Tumor Growth Inhibition by Olaparib in BRCA2 Germline-Mutated Patient-Derived Ovarian Cancer Tissue Xenografts
Tumor Growth Inhibition by Olaparib in BRCA2 Germline-Mutated Patient-Derived Ovarian Cancer Tissue Xenografts
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DOI：
10.1158/1078-0432.ccr-10-1382
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发表时间：
2011-02-15
影响因子：
11.5
通讯作者：
Gilks, C. Blake
中科院分区：
文献类型：
--
作者：
Kortmann, Ursula;McAlpine, Jessica N.;Gilks, C. Blake
目的：大多数卵巢癌患者屈从于他们的疾病，迫切需要改进治疗方法。BRCA突变携带者的肿瘤表现出DNA双链断裂修复缺陷，可以通过抑制PARP-1来治疗，PARP-1是修复DNA单链断裂的关键酶，在肿瘤细胞中产生合成杀伤力。实验设计：为了研究体内的合成致死性，我们建立了直接从人卵巢癌组织发展起来的BRCA2生殖系突变异种移植模型，用PARP抑制剂奥拉帕利布(AZD2281)单独和联合卡铂治疗。结果：我们发现奥拉帕利单独和联合卡铂对BRCA2突变的卵巢浆液性癌的生长有很大的抑制作用。在BRCA功能正常的浆液性癌中没有观察到这种作用，这表明在突变携带者中奥拉帕利具有特异性的抗肿瘤作用。免疫组织化学(裂解caspase-3和Ki-67染色)显示，与未经治疗的对照组相比，奥拉帕利治疗后残留组织的增殖明显减少，细胞凋亡指数明显增加。此外，奥拉帕利布治疗的肿瘤显示PARP-1活性显著降低，且与奥拉帕利布浓度相关。结论：我们建立了一种适合于实验药物测试的BRCA2突变的人卵巢癌异种移植模型。奥拉帕利的体内疗效证明是在针对BRCA突变的卵巢癌患者进行进一步临床试验的临床前基础上进行的。临床癌症资源；17(4)；783-91。(C)2010年AACR。
Purpose: Most patients with ovarian carcinomas succumb to their disease and there is a critical need for improved therapeutic approaches. Carcinomas arising in BRCA mutation carriers display defective DNA double-strand break repair that can be therapeutically exploited by inhibition of PARP-1, a key enzyme in the repair of DNA single-strand breaks, creating synthetic lethality in tumor cells.Experimental Design: To investigate synthetic lethality in vivo, we established a BRCA2 germlinemutated xenograft model that was developed directly from human ovarian cancer tissue, treated with the PARP inhibitor olaparib (AZD2281) alone and in combination with carboplatin.Results: We show that olaparib alone and in combination with carboplatin greatly inhibit growth in BRCA2-mutated ovarian serous carcinoma. This effect was not observed in a serous carcinoma with normal BRCA function, showing a specific antitumor effect of olaparib in mutation carriers. Immunohistochemistry (cleaved caspase-3 and Ki-67 stains) of remnant tissue after olaparib treatment revealed significantly decreased proliferation and increased apoptotic indices in these tumors compared with untreated controls. Furthermore, olaparib-treated tumors showed highly reduced PARP-1 activity that correlated with olaparib levels.Conclusions: We established a BRCA2-mutated human ovarian cancer xenograft model suitable for experimental drug testing. The demonstrated in vivo efficacy of olaparib extends on the preclinical rationale for further clinical trials targeting ovarian cancer patients with BRCA mutations. Clin Cancer Res; 17(4); 783-91. (C) 2010 AACR.