6月20日，Sci Transl Med杂志报道了一项联合用药抗击肝细胞癌最新进展。
肝细胞癌（HCC）影响全球超过五十万人，是第三大常见的癌症死因。由于哺乳动物雷帕霉素靶蛋白（mTOR）信号在50％的肝癌患者中上调，研究者比较了美国食品和药物管理局批准的mTOR的变构抑制剂RAD001和新一代磷脂酰环己六醇3-激酶/mTOR三磷酸腺苷位点竞争性抑制剂BEZ235的作用效果。
不料，这两种药物可协同抑制培养的肝癌细胞的增殖。此协同效应真核细胞起始因子4E结合蛋白1（4E-BP1）的磷酸化密切相关。在模拟人类肝癌的小鼠模型中，两种药物相结合可显著减小肿瘤，但不能单独发挥此作用。然而，在肿瘤中，单独应用BEZ23即可有效地抑制4E-BP1的磷酸化，这意味着额外的靶点也可能参与到这种协同肿瘤抑制作用中。
微阵列技术分析显示，联合使用这两种药物治疗的小鼠恢复多种基因的正常表达，但不能单靠一种药物。这些分析还显示，较正常肝组织，自噬基因在肿瘤中的表达下调了。此外，在肝癌患者中，自噬基因表达的改变与预后较差有关。
与这些研究结果一致，在培养细胞中，这两种药物组合对UNC51样激酶（ULK1）去磷酸化和细胞自噬有着不依赖于4E-BP1的重要影响。该作用与通过自噬降解线粒体的抑癌生物过程相平行。这些研究结果已导致一项研究者发起的1B-2阶段药物试验。该试验为联合应用RAD001 和BEZ235的剂量升级试验，目前针对肝癌及其他晚期实体瘤患者。（生物谷bioon.com）
doi:10.1016/j.cell.2011.10.017
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mTOR Inhibitors Synergize on Regression, Reversal of Gene Expression, and Autophagy in Hepatocellular Carcinoma
Hala Elnakat Thomas1,2, Carol A. Mercer2, Larissa S. Carnevalli1,*, Jongsun Park1,2,?, Jesper B. Andersen3, Elizabeth A. Conner3, Kazuhiro Tanaka4, Tomoo Matsutani4, Akio Iwanami4, Bruce J. Aronow5, Liu Manway6, S. Michel Maira7, Snorri S. Thorgeirsson3, Paul S. Mischel4, George Thomas1,2,8 and Sara C. Kozma1,2,8,?
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.
