近日,，來自Bellvitge生物醫(yī)藥研究院的研究者研究發(fā)現(xiàn)，兩種mTOR蛋白抑制劑結(jié)合之后會(huì)阻止原發(fā)性肝癌的發(fā)展并且可以破壞腫瘤細(xì)胞,，相關(guān)研究成果刊登在了近日的國(guó)際雜志Science Translational Medicine上,。
原發(fā)性肝癌或肝細(xì)胞癌是世界上第五大常見的癌癥,，因其強(qiáng)烈的攻擊性,，是世界上第三大致死性疾病,。在世界范圍內(nèi),，該疾病影響著50萬人的健康，每三個(gè)患者中有兩個(gè)和慢性酒精中毒,、接觸有毒制劑,、乙肝病毒和丙肝病毒有關(guān)；其余的患者和非酒精性的脂肪肝（肥胖疾?。┯嘘P(guān)系,。
候選藥物
目前，抗癌藥物索拉非尼在病人治療上表現(xiàn)出了較好的效果,，但是隨著時(shí)間延續(xù),，藥物的效用卻在慢慢降低。因此,，尋找新的治療方法迫在眉睫,。在許多潛在的藥物中，mTOR信號(hào)途徑的抑制劑表現(xiàn)出更大的治療效果和價(jià)值,。mTOR途徑在肝細(xì)胞癌細(xì)胞中可以被高度激活。
研究者在小鼠體內(nèi)比較了兩種mTOR抑制劑的效應(yīng),，第一種抑制劑是雷帕霉素的衍生物,，成為依維莫司（RAD001），已經(jīng)作為免疫抑制劑治療特殊的癌癥,；第二種是一種新一代的藥物,，稱為BEZ235，可以抑制mTOR途徑,。
在延吉中,，研究者意外地發(fā)現(xiàn)，相比單一使用一種藥物進(jìn)行治療,，將以上兩種藥物結(jié)合以后來治療,，表現(xiàn)出更好的治療效果。同時(shí)服用BEZ235和RAD001以后,，可以明顯抑制腫瘤細(xì)胞的生長(zhǎng)和發(fā)育,，可以促使腫瘤細(xì)胞自我毀滅。
由諾華公司提供支持,，而且基于臨床研究的數(shù)據(jù),，目前美國(guó)已經(jīng)開始評(píng)估兩種藥物聯(lián)合使用的具體效用。研究者Sara Kozma表示,，因?yàn)槔着撩顾匾呀?jīng)批準(zhǔn)用于治療其它的疾病,，如果結(jié)合上BEZ235，將會(huì)是一種更為有用的治療藥物,，而且臨床數(shù)據(jù)也顯示出兩種藥物結(jié)合后的較好的治療效果,。（生物谷：T.Shen編譯）
doi:10.1126/scitranslmed.3003923
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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 upregulated in 50% of HCCs, we compared the effects of the FDA-approved mTOR-allosteric inhibitor, RAD001, with a new generation PI3K/mTOR ATP-site competitive inhibitor, BEZ235. Unexpectedly, the two drugs acted synergistically in inhibiting the proliferation of cultured HCC cells. The synergistic effect closely paralleled 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 dramatic regression in tumor burden. However in the tumor, BEZ235 alone was as effective as the combination in inhibiting 4E-BP1 phosphorylation, which suggest 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.
