MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer.
MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer.
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DOI：
10.1186/s13045-017-0500-5
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发表时间：
2017-07-03
影响因子：
28.5
通讯作者：
Zauli G
中科院分区：
文献类型：
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作者：
Tisato V;Voltan R;Gonelli A;Secchiero P;Zauli G
两个小鼠双分钟(MDM)家族成员MDM2和MDMX作为癌症治疗的分子靶点，处于紧张的临床评估的中心。事实上，这两种蛋白是P53的调节者，P53是众所周知的细胞周期调节和细胞增殖的关键控制器，当改变时，它对癌症的发展和进展起着直接作用。一些证据表明，肿瘤中P53的功能异常在大多数情况下是MDM2和MDMX调节蛋白改变的结果，特别是在血液系统恶性肿瘤患者中，TP53突变频率相对较低，而MDM2和MDMX经常被扩增/过度表达。因此，这两种P53调节因子的药理靶向以恢复或增加P53的表达和活性代表了癌症治疗的一种策略。自从2004年Nutlins被发现以来，已经有几个化合物被开发和报道，它们通过抑制MDM2和/或MDMX来靶向p53-MDM2/X轴。从天然化合物到小分子和装订多肽，这些MDM2/X药物抑制剂已经得到了广泛的研究，在体外和体内实验肿瘤模型中显示出不同的生物学特性和不同的有效率。来自临床前实验的数据/证据使人们能够确定最有希望的分子，并将临床研究的环境作为单一疗法或与常规化疗或不同肿瘤环境下的创新治疗方案相结合进行评估。最近发表了初步结果，报告了有关此类治疗方法的安全性、耐受性、潜在副作用和有效性的数据。鉴于此，本综述的目的是对MDM2/X抑制剂化合物的临床评价的最新进展进行综述，并特别关注血液系统恶性肿瘤和治疗儿童癌症的可能性。
The two murine double minute (MDM) family members MDM2 and MDMX are at the center of an intense clinical assessment as molecular target for the management of cancer. Indeed, the two proteins act as regulators of P53, a well-known key controller of the cell cycle regulation and cell proliferation that, when altered, plays a direct role on cancer development and progression. Several evidence demonstrated that functional aberrations of P53 in tumors are in most cases the consequence of alterations on the MDM2 and MDMX regulatory proteins, in particular in patients with hematological malignancies where TP53 shows a relatively low frequency of mutation while MDM2 and MDMX are frequently found amplified/overexpressed. The pharmacological targeting of these two P53-regulators in order to restore or increase P53 expression and activity represents therefore a strategy for cancer therapy. From the discovery of the Nutlins in 2004, several compounds have been developed and reported with the ability of targeting the P53-MDM2/X axis by inhibiting MDM2 and/or MDMX. From natural compounds up to small molecules and stapled peptides, these MDM2/X pharmacological inhibitors have been extensively studied, revealing different biological features and different rate of efficacy when tested in in vitro and in vivo experimental tumor models. The data/evidence coming from the preclinical experimentation have allowed the identification of the most promising molecules and the setting of clinical studies for their evaluation as monotherapy or in therapeutic combination with conventional chemotherapy or with innovative therapeutic protocols in different tumor settings. Preliminary results have been recently published reporting data about safety, tolerability, potential side effects, and efficacy of such therapeutic approaches. In this light, the aim of this review is to give an updated overview about the state of the art of the clinical evaluation of MDM2/X inhibitor compounds with a special attention to hematological malignancies and to the potential for the management of pediatric cancers.