吳 超(綜述) 鄭 燕, 楊濟(jì)萌 魯 明 董瓊珠 欽倫秀,△(審校)

(1復(fù)旦大學(xué)附屬華山醫(yī)院普外科 上海 200040; 2復(fù)旦大學(xué)腫瘤轉(zhuǎn)移研究所 上海 200040; 3復(fù)旦大學(xué)生物醫(yī)學(xué)研究院 上海 200032)

隨著發(fā)病率和死亡率的不斷增長,腫瘤已成為世界范圍內(nèi)居民死亡的主要原因之一[1-2]。傳統(tǒng)觀念認(rèn)為,腫瘤是由內(nèi)部基因變異和外部暴露所致。作為機(jī)體內(nèi)外環(huán)境交流橋梁的新陳代謝在腫瘤發(fā)生發(fā)展中起著重要作用[3]。基于腫瘤與代謝的密切聯(lián)系,靶向代謝的抗腫瘤藥物研制及臨床影像新技術(shù)近年來不斷取得突破。恰逢第53屆美國臨床腫瘤學(xué)會(huì)(American Society of Clinical Oncology,ASCO)年會(huì)2017年6月在美國芝加哥舉行,本文結(jié)合目前相關(guān)研究進(jìn)展就年會(huì)中有關(guān)腫瘤代謝及臨床營養(yǎng)方面的內(nèi)容進(jìn)行綜述。

靶向代謝通路藥物的臨床研究20世紀(jì)20年代,德國科學(xué)家發(fā)現(xiàn)腫瘤細(xì)胞相對(duì)正常細(xì)胞特有的有氧糖酵解供能表型(Warburg效應(yīng)),由此揭開腫瘤代謝研究的序幕[4]。2011年,Weinberg綜述了癌癥的十大表征,失調(diào)的細(xì)胞供能位列其一[5]?？v觀靶向代謝通路藥物的演變,可歸納為兩個(gè)方向,即二甲雙胍、他汀類調(diào)脂藥的老藥新用和以突變的異檸檬酸脫氫酶(mutant isocitrate dehydrogenase,mIDH)抑制劑為代表的新藥研發(fā)。

二甲雙胍 二甲雙胍用于治療糖尿病已逾50年。除降糖作用外,該藥還能防治多囊卵巢綜合征[6]及腫瘤[7]。既往研究顯示,使用二甲雙胍能夠獨(dú)立地降低丙肝病毒感染所致肝硬化合并2型糖尿病群體的肝癌發(fā)生率和肝臟衰竭或肝移植率[8]。伴有糖尿病的肝癌手術(shù)患者術(shù)后使用二甲雙胍能夠有更好的總體生存率和無復(fù)發(fā)生存率[9]。一項(xiàng)系統(tǒng)評(píng)價(jià)結(jié)果表明,對(duì)比其他降血糖手段,二甲雙胍能夠最優(yōu)效地降低罹患肝癌的風(fēng)險(xiǎn)[10]。該藥物的抗腫瘤效應(yīng)可能通過激活肝癌細(xì)胞中的腺苷酸活化蛋白激酶(adenosine monophosphate activated protein kinase,AMPK),下調(diào)哺乳動(dòng)物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR),從而抑制細(xì)胞增殖,降低體內(nèi)成瘤率[11]。

本次ASCO會(huì)議中,二甲雙胍被認(rèn)為在中晚期卵巢癌、輸卵管癌、原發(fā)腹膜癌、多發(fā)性骨髓瘤中有一定程度的抗癌作用[12-14]。相比其他降糖手段,僅二甲雙胍能夠提升合并糖尿病的肺癌患者生存結(jié)局[15]。對(duì)P53缺失的Li-Franmeni綜合征患者服用二甲雙胍后行代謝組學(xué)研究顯示,干預(yù)組患者的三羧酸循環(huán)產(chǎn)物增加,同時(shí)脂肪酸氧化水平顯著提高[16]。此外,一些研究也探索了二甲雙胍聯(lián)合其他干預(yù)(如運(yùn)動(dòng)和其他通路阻斷劑)的臨床療效。一項(xiàng)旨在探索二甲雙胍和生活方式干預(yù)對(duì)子宮內(nèi)膜癌高危人群(絕經(jīng)后肥胖女性)作用的初步結(jié)果表明,每日服用1 700 mg二甲雙胍同時(shí)對(duì)生活方式干預(yù)可減輕體重,并對(duì)血清學(xué)指標(biāo)變化(如脫氫表雄酮)有積極效果[17]。一項(xiàng)納入139例Ⅰ～Ⅲ期結(jié)直腸癌或乳腺癌患者的Ⅱ期多中心臨床試驗(yàn)表明,運(yùn)動(dòng)和服用二甲雙胍均能顯著改善結(jié)直腸癌或乳腺癌生存者的胰島素、胰島素樣生長因子1(insulin-like growth factor 1,IGF-1)、胰島素樣生長因子結(jié)合蛋白1(insulin-like growth factor-binding protein 1,IGFBP1)等水平并潛在協(xié)同作用于瘦素水平[18]。二甲雙胍聯(lián)合依維莫司治療晚期腫瘤患者的生存分析結(jié)果顯示,盡管不少患者不能耐受兩藥的聯(lián)合治療,但是耐受患者相對(duì)不耐受患者生存期更久[19]。體內(nèi)和體外實(shí)驗(yàn)也證明,二甲雙胍對(duì)血管內(nèi)皮生長因子(vascular endothelial growth factor,VEGF)阻斷劑的抗腫瘤作用有正向調(diào)節(jié)作用[20]。de Censi等[21]比較了結(jié)腸組織和血漿中二甲雙胍的濃度,發(fā)現(xiàn)二甲雙胍在結(jié)腸組織中濃度聚集的現(xiàn)象,從藥物動(dòng)力學(xué)上闡釋了二甲雙胍的抗癌作用。該研究組同時(shí)發(fā)布了一項(xiàng)Ⅰ～Ⅲ期結(jié)直腸癌患者使用二甲雙胍和阿司匹林獨(dú)立或協(xié)同抗癌作用的臨床試驗(yàn)簡要方案[22]。

雖然不少研究表明二甲雙胍的抗腫瘤效應(yīng),但是一項(xiàng)在實(shí)體瘤中聯(lián)合mTOR抑制劑(西羅莫司)和二甲雙胍的臨床試驗(yàn)因?qū)Τ跗诮Y(jié)果分析發(fā)現(xiàn)首要終點(diǎn)指標(biāo)無差異而被中止[23]。此外,意大利的研究團(tuán)隊(duì)基于先前研究結(jié)論的擴(kuò)大樣本分析(280例)提示,對(duì)服用索拉菲尼的伴有糖尿病晚期肝癌患者,使用二甲雙胍控制血糖相比胰島素會(huì)促進(jìn)腫瘤進(jìn)展和索拉菲尼的耐藥[24-25]。作者分析認(rèn)為,這樣的促腫瘤現(xiàn)象可能是由于藥效或藥物動(dòng)力學(xué)上的轉(zhuǎn)運(yùn)基因或轉(zhuǎn)錄因子的分子改變從而導(dǎo)致聯(lián)合用藥的失敗。

總之,目前不少回顧性隊(duì)列研究和病例對(duì)照研究均顯示出二甲雙胍的抗腫瘤作用,而少數(shù)持相反觀點(diǎn)的研究結(jié)論均來自對(duì)中小樣本量的回顧性分析。因此,二甲雙胍的抗癌作用是否成立仍需嚴(yán)格設(shè)計(jì)的前瞻性隨機(jī)對(duì)照研究進(jìn)行檢驗(yàn),同時(shí)需明確二甲雙胍對(duì)非糖尿病癌癥患者的作用。

mIDH抑制劑 異檸檬酸脫氫酶(isocitrate dehydrogenase,IDH)是三羧酸循環(huán)中的關(guān)鍵酶之一,分為IDH1、IDH2等,可將異檸檬酸轉(zhuǎn)化為α-酮戊二酸。

一項(xiàng)對(duì)384例急性髓系白血病(acute myelocytic leukemia,AML)患者的研究發(fā)現(xiàn),其中13例(3.4%)和27例(7%)發(fā)生了IDH1/2突變,均低于文獻(xiàn)報(bào)道[26]。來自美國MD Anderson的科學(xué)家對(duì)334例多種腫瘤組織二代測序數(shù)據(jù)的分析結(jié)果顯示,IDH突變常常伴有TP53、Kras等基因突變[27]。IDH突變可使癌代謝物2-HG的S型構(gòu)象轉(zhuǎn)換為R型對(duì)映異構(gòu)體的積聚。Sim等[28]研究發(fā)現(xiàn)膠質(zhì)瘤組織中R/S比例能夠有效區(qū)分是否有IDH突變,此現(xiàn)象可為臨床實(shí)時(shí)決策(如術(shù)中切緣)提供幫助。同樣在膠質(zhì)瘤中,經(jīng)Toca511和Toca FC治療(Toca511為逆轉(zhuǎn)錄病毒復(fù)制載體藥物,Toca FC為5-Fu的緩釋劑型)的患者其IDH1突變情況和客觀反應(yīng)相關(guān)[29]。我們既往研究發(fā)現(xiàn)IDH1在肝內(nèi)膽管癌中也存在一定的突變率[30]。AG120是目前正在試驗(yàn)的靶向IDH1突變實(shí)體瘤的口服藥物。會(huì)議摘要編號(hào)4015的研究報(bào)道了該藥物的Ⅰ期臨床試驗(yàn)初步結(jié)果[31]。截至2016年底,73例患者接受AG120治療,僅2例患者出現(xiàn)3級(jí)不良反應(yīng),但無因不良反應(yīng)而中斷治療的情況發(fā)生。這些患者中,4例確認(rèn)部分緩解,56例患者維持病情穩(wěn)定,達(dá)到6個(gè)月無進(jìn)展生存比例為40%。因此,AG120對(duì)IDH1突變的膽管癌患者顯示出一定安全性并能延長疾病穩(wěn)定期。該藥物的Ⅲ期臨床試驗(yàn)(ClarIDHy)簡要方案同期公布[32]。

IDH2抑制劑AG221在復(fù)發(fā)難治的AML Ⅰ期臨床試驗(yàn)中顯示出較好的耐受性并能誘導(dǎo)疾病完全緩解[33]。即使產(chǎn)生AG221相關(guān)的分化綜合征等并發(fā)癥,系統(tǒng)性激素治療、密切血流動(dòng)力學(xué)管理及羥基脲的及早使用仍是有效的[34]。

他汀類調(diào)脂藥 他汀類藥物通過抑制內(nèi)源性膽固醇合成限速酶羥甲基戊二酰輔酶A(hydroxymethylglutaryl-coenzyme A,HMG-CoA)還原酶,減少胞內(nèi)膽固醇合成并反饋性促進(jìn)胞膜低密度脂蛋白受體數(shù)量和活性增加,從而清除血清膽固醇,達(dá)到降脂目的。

針對(duì)Framingham隊(duì)列的一項(xiàng)研究發(fā)現(xiàn),是否達(dá)到指南中他汀藥物的適應(yīng)證可篩選出高患癌風(fēng)險(xiǎn)和癌死亡風(fēng)險(xiǎn)人群[35]。另2個(gè)隊(duì)列研究也發(fā)現(xiàn)他汀類藥物能降低食管腺癌、結(jié)腸癌的患癌風(fēng)險(xiǎn)或癌死亡風(fēng)險(xiǎn)[36-37]。Rutledge等對(duì)10 868例服用他汀類調(diào)脂藥的絕經(jīng)后女性分析發(fā)現(xiàn),服用他汀類藥物和晚期結(jié)直腸癌診斷率的下降顯著相關(guān)[38]。此外,阿比特龍治療去勢(shì)抵抗前列腺癌患者聯(lián)合他汀類藥物治療對(duì)疾病預(yù)后有正向作用[39]。一項(xiàng)納入197 048例女性的薈萃分析表明乳腺癌患者服用親脂性他汀類藥物有更強(qiáng)的保護(hù)作用,但這種作用僅在隨訪的前4年中可觀察到[40]。通過對(duì)7 298例姑息治療的老年非小細(xì)胞肺癌患者分析發(fā)現(xiàn),他汀類藥物而非二甲雙胍使患者獲得更好的生存獲益[41]。

其他代謝分子抑制劑 除了糖脂代謝通路的明星藥物外,本次會(huì)議對(duì)其他代謝分子抑制劑也有報(bào)道。葉酸受體在肺腺癌等眾多腫瘤中高表達(dá),而在絕大多數(shù)正常組織中表達(dá)量低。EC1456為靶向葉酸受體的小分子化合物。一項(xiàng)EC1456的Ⅰ期劑量爬坡臨床試驗(yàn)初步結(jié)果顯示大部分患者對(duì)藥物耐受良好[42]。通常情況,癌細(xì)胞通過糖酵解生成乳酸并排出胞外,而MCT1為乳酸排泄胞外的關(guān)鍵轉(zhuǎn)運(yùn)酶。英國研究團(tuán)隊(duì)報(bào)道了靶向MCT1藥物AZD3965劑量探索臨床試驗(yàn)結(jié)果:最大耐受劑量為每天20 mg[43]。SM88是一種選擇性增加癌細(xì)胞代謝氧化應(yīng)激的抗癌藥物,本次會(huì)議上報(bào)道了其Ⅱ期臨床試驗(yàn)的簡要方案[44]。

靶向代謝聯(lián)合免疫治療 雖然有關(guān)腫瘤免疫檢查點(diǎn)抑制劑的研究是當(dāng)前熱點(diǎn),但臨床實(shí)踐發(fā)現(xiàn),對(duì)一些患者使用已批準(zhǔn)的免疫檢查點(diǎn)抑制劑,其臨床效果甚微。聯(lián)合免疫檢查點(diǎn)藥物的靶向代謝治療有望能使部分患者獲益。有研究表明,癌細(xì)胞能夠通過代謝使得腫瘤微環(huán)境和免疫調(diào)節(jié)受體發(fā)生改變,從而抑制效應(yīng)T細(xì)胞[45]。Beckermann等[46]致力于闡明腎細(xì)胞癌中代謝狀態(tài)如何抑制T細(xì)胞發(fā)揮抗腫瘤作用。運(yùn)用皮下瘤接種模型研究發(fā)現(xiàn),腫瘤浸潤C(jī)D8淋巴細(xì)胞處于失衡的代謝狀態(tài),即活性氧和線粒體損傷水平而非糖代謝水平被上調(diào),是免疫治療的障礙。來自中美兩國的聯(lián)合研究團(tuán)隊(duì)同樣利用肺腺癌小鼠模型研究程序性細(xì)胞死亡1(programmed cell death-1,PD1)抑制劑耐藥機(jī)制,發(fā)現(xiàn)PD1抑制劑耐藥組中脂質(zhì)代謝通路高度富集。脂質(zhì)代謝網(wǎng)絡(luò)通過免疫抑制細(xì)胞的積聚來驅(qū)動(dòng)PD1抑制劑耐藥[47],故聯(lián)合靶向脂質(zhì)代謝通路的抑制劑可能是PD1耐藥后續(xù)治療的選擇之一。

基于代謝原理的腫瘤顯像技術(shù)目前臨床實(shí)踐中運(yùn)用最廣泛也最成熟的代謝顯像技術(shù)是氟18標(biāo)記的脫氧葡萄糖正電子發(fā)射計(jì)算機(jī)斷層顯像(18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography,18F-FDG PET/CT)。本次會(huì)議中2篇摘要報(bào)道了該技術(shù)能早期預(yù)測納武單抗治療非小細(xì)胞肺癌患者的效果及預(yù)后[48-49]。早期代謝反應(yīng)評(píng)估預(yù)測治療效果同樣適用于局部高級(jí)別鼻咽癌、彌漫性大B細(xì)胞淋巴瘤和HER2陽性的轉(zhuǎn)移性乳腺癌[50-52]。Huang等[53]報(bào)道了早期PET掃描用于評(píng)估局部晚期食管鱗癌新輔助放化療一個(gè)療程的預(yù)測效果。雖然結(jié)果與預(yù)期不符,但是作者分析時(shí)發(fā)現(xiàn)化療后標(biāo)準(zhǔn)攝取最大值(maximum of standard uptake value,SUVmax)是這些患者無進(jìn)展生存時(shí)間和總體生存時(shí)間的獨(dú)立預(yù)測因子。作者進(jìn)一步分析預(yù)測失敗的原因可能是選取終點(diǎn)指標(biāo)不夠完善。一項(xiàng)來自日本的研究通過對(duì)18例患者分析發(fā)現(xiàn)PET/MRI聯(lián)合檢測對(duì)婦科腫瘤淋巴結(jié)轉(zhuǎn)移有較高的診斷價(jià)值[54]。PET結(jié)合彌散加權(quán)成像(diffusion weighted image,DWI)序列可以提供比這兩種方法單獨(dú)診斷更高的準(zhǔn)確率。PET/MRI 最大優(yōu)勢(shì)在于 PET 與 MRI 掃描同時(shí)進(jìn)行,較 PET/CT 能縮短時(shí)間并簡化步驟。

本次大會(huì)公布了聯(lián)合影像學(xué)和液體活檢技術(shù)用于聯(lián)合診斷的探索研究結(jié)果。因目前暫無有效的生物預(yù)測指標(biāo)反映瑞戈非尼治療轉(zhuǎn)移性結(jié)直腸癌患者的預(yù)后,Woff等[55]將基線細(xì)胞游離DNA(cell free DNA,cfDNA)結(jié)合腫瘤代謝體積及體重指數(shù)用來預(yù)測瑞戈非尼治療轉(zhuǎn)移性結(jié)直腸癌患者的預(yù)后,并顯示了良好的預(yù)測效能。來自西班牙的研究團(tuán)隊(duì)通過基因表達(dá)芯片技術(shù)在71例不同組織類型的轉(zhuǎn)移性腫瘤患者中進(jìn)行測試,從13例患者中篩選出葡萄糖攝取環(huán)節(jié)關(guān)聯(lián)基因,結(jié)合SUV發(fā)現(xiàn)909個(gè)探針有意義,基于這909個(gè)探針的構(gòu)建了PLS-3模型,并對(duì)比發(fā)現(xiàn)其能夠準(zhǔn)確預(yù)測SUV[56]。

代謝分子在腫瘤發(fā)生發(fā)展中的作用和機(jī)制代謝通路及通路涉及的分子紛繁復(fù)雜。但正是由于對(duì)關(guān)鍵分子的不斷探索,二甲雙胍、他汀類等藥物才有機(jī)會(huì)在抗癌治療中得到實(shí)踐。Millis等[57]回顧分析1 781例前列腺癌患者全基因組數(shù)據(jù)發(fā)現(xiàn)延胡索酸脫氫酶基因變異率為3%,且大部分位于C末端結(jié)合區(qū)域,對(duì)進(jìn)一步藥物研發(fā)有提示作用。復(fù)旦大學(xué)附屬腫瘤醫(yī)院的研究團(tuán)隊(duì)報(bào)道了FOXC1通過在轉(zhuǎn)錄水平調(diào)控糖酵解通路中關(guān)鍵酶二磷酸果糖酶(fructose-bisphosphatase 1,FBP1)并形成反饋軸,增強(qiáng)了腫瘤Warburg效應(yīng),參與結(jié)直腸癌的惡性進(jìn)展[58]。Trapp等[59]研究發(fā)現(xiàn)乳腺癌循環(huán)腫瘤細(xì)胞可能通過肝激酶B1(liver kinase B1,LKB1)的上調(diào)表達(dá),對(duì)早期內(nèi)滲階段代謝壓力進(jìn)行反饋,從而促進(jìn)轉(zhuǎn)移。因此,LKB1有望成為捕獲循環(huán)腫瘤細(xì)胞、防止轉(zhuǎn)移的新治療靶點(diǎn)。Hu等[60]基于先前發(fā)現(xiàn)Kras突變的雜合性缺失(loss of heterozygosity,LOH)和Redd1表達(dá)上調(diào)相關(guān),對(duì)比基因工程小鼠來源的Kras突變和Kras-LOH胰腺癌細(xì)胞,發(fā)現(xiàn)Kras-LOH使得胰腺癌細(xì)胞嗜糖酵解并通過Redd1促進(jìn)增殖和侵襲。

臨床營養(yǎng)方案和營養(yǎng)評(píng)估癌癥患者,特別是癌癥晚期患者,因疾病本身或相關(guān)治療易導(dǎo)致惡病質(zhì)[61],故臨床實(shí)踐中有效的營養(yǎng)方案和恰當(dāng)?shù)脑u(píng)估很有必要。

Li等[62]公布的食管癌同期放化療患者行腸內(nèi)營養(yǎng)的隨機(jī)對(duì)照臨床試驗(yàn)結(jié)果顯示,對(duì)存在高營養(yǎng)不良風(fēng)險(xiǎn)的患者群體給予腸內(nèi)營養(yǎng)能夠提升個(gè)體營養(yǎng)狀態(tài),增加治療耐受性,其1年和2年的總體生存率明顯提高。相似地,頭頸部腫瘤行放療患者口服營養(yǎng)素也能更好地維持體重,獲得更優(yōu)的生存質(zhì)量和治療耐受性[63]。992例Ⅲ期結(jié)腸癌患者的CALGB 89803研究證明,遵從ASCO腫瘤患者營養(yǎng)及運(yùn)動(dòng)指南的結(jié)腸癌患者能獲得更長的無疾病進(jìn)展期和總體生存期[64]。該研究還得出另一個(gè)有趣的結(jié)論:更多堅(jiān)果的食用可能和結(jié)腸癌患者更低的復(fù)發(fā)和死亡率有關(guān)[65]。除了有效的營養(yǎng)方案,恰當(dāng)?shù)脑u(píng)估也十分重要。Herrera等[66]將包含血清白蛋白水平和總淋巴細(xì)胞數(shù)的預(yù)測營養(yǎng)指數(shù)(prognostic nutrition index,PNI)用于91例胃癌術(shù)后患者的營養(yǎng)評(píng)估,結(jié)果發(fā)現(xiàn)PNI低于38.7的患者總體生存率更低(46個(gè)月vs.25個(gè)月,P=0.009)。這種評(píng)估方案同樣適合乳腺癌患者[67]。

結(jié)語腫瘤代謝和營養(yǎng)支持與目前的臨床實(shí)踐密切相關(guān),且在實(shí)踐中可嘗試二甲雙胍、他汀類藥物及營養(yǎng)素?cái)z入等干預(yù)手段。在靶向腫瘤代謝的基礎(chǔ)研究中,除mIDH抑制劑外的大多數(shù)藥物仍停留在Ⅰ或Ⅱ期臨床試驗(yàn)階段。隨著新技術(shù)和算法的應(yīng)用,基于腫瘤代謝的腫瘤顯像不斷取得進(jìn)展。對(duì)于其他傳統(tǒng)或新興治療耐藥的患者,聯(lián)合靶向代謝治療初現(xiàn)優(yōu)勢(shì)。

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