Department of Pathology, Karmanos Cancer Institute HWCRC Building 732, 4100 John R, Detroit, MI 48201, USA.
Curr Pharm Des. 2011;17(6):640-52. doi: 10.2174/138161211795222612.
The discovery of small molecule inhibitors of HDM2-p53 interaction is considered one of the most significant therapeutic developments in the area p53 research. Intensive work on different classes of HDM2 inhibitors has proven their therapeutic utility as activators of p53 in multiple tumor models. Many laboratories have shown that HDM2 inhibitors can synergize with chemotherapeutic agents resulting in enhanced efficacy through both p53-dependent and independent mechanisms. In our hands HDM2 inhibitor and platinum drug combination showed remarkable antitumor activity that led tumor free survival in one of the most resistant and complex pancreatic xenograft models. Although antitumor efficacy of such combinations has been studied in detail, not much is known on the molecular mechanisms governing this synergy. This is partly due to complexity of multiple pathways modulated by p53 and HDM2. We are of the view that in order to decode this complexity, an integrated approach is needed that considers both HDM2 and p53 as components of a network and not in isolation. This review highlights recent advancements in our understanding of HDM2 inhibitor combination therapy based on network modeling and systems biology driven science. Our recent findings support such a network view as integrated gene expression profiling and pathway network modeling on MI-219-oxaliplatin treated cells revealed activation of multiple and closely knit biological networks. We anticipate that in the near future such network-centric approaches will benefit clinical development of HDM2 inhibitors for genetically predefined subsets of cancer patients and this will be a step towards personalized medicine.
小分子抑制剂与 HDM2-p53 相互作用的发现被认为是 p53 研究领域最重大的治疗进展之一。对不同类型的 HDM2 抑制剂的深入研究证明了它们作为 p53 激活剂在多种肿瘤模型中的治疗效用。许多实验室已经表明，HDM2 抑制剂可以与化学治疗药物协同作用，通过 p53 依赖和非依赖机制增强疗效。在我们的研究中，HDM2 抑制剂和铂类药物联合使用显示出显著的抗肿瘤活性，使一种最耐药和复杂的胰腺异种移植模型中的肿瘤无进展生存。尽管已经详细研究了这些组合的抗肿瘤功效，但对于控制这种协同作用的分子机制知之甚少。这部分是由于 p53 和 HDM2 调节的多个途径的复杂性。我们认为，为了解码这种复杂性，需要采用一种综合方法，将 HDM2 和 p53 视为网络的组成部分，而不是孤立的部分。这篇综述强调了基于网络建模和系统生物学驱动的科学，我们对 HDM2 抑制剂联合治疗的最新理解进展。我们最近的发现支持这种网络观点，因为对 MI-219-奥沙利铂处理的细胞进行综合基因表达谱分析和途径网络建模揭示了多个紧密结合的生物学网络的激活。我们预计，在不久的将来，这种以网络为中心的方法将有助于为具有特定遗传特征的癌症患者开发 HDM2 抑制剂，这将是迈向个性化医疗的一步。
