p53 Laboratory, A*STAR, Singapore.
Nat Rev Clin Oncol. 2011 Jan;8(1):25-37. doi: 10.1038/nrclinonc.2010.174. Epub 2010 Oct 26.
Mutations in the TP53 gene are a feature of 50% of all reported cancer cases. In the other 50% of cases, the TP53 gene itself is not mutated but the p53 pathway is often partially inactivated. Cancer therapies that target specific mutant genes are proving to be highly active and trials assessing agents that exploit the p53 system are ongoing. Many trials are aimed at stratifying patients on the basis of TP53 status. In another approach, TP53 is delivered as a gene therapy; this is the only currently approved p53-based treatment. The p53 protein is overexpressed in many cancers and p53-based vaccines are undergoing trials. Processed cell-surface p53 is being exploited as a target for protein-drug conjugates, and small-molecule drugs that inhibit the activity of MDM2, the E3 ligase that regulates p53 levels, have been developed by several companies. The first MDM2 inhibitors are being trialed in both hematologic and solid malignancies. Finally, the first agent found to restore the active function of mutant TP53 has just entered the clinic. Here we discuss the basis of these trials and the future of p53-based therapy.
TP53 基因突变是所有报道的癌症病例的 50%的特征。在另外 50%的病例中，TP53 基因本身没有突变，但 p53 通路通常部分失活。针对特定突变基因的癌症疗法已被证明具有高度活性，正在评估利用 p53 系统的药物的试验也在进行中。许多试验旨在根据 TP53 状态对患者进行分层。在另一种方法中，TP53 被用作基因疗法；这是目前唯一获得批准的基于 p53 的治疗方法。p53 蛋白在许多癌症中过表达，基于 p53 的疫苗正在进行试验。已加工的细胞表面 p53 被用作蛋白药物偶联物的靶标，并且几家公司已经开发了抑制调节 p53 水平的 E3 连接酶 MDM2 活性的小分子药物。第一批 MDM2 抑制剂正在血液系统恶性肿瘤和实体恶性肿瘤中进行试验。最后，刚刚发现一种能够恢复突变 TP53 活性功能的药物进入了临床阶段。在这里，我们讨论了这些试验的基础和基于 p53 的治疗的未来。
