Molecular targeted therapies in hepatocellular carcinoma.
Molecular targeted therapies in hepatocellular carcinoma.
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DOI：
10.1002/hep.22506
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发表时间：
2008-10
期刊：
影响因子：
13.5
通讯作者：
Bruix, Jordi
中科院分区：
文献类型：
--
作者：
Llovet, Josep M.;Bruix, Jordi
肝细胞癌（HCC）是一种复杂且具有异质性的肿瘤，存在多种基因改变。有证据表明，一些信号级联存在异常激活，例如表皮生长因子受体（EGFR）、Ras/细胞外调节蛋白激酶（ERK）、磷脂酰肌醇-3激酶/哺乳动物雷帕霉素靶蛋白（PI3K/MTOR）、肝细胞生长因子/间质上皮转化因子（HGF/MET）、Wnt、刺猬蛋白以及凋亡信号通路。最近，一种多激酶抑制剂索拉非尼在晚期肝细胞癌患者中显示出了生存获益。这一进展是治疗这种复杂疾病的一个突破，并证明分子疗法在肝细胞癌中可以是有效的。然而，越来越明显的是，为了克服肝细胞癌中基因异常的复杂性，联合疗法将至关重要。II期研究已经对阻断EGFR、血管内皮生长因子/血小板衍生生长因子受体（VEGF/PDGFR）和mTOR信号通路的药物进行了测试。到目前为止，联合疗法尚未产生相关数据。预计未来的研究将确定新的化合物来阻断重要的难以成药的通路，例如Wnt信号通路，并通过新的高通量技术确定新的癌基因作为治疗靶点。
近期的指南为肝细胞癌临床试验的设计建立了一个新框架。提出以疾病进展时间为终点的随机II期试验对于获取新药的益处至关重要。生存期仍然是III期研究中衡量有效性的主要终点。分配到对照组的患者应接受标准治疗，即中期疾病患者接受化疗栓塞，晚期疾病患者接受索拉非尼。生物标志物和分子成像应成为试验的一部分，以便优化研究人群的富集并确定药物应答者。最终，基于全基因组研究对肝细胞癌进行分子分类，并根据药物反应性确定患者亚类，将导致更个性化的医疗。
Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with several genomic alterations. There is evidence of aberrant activation of several signaling cascades such as EGFR, Ras/ERK, PI3K/MTOR, HGF/MET, Wnt, Hedgehog and apoptotic signaling, Recently a multikinase inhibitor, sorafenib, has shown survival benefits in patients with advanced hepatocellular carcinoma. This advancement represents a breakthrough in the treatment of this complex disease, and proves that molecular therapies can be effective in HCC. It is becoming apparent, however, that to overcome the complexity of genomic aberrations in HCC, combination therapies will be critical. Phase II studies have tested drugs blocking EGFR, VEGF/PDGFR and mTOR signaling. No relevant data has been produced so far in combination therapies. Future research is expected to identify new compounds to block important undruggable pathways, such as Wnt signaling, and to identify new oncogenes as targets for therapies through novel high-throughput technologies. Recent guidelines have established a new frame for the design of clinical trials in HCC. Randomized phase II trials with a time to progression endpoint are proposed as pivotal for capturing benefits from novel drugs. Survival remains the main endpoint to measure effectiveness in phase III studies. Patients assigned to the control arm should receive standard-of-care therapy, that is, chemoembolization for patients with intermediate-stage disease and sorafenib for patients with advanced-stage disease. Biomarkers and molecular imaging should be part of the trials, in order to optimize the enrichment of study populations and identify drug responders. Ultimately, a molecular classification of HCC based on genome-wide investigations and identification of patient subclasses according to drug-responsiveness will lead to a more personalized medicine.
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影响因子：
13.5
作者：
Fausto, N;Campbell, JS;Riehle, KJ
通讯作者：
Riehle, KJ
DOI：
10.1073/pnas.0409722102
发表时间：
2005-03-01
影响因子：
11.1
作者：
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通讯作者：
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158.5
作者：
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通讯作者：
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45.3
作者：
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通讯作者：
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影响因子：
8
作者：
Ferber, MJ;Montoya, DP;Roberts, LR
通讯作者：
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