Lianos Georgios D, Vlachos Konstantinos, Zoras Odysseas, Katsios Christos, Cho William C, Roukos Dimitrios H
Centre for Biosystems and Genomic Network Medicine, Ioannina University, Ioannina, Greece.
Department of Surgery, Ioannina University Hospital, Ioannina, Greece.
Onco Targets Ther. 2014 Mar 24;7:491-500. doi: 10.2147/OTT.S34235. eCollection 2014.
Progress in the treatment of cancer over the past decade has been slow. Targeting a mutated gene of an individual patient tumor, tumor-guided agents, and the first draft of the human genome sequence have created an overenthusiasm to achieve personalized medicine. However, we now know that this effort is misleading. Extreme interpatient and intratumor heterogeneity, scarce knowledge in how genome-wide mutational landscape and epigenetic changes affect transcriptional processes, gene expression, signaling transduction networks and cell regulation, and clinical assessment of temporary efficacy of targeted drugs explain the limitations of these currently available agents. Trastuzumab and a few other monoclonal antibodies or small-molecule tyrosine kinase inhibitors (TKIs) represent an exception to this rule. By blocking ligand-binding receptor in patients with human epidermal growth factor receptor 2 (HER2) amplification and overexpression, trastuzumab added to chemotherapy in HER2-positive patients has been proven to provide significant overall survival benefit in both metastatic and adjuvant settings. Lapatinib, a small-molecule dual inhibitor (TKI) of both HER2 and EGFR (epidermal growth factor receptor) pathways, has an antitumor activity translated into progression-free survival benefit in HER2-positive metastatic patients previously treated with a taxane, an anthracycline, and trastuzumab. Despite these advances, ~25% of patients with HER2-positive breast cancer experience recurrence in the adjuvant setting, while in the metastatic setting, median survival time is 25 months. In this review, we discuss the safety, efficacy, and limitations of the trastuzumab emtansine (T-DM1) conjugate in the treatment of HER2-positive metastatic breast cancer. We also highlight Phase III randomized trials, currently underway, using either the T-DM1 conjugate or various combinations of monoclonal antibodies and TKIs. Moreover, in contrast with all these agents developed on the basis of "central dogma" of simplified reductionist transcription and single gene-phenotype linear relationship, we summarize the emerging, amazing era of next-generation, transcriptional circuitry and intracellular signaling network-based drugs guided by the latest advances in genome science and dynamics of network biology.
在过去十年中，癌症治疗进展缓慢。针对个体患者肿瘤的突变基因、肿瘤导向药物以及人类基因组序列初稿，催生了人们对实现个性化医疗的过度热情。然而，我们现在知道这种努力具有误导性。患者间和肿瘤内的极端异质性、对全基因组突变格局和表观遗传变化如何影响转录过程、基因表达、信号转导网络和细胞调控的了解匮乏，以及靶向药物临时疗效的临床评估，都解释了这些现有药物的局限性。曲妥珠单抗和其他一些单克隆抗体或小分子酪氨酸激酶抑制剂（TKIs）是这条规则的例外。通过阻断人表皮生长因子受体2（HER2）扩增和过表达患者的配体结合受体，在HER2阳性患者的化疗中添加曲妥珠单抗已被证明在转移性和辅助治疗环境中均能显著提高总生存率。拉帕替尼是一种同时抑制HER2和表皮生长因子受体（EGFR）途径的小分子双抑制剂（TKI），其抗肿瘤活性转化为先前接受过紫杉烷、蒽环类药物和曲妥珠单抗治疗的HER2阳性转移性患者的无进展生存获益。尽管有这些进展，但约25%的HER2阳性乳腺癌患者在辅助治疗环境中会复发，而在转移性环境中，中位生存时间为25个月。在这篇综述中，我们讨论了曲妥珠单抗偶联物ado曲妥珠单抗（T-DM1）治疗HER2阳性转移性乳腺癌的安全性、疗效和局限性。我们还重点介绍了目前正在进行的使用T-DM1偶联物或单克隆抗体与TKIs各种组合的III期随机试验。此外，与所有基于简化还原论转录的“中心法则”和单基因-表型线性关系开发的这些药物形成对比的是，我们总结了基于基因组科学的最新进展和网络生物学动态的下一代、转录回路和细胞内信号网络导向药物的崭新时代。
