Proof of concept: network and systems biology approaches aid in the discovery of potent anticancer drug combinations.
Proof of concept: network and systems biology approaches aid in the discovery of potent anticancer drug combinations.
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DOI：
10.1158/1535-7163.mct-10-0642
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发表时间：
2010-12
影响因子：
5.7
通讯作者：
Sarkar FH
中科院分区：
文献类型：
--
作者：
Azmi AS;Wang Z;Philip PA;Mohammad RM;Sarkar FH
靶向关键分子的癌症疗法尚未实现对大多数常见恶性肿瘤的预期承诺。主要挑战包括对患者中这些靶点的不完全理解和验证，大多数癌症中遗传和表观遗传变化的多样性和复杂性，以及关键信号通路中发现的冗余和串扰。总的来说，单通路靶向方法的使用不是人类恶性肿瘤的有效疗法。为了克服这些障碍，重要的是要了解关键信号通路之间的分子串扰以及它们如何被靶向药物改变。这需要创新的方法，例如了解靶蛋白的整体生理环境以及在不丢失关键分子细节的情况下修饰它们的效果。这些策略将有助于设计针对多方面疾病的新型疗法及其组合，其中有效的组合疗法将专注于改变多个途径而不是单一蛋白质。集成网络建模和系统生物学已成为一个强大的工具，有利于我们了解药物的作用机制，在真实的时间。这篇简短的综述强调了基于网络和系统生物学的策略的重要性，并提出了一个“概念验证”，最近在我们的实验室中使用奥沙利铂和MDM 2抑制剂MI-219联合治疗遗传复杂和不可治愈的胰腺癌的例子进行了验证。
Cancer therapies that target key molecules have not fulfilled expected promises for most common malignancies. Major challenges include the incomplete understanding and validation of these targets in patients, the multiplicity and complexity of genetic and epigenetic changes in the majority of cancers, and the redundancies and cross-talk found in key signaling pathways. Collectively, the uses of single-pathway targeted approaches are not effective therapies for human malignances. To overcome these barriers, it is important to understand the molecular cross-talk among key signaling pathways and how they may be altered by targeted agents. This requires innovative approaches such as understanding the global physiological environment of target proteins and the effects of modifying them without losing key molecular details. Such strategies will aid the design of novel therapeutics and their combinations against multifaceted diseases where efficacious combination therapies will focus on altering multiple pathways rather than single proteins. Integrated network modeling and systems biology has emerged as a powerful tool benefiting our understanding of drug mechanism of action in real time. This mini-review highlights the significance of the network and systems biology-based strategy and presents a “proof-of-concept” recently validated in our laboratory using the example of a combination treatment of oxaliplatin and the MDM2 inhibitor MI-219 in genetically complex and incurable pancreatic adenocarcinoma.