文章：

将基于p53的癌症疗法应用于临床

Translating p53-based therapies for cancer into the clinic

原文发布日期：2024-01-29

DOI: 10.1038/s41568-023-00658-3

类型: Review Article

开放获取: 否

英文摘要：

Inactivation of the most important tumour suppressor gene TP53 occurs in most, if not all, human cancers. Loss of functional wild-type p53 is achieved via two main mechanisms: mutation of the gene leading to an absence of tumour suppressor activity and, in some cases, gain-of-oncogenic function; or inhibition of the wild-type p53 protein mediated by overexpression of its negative regulators MDM2 and MDMX. Because of its high potency as a tumour suppressor and the dependence of at least some established tumours on its inactivation, p53 appears to be a highly attractive target for the development of new anticancer drugs. However, p53 is a transcription factor and therefore has long been considered undruggable. Nevertheless, several innovative strategies have been pursued for targeting dysfunctional p53 for cancer treatment. In mutant p53-expressing tumours, the predominant strategy is to restore tumour suppressor function with compounds acting either in a generic manner or otherwise selective for one or a few specific p53 mutations. In addition, approaches to deplete mutant p53 or to target vulnerabilities created by mutant p53 expression are currently under development. In wild-type p53 tumours, the major approach is to protect p53 from the actions of MDM2 and MDMX by targeting these negative regulators with inhibitors. Although the results of at least some clinical trials of MDM2 inhibitors and mutant p53-restoring compounds are promising, none of the agents has yet been approved by the FDA. Alternative strategies, based on a better understanding of p53 biology, the mechanisms of action of compounds and treatment regimens as well as the development of new technologies are gaining interest, such as proteolysis-targeting chimeras for MDM2 degradation. Other approaches are taking advantage of the progress made in immune-based therapies for cancer. In this Review, we present these ongoing clinical trials and emerging approaches to re-evaluate the current state of knowledge of p53-based therapies for cancer.

摘要翻译： 

最重要的肿瘤抑制基因TP53的失活发生在大多数（如果不是全部）人类癌症中。功能性野生型p53的丧失主要通过两种机制实现：基因突变导致肿瘤抑制活性缺失，并在某些情况下获得致癌功能；或通过其负调控因子MDM2和MDMX的过表达介导对野生型p53蛋白的抑制。由于其强大的肿瘤抑制能力，且至少部分已形成的肿瘤依赖于其失活，p53成为开发新型抗癌药物极具吸引力的靶点。然而，p53作为一种转录因子，长期被认为不可成药。尽管如此，针对功能失调的p53已发展出多种创新性癌症治疗策略。在表达突变型p53的肿瘤中，主要策略是通过化合物恢复肿瘤抑制功能，这些化合物或以通用方式发挥作用，或选择性针对一种或少数特定p53突变。此外，目前正在开发耗竭突变型p53或靶向突变p53表达所产生脆弱性的方法。在野生型p53肿瘤中，主要方法是通过抑制剂靶向MDM2和MDMX这些负调控因子以保护p53。尽管MDM2抑制剂和突变p53修复化合物的部分临床试验结果令人鼓舞，但尚未有任何药物获得FDA批准。基于对p53生物学、化合物作用机制及治疗方案更深入理解的新策略，以及新技术的发展正受到关注，例如针对MDM2降解的蛋白水解靶向嵌合体。其他方法则利用基于免疫的癌症治疗取得的进展。本综述将介绍这些正在进行中的临床试验和新兴方法，以重新评估基于p53的癌症疗法的当前认知状态。

原文链接：

Translating p53-based therapies for cancer into the clinic