卵巢癌药物奥拉帕尼或可治疗一系列遗传性基因缺失相关的癌症

  近日，发表在国际杂志Oncotarget上的一篇研究论文中，来自伦敦癌症研究所等处的研究人员通过研究表示，一系列靶向作用携带BRCA乳腺癌基因突变的癌症先锋药物或可帮助抵御其它遗传缺陷类型的肿瘤；文章中研究者发现名为CLBC基因的错误或会导致癌细胞对PARP抑制药物表现比较敏感，而所有肿瘤中大约有2%携带有CLBC基因缺失。

  奥拉帕尼作为一种PARP抑制剂，其作为第一个癌症药物可以靶向作用遗传性的基因缺失，在去年12月时其被批准用于治疗携带BRCA1和BRCA2突变的卵巢癌患者，其也因此而进入药物市场；利用RNA干扰筛查技术，研究人员就可以系统性地在人类基因组中2.5万个基因中进行检测来寻找影响癌细胞对奥拉帕尼反应的基因。研究者表示，携带CLBC基因缺失的癌细胞往往和BRCA2基因缺失一样对药物非常敏感，而通过分析CBLC基因的控制过程，研究者发现，该基因在正常情况下可以通过将破碎的DNA链组装在一起来修复损伤的DNA。

  而本文研究也揭示了DNA修复机制的缺陷，这或许可以帮助解释CBLC缺失的癌细胞对PARP抑制剂产生敏感性的原因，DNA修复在癌细胞中往往会被打断，这样一来癌细胞就会获得大量的突变从而使其进行失控生长，而由于癌细胞可能缺失任何可替换的功能性修复系统，因此其或许对药物尤为敏感进而阻断DNA修复蛋白的功能。

  研究者Chris Lord教授表示，我们研究发现名为CLBC的DNA修复基因的缺失似乎可以增加癌细胞对奥拉帕尼的敏感性，奥拉帕尼是一种PARP抑制剂，这种抑制剂当前已经被批准用于治疗BRCA突变的癌症。PARP抑制剂是一种新型的癌症药物，揭示不同类型肿瘤细胞对PARP抑制剂的反应或许对于开发新型有效药物来治疗癌症非常关键。

  当前PARP抑制剂药物在英国的开发比较成功，很多研究团体已经联合进行了开发并且进行了BRCA突变癌症的临床试验，而且就在前几个月批准了药物奥拉帕尼的使用，本文研究也正揭示了PARP抑制剂或可有效治疗包括BRCA突变在内的一系列癌症患者，这对于后期更多新型癌症治疗药物的开发提供了新的研究线索和依据。（转化医学网360zhyx.com）

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Scientists at The Institute of Cancer Research, London, found that errors in a gene called CLBC leave cancer cells vulnerable to PARP inhibitor drugs. Around 2 per cent of all tumours have defects in CLBC.

The study, which was carried out in collaboration with colleagues in Denmark and the Czech Republic, was funded in the UK by the European Union, and was published in the journal Oncotarget.

Olaparib, a PARP inhibitor, became the first cancer drug targeted at an inherited genetic fault to reach the market when it was approved in December for use in ovarian cancer patients with BRCA1 or BRCA2 mutations. Its development was underpinned by research at The Institute of Cancer Research (ICR).

Using an approach known as RNA interference screening -- which 'silences' genes to analyse their function -- researchers systematically tested which of the 25,000 genes in the human genome affected the response of cancer cells to olaparib.

The ICR team found that cancer cells with a defect in the CBLC gene were as sensitive to the drug as those with a faulty BRCA2 gene.

By analysing the molecular processes that the CBLC gene controls, researchers found that it normally allows cells to repair damaged DNA by fixing broken DNA strands back together.

This finding indicates that a flaw in DNA repair mechanisms explains the sensitivity of CBLC-defective cancer cells to PARP inhibitors -- which knock out the action of another DNA repair mechanism.

DNA repair is often disrupted in cancer cells, which sacrifice genetic stability as they gain mutations that allow them to divide uncontrollably. These cancer cells may be particularly vulnerable to drugs to block DNA repair proteins, since they may lack any alternative functioning repair systems to fall back on.

Study co-leader Dr Chris Lord, Team Leader in Gene Function at The Institute of Cancer Research, London, said:

"Our study has found that defects in a rather poorly studied DNA repair gene called CLBC seem to greatly increase sensitivity to olaparib, a PARP inhibitor which is currently licensed only for BRCA-mutated cancer......