, as are biomarkers that have been proposed and are being investigated to develop optimal drug schedule and patient selection criteria for these DNA repair targeting approaches.
一般来说，上皮癌是由于原始组织器官的亲代体细胞克隆中获得和选择多个突变而产生的。在过去的二十年中，在 DNA 损伤反应的关键区域发挥作用的基因组守护者被认为是重要的肿瘤抑制基因。这些基因的失活突变既可以作为种系突变，也可以作为体细胞突变，越来越多的证据表明表观遗传沉默是功能丧失的另一个原因。无论如何，肿瘤细胞前体克隆中的功能丧失会导致加速获得突变，并为肿瘤的病因提供依据。随着对 DNA 损伤反应这一复杂网络的理解不断加深，已经认识到作为建立癌症表型的核心信号通路，正在获得作为 DNA 修复控制器的额外作用。这与鉴定更广泛的肿瘤患者群体有关，这些患者对针对 DNA 修复缺陷的方法敏感。这些方法经典上是用 DNA 损伤化疗，但最近开发的聚 ADP 聚合酶 PARP-1 和 PARP-2 等 DNA 修复酶的小分子抑制剂已被证明可靶向肿瘤 DNA 修复缺陷，并使 DNA 损伤治疗药物（如辐射和化疗）更敏感。已经提出了具有疗效终点的早期阶段试验，用于 PARP 抑制剂 AG014699、奥拉帕尼、veliparib、iniparib 和 MK4827。探索单药 PARP 抑制剂策略的首次 II 期临床试验结果已经出现，并在此进行了回顾。讨论了在这些情况下与 DNA 损伤治疗联合使用的临床试验，特别是乳腺癌，并讨论了已提出并正在研究的生物标志物，以开发这些 DNA 修复靶向方法的最佳药物方案和患者选择标准。
