Guillén-Ahlers Héctor
W.M. Keck Center for Transgene Research, Department of Chemistry and Biochemistry, University of Notre Dame, USA.
Curr Drug Targets. 2008 Jul;9(7):591-600. doi: 10.2174/138945008784911813.
About one fourth of people diagnosed with kidney cancer in 2007, are expected to die of this disease within 5 years from the date of diagnosis. Recent years have produced novel drugs, some with FDA approval, and many in clinical trials, all showing very discrete results. Failure in finding effective treatments to improve survival with drugs mainly targeting VEGF and its downstream effectors, urges to shift the drug development targets to other unexploited pathways shown to be also involved in renal cancer. Several studies show alterations in the Wnt signaling pathway, many of which differ from those implicated in other human cancers. Unlike colorectal or hepatocellular carcinomas, where APC and axin mutations, respectively, are the main Wnt signaling deregulating event, renal carcinomas seem to be affected by other factors. Recent studies have presented VHL, a tumor suppressor gene strongly associated with renal cell carcinoma, as a beta-catenin target. This confirms that Wnt signaling is likely playing a central role during renal carcinoma development, which needs to be considered and addressed to treat this disease. This review outlines briefly the molecular biology of the most common renal cancers and the drug treatments currently used to treat the disease. The canonical Wnt pathway is reviewed more carefully adding specific features in a renal carcinoma context, which present potential targets for drug development and biomarker use.
2007年被诊断出患有肾癌的患者中，约有四分之一预计将在确诊之日起5年内死于这种疾病。近年来出现了一些新药，其中一些已获得美国食品药品监督管理局（FDA）批准，还有许多处于临床试验阶段，所有这些药物的效果都非常有限。由于未能找到以VEGF及其下游效应器为主要靶点的有效治疗方法来提高生存率，因此迫切需要将药物开发靶点转向其他未被开发但也被证明与肾癌有关的途径。多项研究表明Wnt信号通路存在改变，其中许多改变与其他人类癌症中涉及的改变不同。与分别以APC和axin突变为主要Wnt信号失调事件的结直肠癌或肝细胞癌不同，肾癌似乎受其他因素影响。最近的研究表明，VHL（一种与肾细胞癌密切相关的肿瘤抑制基因）是β-连环蛋白的靶点。这证实了Wnt信号在肾癌发展过程中可能起着核心作用，在治疗这种疾病时需要考虑并解决这一问题。本综述简要概述了最常见肾癌的分子生物学以及目前用于治疗该疾病的药物治疗方法。对经典Wnt途径进行了更仔细的综述，并增加了肾癌背景下的特定特征，这些特征为药物开发和生物标志物的使用提供了潜在靶点。
