Petricoin Emanuel F, Bichsel Verena E, Calvert Valerie S, Espina Virginia, Winters Mary, Young Lynn, Belluco Claudio, Trock Bruce J, Lippman Marc, Fishman David A, Sgroi Dennis C, Munson Peter J, Esserman Laura J, Liotta Lance A
US Food and Drug Administration-National Cancer Institute Clinical Proteomics Program, Office of Cellular and Gene Therapy, Center for Biologics Evaluation and Research, FDA, Bethesda, MD, USA.
J Clin Oncol. 2005 May 20;23(15):3614-21. doi: 10.1200/JCO.2005.02.509.
Mapping tumor cell protein networks in vivo will be critical for realizing the promise of patient-tailored molecular therapy. Cancer can be defined as a dysregulation or hyperactivity in the network of intracellular and extracellular signaling cascades. These protein signaling circuits are the ultimate targets of molecular therapy. Each patient's tumor may be driven by a distinct series of molecular pathogenic defects. Thus, for any single molecular targeted therapy, only a subset of cancer patients may respond. Individualization of therapy, which tailors a therapeutic regimen to a tumor molecular portrait, may be the solution to this dilemma. Until recently, the field lacked the technology for molecular profiling at the genomic and proteomic level. Emerging proteomic technology, used concomitantly with genomic analysis, promises to meet this need and bring to reality the clinical adoption of molecular stratification. The activation state of kinase-driven signal networks contains important information relative to cancer pathogenesis and therapeutic target selection. Proteomic technology offers a means to quantify the state of kinase pathways, and provides post-translational phosphorylation data not obtainable by gene arrays. Case studies using clinical research specimens are provided to show the feasibility of generating the critical information needed to individualize therapy. Such technology can reveal potential new pathway interconnections, including differences between primary and metastatic lesions. We provide a vision for individualized combinatorial therapy based on proteomic mapping of phosphorylation end points in clinical tissue material.
在体内绘制肿瘤细胞蛋白质网络对于实现患者个性化分子治疗的前景至关重要。癌症可被定义为细胞内和细胞外信号级联网络的失调或过度活跃。这些蛋白质信号传导回路是分子治疗的最终靶点。每个患者的肿瘤可能由一系列独特的分子致病缺陷驱动。因此，对于任何单一的分子靶向治疗，只有一部分癌症患者可能会有反应。根据肿瘤分子特征量身定制治疗方案的个体化治疗可能是解决这一困境的方法。直到最近，该领域还缺乏在基因组和蛋白质组水平进行分子分析的技术。与基因组分析同时使用的新兴蛋白质组技术有望满足这一需求，并使分子分层在临床上得到应用。激酶驱动的信号网络的激活状态包含与癌症发病机制和治疗靶点选择相关的重要信息。蛋白质组技术提供了一种量化激酶途径状态的方法，并提供了基因阵列无法获得的翻译后磷酸化数据。提供了使用临床研究标本的案例研究，以展示生成个体化治疗所需关键信息的可行性。此类技术可以揭示潜在的新途径相互联系，包括原发性和转移性病变之间的差异。我们基于临床组织材料中磷酸化终点的蛋白质组图谱，提出了个体化联合治疗的设想。
