Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Pathology & Laboratory Medicine, The Warren Alpert Medical School of Brown University, The Joint Program in Cancer Biology, Brown University and Lifespan Health System, Division of Hematology/Oncology, The Warren Alpert Medical School of Brown University, Providence, Rhode Island.
Legorreta Cancer Center at Brown University, Providence, Rhode Island.
Cancer Res. 2023 Apr 4;83(7):979-982. doi: 10.1158/0008-5472.CAN-22-0995.
Tumor suppressor TP53 is an important gene in human cancer because it is mutated in the majority of tumors, leading to loss-of-function or gain-of-function phenotypes. Mutated TP53 acts like an oncogene, driving cancer progression and causing poor patient outcomes. The role of mutated p53 in cancer has been known for over three decades, yet there is no FDA-approved drug to address the problem. This brief historical perspective highlights some of the insightful advances as well as challenges in therapeutic targeting of p53, especially the mutated forms. The article focuses on a functional p53 pathway restoration approach to drug discovery that years ago was not mainstream, encouraged by anyone, taught in textbooks, or embraced by medicinal chemists. With some knowledge, a clinician scientist's interest, and motivation, the author pursued a unique line of investigation leading to insights for functional bypass of TP53 mutations in human cancer. Like mutated Ras proteins, mutant p53 is fundamentally important as a therapeutic target in cancer and probably deserves a "p53 initiative" like the NCI's "Ras initiative." There is a link between naivete and enthusiasm for pursuing difficult problems, but important solutions are discovered through hard work and persistence. Hopefully, some benefit comes to patients with cancer from such drug discovery and development efforts.
抑癌基因 TP53 是人类癌症中的一个重要基因，因为它在大多数肿瘤中发生突变，导致功能丧失或获得功能表型。突变的 TP53 像癌基因一样发挥作用，推动癌症进展并导致患者预后不良。突变 p53 在癌症中的作用已经被人们认识了三十多年，但目前还没有获得 FDA 批准的药物来解决这个问题。本文简要回顾了在靶向治疗 p53，尤其是突变形式方面的一些有见地的进展和挑战。本文重点介绍了一种功能性 p53 通路恢复方法，用于药物发现，多年前，这种方法并不主流，也没有人鼓励、教授或接受药物化学家的支持。作者凭借一些知识、临床科学家的兴趣和动力，从事了一条独特的研究路线，为人类癌症中功能性旁路突变 TP53 提供了一些见解。像突变的 Ras 蛋白一样，突变 p53 作为癌症治疗靶点非常重要，可能值得像 NCI 的“Ras 倡议”一样发起一个“p53 倡议”。对解决困难问题的天真和热情之间存在联系，但重要的解决方案是通过努力和坚持发现的。希望癌症患者能够从这些药物发现和开发努力中获益。
