6月20日,,Sci Transl Med雜志報道了一項聯(lián)合用藥抗擊肝細胞癌最新進展,。
肝細胞癌(HCC)影響全球超過五十萬人,是第三大常見的癌癥死因,。由于哺乳動物雷帕霉素靶蛋白(mTOR)信號在50%的肝癌患者中上調,,研究者比較了美國食品和藥物管理局批準的mTOR的變構抑制劑RAD001和新一代磷脂酰環(huán)己六醇3-激酶/mTOR三磷酸腺苷位點競爭性抑制劑BEZ235的作用效果。
不料,,這兩種藥物可協(xié)同抑制培養(yǎng)的肝癌細胞的增殖,。此協(xié)同效應真核細胞起始因子4E結合蛋白1(4E-BP1)的磷酸化密切相關。在模擬人類肝癌的小鼠模型中,,兩種藥物相結合可顯著減小腫瘤,,但不能單獨發(fā)揮此作用。然而,,在腫瘤中,,單獨應用BEZ23即可有效地抑制4E-BP1的磷酸化,這意味著額外的靶點也可能參與到這種協(xié)同腫瘤抑制作用中,。
微陣列技術分析顯示,,聯(lián)合使用這兩種藥物治療的小鼠恢復多種基因的正常表達,但不能單靠一種藥物,。這些分析還顯示,,較正常肝組織,自噬基因在腫瘤中的表達下調了,。此外,,在肝癌患者中,自噬基因表達的改變與預后較差有關,。
與這些研究結果一致,,在培養(yǎng)細胞中,這兩種藥物組合對UNC51樣激酶(ULK1)去磷酸化和細胞自噬有著不依賴于4E-BP1的重要影響,。該作用與通過自噬降解線粒體的抑癌生物過程相平行,。這些研究結果已導致一項研究者發(fā)起的1B-2階段藥物試驗。該試驗為聯(lián)合應用RAD001 和BEZ235的劑量升級試驗,,目前針對肝癌及其他晚期實體瘤患者,。(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.