Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, 77204, USA.
Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, 77204, USA; Drug Discovery Institute, University of Houston, Houston, TX, 77204, USA.
Cancer Lett. 2021 Jan 1;496:16-29. doi: 10.1016/j.canlet.2020.09.023. Epub 2020 Sep 29.
Despite being the subject of extensive research and clinical trials, neuroblastoma remains a major therapeutic challenge in pediatric oncology. The p53 protein is a central safeguard that protects cells against genome instability and malignant transformation. Mutated TP53 (the gene encoding p53) is implicated in many human cancers, but the majority of neuroblastomas have wild type p53 with intact transcriptional function. In fact, the TP53 mutation rate does not exceed 1-2% in neuroblastomas. However, overexpression of the murine double minute 2 (MDM2) gene in neuroblastoma is relatively common, and leads to inhibition of p53. It is also associated with other non-canonical p53-independent functions, including drug resistance and increased translation of MYCN and VEGF mRNA. The p53-MDM2 pathway in neuroblastoma is also modulated at several different molecular levels, including via interactions with other proteins (MYCN, p14). In addition, the overexpression of MDM2 in tumors is linked to a poorer prognosis for cancer patients. Thus, restoring p53 function by inhibiting its interaction with MDM2 is a potential therapeutic strategy for neuroblastoma. A number of p53-MDM2 antagonists have been designed and studied for this purpose. This review summarizes the current understanding of p53 biology and the p53-dependent and -independent oncogenic functions of MDM2 in neuroblastoma, and also the regulation of the p53-MDM2 axis in neuroblastoma. This review also highlights the use of MDM2 as a molecular target for the disease, and describes the MDM2 inhibitors currently being investigated in preclinical and clinical studies. We also briefly explain the various strategies that have been used and future directions to take in the development of effective MDM2 inhibitors for neuroblastoma.
尽管神经母细胞瘤是医学研究的热门课题，并且已经进行了广泛的研究和临床试验，但它仍然是儿科肿瘤学的主要治疗挑战。p53 蛋白是一种中央保护机制，可保护细胞免受基因组不稳定和恶性转化的影响。突变型 TP53（编码 p53 的基因）与许多人类癌症有关，但大多数神经母细胞瘤具有野生型 p53，其转录功能完整。实际上，TP53 突变率在神经母细胞瘤中不超过 1-2%。然而，鼠双微体 2（MDM2）基因在神经母细胞瘤中的过表达相对常见，并且导致 p53 抑制。它还与其他非典型的 p53 独立功能相关，包括耐药性和 MYCN 和 VEGF mRNA 的翻译增加。神经母细胞瘤中的 p53-MDM2 途径也在几个不同的分子水平上进行调节，包括与其他蛋白质（MYCN、p14）的相互作用。此外，肿瘤中 MDM2 的过表达与癌症患者的预后较差有关。因此，通过抑制 p53 与其相互作用来恢复 p53 功能是治疗神经母细胞瘤的一种潜在治疗策略。为此，已经设计并研究了许多 p53-MDM2 拮抗剂。这篇综述总结了目前对 p53 生物学以及 MDM2 在神经母细胞瘤中的 p53 依赖性和非依赖性致癌功能的理解，以及神经母细胞瘤中 p53-MDM2 轴的调节。这篇综述还强调了将 MDM2 用作该疾病的分子靶标，并描述了目前正在进行的临床前和临床研究中的 MDM2 抑制剂。我们还简要说明了在开发有效的神经母细胞瘤 MDM2 抑制剂方面已经使用的各种策略和未来方向。
