Personalizing cancer treatment in the age of global genomic analyses: PALB2 gene mutations and the response to DNA damaging agents in pancreatic cancer.
Personalizing cancer treatment in the age of global genomic analyses: PALB2 gene mutations and the response to DNA damaging agents in pancreatic cancer.
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DOI：
10.1158/1535-7163.mct-10-0893
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发表时间：
2011-01
影响因子：
5.7
通讯作者：
Hidalgo M
中科院分区：
文献类型：
--
作者：
Villarroel MC;Rajeshkumar NV;Garrido-Laguna I;De Jesus-Acosta A;Jones S;Maitra A;Hruban RH;Eshleman JR;Klein A;Laheru D;Donehower R;Hidalgo M
转移和耐药是胰腺癌患者死亡的主要原因。一旦发展，胰腺癌转移的进展在目前的治疗中几乎是不可阻挡的。在这里，我们报告了一个先进的，吉西他滨耐药，胰腺癌患者的显着的临床结果，后来用DNA损伤剂治疗，根据观察到的显着活性，这类药物对个性化异种移植物产生的患者的手术切除的肿瘤。丝裂霉素C治疗（基于其在患者肿瘤产生的个性化异种移植物中的稳健临床前活性而选择）导致长期持续（36+个月）的肿瘤缓解。全球基因组测序揭示了该患者癌症中编码PalB2蛋白的基因的双等位基因失活，预测该突变会破坏对DNA双链断裂修复至关重要的BRCA1和BRCA2相互作用。这项工作表明，PALB2基因的失活是胰腺癌对DNA损伤反应的决定因素，也是个性化癌症治疗的新靶点。将个性化异种移植物与无偏外显子组测序整合导致定制治疗，针对患者肿瘤的遗传环境定制，并鉴定致命癌症中药物反应的新生物标志物。
Metastasis and drug resistance are the major causes of mortality in patients with pancreatic cancer. Once developed, the progression of pancreatic cancer metastasis is virtually unstoppable with current therapies. Here we report the remarkable clinical outcome of a patient with advanced, gemcitabine-resistant, pancreatic cancer who was later treated with DNA damaging agents, based on the observation of significant activity of this class of drugs against a personalized xenograft generated from the patient’s surgically resected tumor. Mitomycin C treatment, selected based on its robust preclinical activity in a personalized xenograft generated from the patient’s tumor, resulted in long lasting (36+ months) tumor response. Global geneomic sequencing revealed biallelic inactivation of the gene encoding PalB2 protein in this patient’s cancer, the mutation is predicted to disrupt BRCA1 and BRCA2 interactions critical to DNA double strand break repair. This work suggests that inactivation of the PALB2 gene is a determinant of response to DNA damage in pancreatic cancer and a new target for personalizing cancer treatment. Integrating personalized xenografts with unbiased exomic sequencing led to customize therapy, tailored to the genetic environment of patient’s tumor and identification of a new biomarker of drug response in a lethal cancer.