mTOR inhibitors synergize on regression, reversal of gene expression, and autophagy in hepatocellular carcinoma.
mTOR inhibitors synergize on regression, reversal of gene expression, and autophagy in hepatocellular carcinoma.
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MTOR抑制剂在肝细胞癌中的回归，基因表达的逆转和自噬协同。
DOI：
10.1126/scitranslmed.3003923
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发表时间：
2012-06-20
影响因子：
17.1
通讯作者：
Kozma SC
中科院分区：
文献类型：
--
作者：
Thomas HE;Mercer CA;Carnevalli LS;Park J;Andersen JB;Conner EA;Tanaka K;Matsutani T;Iwanami A;Aronow BJ;Manway L;Maira SM;Thorgeirsson SS;Mischel PS;Thomas G;Kozma SC
肝细胞癌（HCC）影响全世界50多万人，是癌症死亡的第三大常见原因。由于哺乳动物雷帕霉素靶蛋白（mTOR）信号在50%的HCC中上调，我们比较了美国食品和药物管理局批准的mTOR变构抑制剂RAD 001与新一代磷脂酰肌醇3-激酶/mTOR三磷酸腺苷位点竞争性抑制剂BEZ 235的作用。出乎意料的是，这两种药物在抑制培养的HCC细胞增殖方面具有协同作用。这种协同效应与真核起始因子4 E结合蛋白1（4 E-BP 1）去磷酸化密切相关，这与抑制肿瘤细胞增殖有关。在接近人HCC的小鼠模型中，联合用药（而非单独用药）诱导肿瘤负荷显著消退。然而，在肿瘤中，单独使用BEZ 235与联合使用在抑制4 E-BP 1磷酸化方面一样有效，这表明还可能涉及其他靶点。微阵列分析显示，在用两种药物治疗的小鼠中，大量基因恢复到正常的肝组织表达，但单独使用任何一种药物都不行。这些分析还揭示了与正常肝脏相比，肿瘤中自噬基因的下调。此外，在HCC患者中，自噬基因表达的改变与预后不良相关。与这些发现一致，药物组合对培养物中的UNC 51样激酶1（ULK 1）去磷酸化和自噬具有深远的影响，独立于4 E-BP 1，并平行诱导肿瘤线粒体自噬，这是肝脏中的肿瘤抑制过程。这些观察结果导致了一项在HCC和其他晚期实体瘤患者中使用RAD 001联合BEZ 235的药物启动的1B-2期剂量递增试验。
Hepatocellular carcinoma (HCC) affects more than half a million people worldwide and is the third most common cause of cancer deaths. Because mammalian target of rapamycin (mTOR) signaling is up-regulated in 50% of HCCs, we compared the effects of the U.S. Food and Drug Administration–approved mTOR-allosteric inhibitor, RAD001, with a new-generation phosphatidylinositol 3-kinase/mTOR adenosine triphosphate–site competitive inhibitor, BEZ235. Unexpectedly, the two drugs acted synergistically in inhibiting the proliferation of cultured HCC cells. The synergistic effect closely paralleled eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) dephosphorylation, which is implicated in the suppression of tumor cell proliferation. In a mouse model approximating human HCC, the drugs in combination, but not singly, induced a marked regression in tumor burden. However, in the tumor, BEZ235 alone was as effective as the combination in inhibiting 4E-BP1 phosphorylation, which suggests that additional target(s) may also be involved. Microarray analyses revealed a large number of genes that reverted to normal liver tissue expression in mice treated with both drugs, but not either drug alone. These analyses also revealed the down-regulation of autophagy genes in tumors compared to normal liver. Moreover, in HCC patients, altered expression of autophagy genes was associated with poor prognosis. Consistent with these findings, the drug combination had a profound effect on UNC51-like kinase 1 (ULK1) dephosphorylation and autophagy in culture, independent of 4E-BP1, and in parallel induced tumor mitophagy, a tumor suppressor process in liver. These observations have led to an investigator-initiated phase 1B-2 dose escalation trial with RAD001 combined with BEZ235 in patients with HCC and other advanced solid tumors.
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雷帕霉素在I期试验中针对复发性PTEN缺陷型胶质母细胞瘤患者的抗肿瘤活性。
影响因子：
15.8
作者：
Cloughesy, Tim F.;Yoshimoto, Koji;Nghiemphu, Phioanh;Brown, Kevin;Dang, Julie;Zhu, Shaojun;Hsueh, Teli;Chen, Yinan;Wang, Wei;Youngkin, David;Liau, Linda;Martin, Neil;Becker, Don;Bergsneider, Marvin;Lai, Albert;Green, Richard;Oglesby, Tom;Koleto, Michael;Trent, Jeff;Horvath, Steve;Mischel, Paul S.;Mellinghoff, Ingo K.;Sawyers, Charles L.
通讯作者：
Sawyers, Charles L.
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
17.1
作者：
Andersen JB;Factor VM;Marquardt JU;Raggi C;Lee YH;Seo D;Conner EA;Thorgeirsson SS
通讯作者：
Thorgeirsson SS
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
索拉非尼对亚太地区晚期肝细胞癌患者的疗效和安全性：一项 III 期随机、双盲、安慰剂对照试验
影响因子：
51.1
作者：
Cheng, Ann-Lii;Kang, Yoon-Koo;Guan, Zhongzhen
通讯作者：
Guan, Zhongzhen