Hereditary cancer syndromes: utilizing DNA repair deficiency as therapeutic target.
Hereditary cancer syndromes: utilizing DNA repair deficiency as therapeutic target.
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DOI：
10.1007/s10689-016-9883-7
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发表时间：
2016-07
期刊：
影响因子：
2.2
通讯作者：
Silberstein PT
中科院分区：
文献类型：
--
作者：
Goyal G;Fan T;Silberstein PT
人类细胞拥有众多修复机制来对抗DNA遭受的各种损伤。这些修复机制中的任何突变都可能导致DNA错误的累积和致癌作用。本综述旨在讨论两种最常见的DNA修复缺陷癌症综合征的治疗选择，即林奇综合征（遗传性非息肉病性结直肠癌）以及与乳腺癌易感基因（BRCA）相关的卵巢癌和乳腺癌。DNA修复机制的缺陷使这些肿瘤对铂类药物的敏感性增加。关于利用DNA修复缺陷作为这些综合征癌症治疗靶点的信息越来越多。聚（ADP - 核糖）聚合酶（PARP）抑制剂等新型疗法就是其中一个例子，在同源DNA修复缺陷的患者中，DNA双链断裂的诱导会产生杀肿瘤效应。有趣的是，DNA修复缺陷的患者往往比散发性恶性肿瘤预后更好。在微卫星高度不稳定的结直肠癌患者中，这归因于肿瘤微环境中CD8 + T淋巴细胞募集增加。然而，这些肿瘤能够通过激活免疫检查点来限制宿主免疫反应，而免疫检查点似乎是未来有吸引力的治疗靶点。
Human cells have numerous repair mechanisms to counteract various insults incurred on the DNA. Any mutation in these repair mechanisms can lead to accumulation of DNA errors and carcinogenesis. This review aims to discuss the therapeutic options in the two most common DNA repair deficient cancer syndromes, namely Lynch syndrome (hereditary non-polyposis colorectal cancer) and breast cancer susceptibility gene (BRCA) associated ovarian and breast cancer. Deficiency in DNA repair mechanisms renders these tumors with increased sensitivity to platinum agents. There has been increasing amount of information on the utility of the defects in DNA repair as targets for cancer therapy in these syndromes. Novel therapies like poly (ADP-ribose) polymerase (PARP) inhibitors are one of such example where the induction of double stranded breaks in DNA leads to tumoricidal effect in patients with homologous DNA repair deficiency. Interestingly, patients with DNA repair deficiencies tend to have a more favorable prognosis than sporadic malignancies. In microsatellite high colorectal cancer patients, this has been attributed to increased recruitment of CD8+ T lymphocytes in tumor microenvironment. However, these tumors are able to limit the host immune response by activation of immune checkpoints that seem like attractive targets of therapy in the future.