Pharmacological activation of wild-type p53 in the therapy of leukemia.
Pharmacological activation of wild-type p53 in the therapy of leukemia.
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DOI：
10.1016/j.exphem.2016.05.014
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发表时间：
2016-09
影响因子：
2.6
通讯作者：
Andreeff, Michael
中科院分区：
文献类型：
--
作者：
Kojima, Kensuke;Ishizawa, Jo;Andreeff, Michael
大多数人类实体瘤中的肿瘤抑制因子 p53 因突变而失活。相反，在白血病中，p53突变很少见，因为它们仅在一小部分患者群体中观察到，主要是在患有复杂核型急性髓细胞白血病或亚二倍体急性淋巴细胞白血病的患者中。然而，白血病细胞中 p53 功能的丧失通常是由 p53 调节蛋白的异常引起的，包括 MDM2/MDMX 的过度表达、CDKN2A/ARF 的缺失和 ATM 的改变。例如，MDM2 抑制 p53 介导的转录，促进其核输出，并诱导蛋白酶体依赖性降解。 MDM2 同源物 MDMX 是 p53 的另一个直接调节因子，可抑制 p53 介导的转录。几种针对 MDM2 和 MDMX 的小分子抑制剂和钉合肽已经开发出来，并且最近已进入临床试验。第一个临床使用的 MDM2 抑制剂 RG7112 的临床试验结果证明了白血病细胞中 p53 激活和细胞凋亡诱导的前景，作为概念证明。 RG7112的副作用最突出的是抑制白血病患者的血小板生成和胃肠道症状。已经提出了对 MDM2 抑制剂反应的预测生物标志物，但它们需要在体外和体内进一步验证，以便积累有关白血病病理性 p53 失调的知识，以及克服这种失调的新分子靶向策略，可以安全有效地转化为新的临床治疗方法。
The tumor suppressor p53 is inactivated by mutations in a majority of human solid tumors. Conversely, in leukemias p53 mutations are rare since they are only observed in a small fraction of the patient population, predominately in patients with complex karyotype acute myeloid leukemia or hypodiploid acute lymphoblastic leukemia. However, the loss of p53 function in leukemic cells is often caused by abnormalities in p53-regulatory proteins, including overexpression of MDM2/MDMX, deletion of CDKN2A/ARF, and ATM alterations. For example, MDM2 inhibits p53-mediated transcription, promotes its nuclear export, and induces proteasome-dependent degradation. The MDM2 homolog MDMX is another direct regulator of p53, which inhibits p53-mediated transcription. Several small molecule inhibitors and stapled peptides targeting MDM2 and MDMX have been developed and have recently entered clinical trials. The clinical trial results of the first clinically used MDM2 inhibitor, RG7112, illustrated promising p53 activation and apoptosis induction in leukemia cells as proof of concept. Side effects of RG7112 were most prominent in suppression of thrombopoiesis and gastrointestinal symptoms in the leukemia patients. Predictive biomarkers for response to MDM2 inhibitors have been proposed, but they require further validation both in vitro and in vivo such that the accumulated knowledge concerning pathological p53 dysregulation in leukemia, and novel molecular targeted strategies to overcome this dysregulation, can be translated safely and efficiently in to novel clinical therapeutics.
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影响因子：
8
作者：
Aziz, M. H.;Shen, H.;Maki, C. G.
通讯作者：
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影响因子：
7.3
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Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
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影响因子：
30.8
作者：
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通讯作者：
Mullighan, Charles G.
影响因子：
3.7
作者：
Borthakur G;Duvvuri S;Ruvolo V;Tripathi DN;Piya S;Burks J;Jacamo R;Kojima K;Ruvolo P;Fueyo-Margareto J;Konopleva M;Andreeff M
通讯作者：
Andreeff M
DOI：
10.1073/pnas.1303002110
发表时间：
2013-09-03
影响因子：
11.1
作者：
Chang, Yong S.;Graves, Bradford;Sawyer, Tomi K.
通讯作者：
Sawyer, Tomi K.