The Proteomic Search for Diagnostic Biomarkers IN TRANSLATION
The Proteomic Search for Diagnostic Biomarkers IN TRANSLATION
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翻译中诊断生物标志物的蛋白质组学搜索
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发表时间：
2006
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通讯作者：
W. Zolg
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作者：
W. Zolg
基于蛋白质组发现策略的生物标志物的搜索正在不同的科学集群中进行。一个主要的组织是围绕政府资助的项目，包括一个系统地关注生物标志物的学术机构网络。在美国，这种多中心倡议的一个例子是“主任挑战计划”，其目的是描述主要癌症的分子基础和蛋白质表达的相关变化（www.cancerdiagnosis.nci.nhi.gov/challenge）。同时，制药行业的主要研究和开发项目也集中在生物标志物的鉴定上，但原因不同（1）。学术机构之间以及产业界与学术界之间也建立了各种联盟和伙伴关系。整个过程都集中在生物标志物的诊断应用上，而忽略了鉴定可作为药物靶点的蛋白质的更大努力，行业驱动的努力的目标主要不是鉴定诊断相关蛋白质本身，但明确的经济必要性要求最终将这些新型生物标志物引入市场。到目前为止，金融分析师估计，已经有近10亿美元被投资或投入到具有基于蛋白质组学策略的商业模式的公司，用于识别药物靶标和/或生物标志物，包括诊断生物标志物。然而，很少有新的生物标志物通过完成鉴定、临床试验验证和监管机构批准的蛋白质组学过程链而产生商业产品。相反，注册机构批准的新蛋白质靶点数量在过去十年中一直在下降，这一趋势没有被蛋白质组学的任何正在进行的活动所逆转，甚至停止。此外，对用作诊断工具的市售产品的调查显示，人类蛋白质组中数量少得惊人的蛋白质已被鉴定为诊断相关靶标，但相反，已开发出以不同配置靶向相同蛋白质的整个检测系列（2）。此外，科学界以及公众已经相信，由于蛋白质组学的活动，已经实现了重大的诊断突破，因此一系列新的诊断生物标志物已经到位，以可靠和有益的方式填补诊断空白。这种误导性的信息政策已经证明是适得其反的，因为人们的期望已经提高，但最终却经不起审查。一方面投资高，另一方面成功率低。考虑到这种差异，人们感到很难开始分析从发现阶段到验证阶段再到产品开发的过程中的一些潜在障碍。这些连续步骤的基本原理已经概述（1、3、4），但应从不同角度重新审视几个方面。2005年10月在第21届阿西洛马质谱会议上提出了以下一些考虑。
The search for biomarkers based on proteomic discovery strategies is being conducted in different scientific constellations. One major group is organized around governmentsponsored programs involving a network of academic institutions focusing on biomarkers systematically. An example of such a multicenter initiative for the United States is the “Directors Challenge Program,” which aims to characterize the molecular basis and related changes in protein expression of major cancers (www.cancerdiagnosis.nci.nhi.gov/challenge). Simultaneously there are major research and development programs in the pharmaceutical industry also focused on the identification of biomarkers but for different reasons (1). Various alliances and partnerships have also been formed between academic institutions and between industry and academia. Focusing throughout on diagnostic applications of biomarkers and ignoring the even larger efforts to identify proteins that can serve as drug targets, the goal of industry-driven efforts is not primarily the identification of diagnostically relevant proteins itself, but clear economic imperatives call for the eventual introduction of those novel biomarkers into the market. So far, financial analysts estimate that close to one billion dollars have been spent by or invested into companies with business models based on proteomic strategies for the identification of drug targets and/or biomarkers, including diagnostic biomarkers. However, there are few, if any, new biomarkers that have resulted in a commercial product by completing the proteomic process chain of identification, validation in clinical trials, and approval by regulatory agencies. On the contrary, the number of new protein targets approved by the registration agencies has been declining over the past decade, a trend not reversed or even stopped by any of the ongoing activities in proteomics. Moreover a survey of commercially available products used as diagnostic tools reveals that an amazingly small number of proteins in the human proteome have been identified as diagnostically relevant targets, but instead entire assay families have been developed that target the very same proteins in different configurations (2). Furthermore the scientific community as well as the general public has been led to believe that major diagnostic breakthroughs have already been achieved as a result of activities in proteomics and that consequently a series of novel diagnostic biomarkers are in place to fill the diagnostic gaps in a reliable and beneficial way. This misleading information policy has already proven to be counterproductive because expectations have been raised that have ultimately not held up to scrutiny. There have been high investments on one side but a low success rate on the other. Given this discrepancy, one feels challenged to start analyzing some of the potential hurdles in the processes leading from the discovery phase to the validation phase to product development. The rationale for these sequential steps has already been outlined (1, 3, 4), but several aspects should be revisited from different angles. Some of the considerations below were presented at the 21st Asilomar Conference on Mass Spectrometry in October 2005.