從2017 ASCO年會看腫瘤代謝及營養支持研究的進展

吳 超(綜述) 鄭 燕, 楊濟萌 魯 明 董瓊珠 欽倫秀,△(審校)

(1復旦大學附屬華山醫院普外科 上海 200040; 2復旦大學腫瘤轉移研究所 上海 200040; 3復旦大學生物醫學研究院 上海 200032)

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

靶向代謝通路藥物的臨床研究20世紀20年代,德國科學家發現腫瘤細胞相對正常細胞特有的有氧糖酵解供能表型(Warburg效應),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,失調的細胞供能位列其一[5]。縱觀靶向代謝通路藥物的演變,可歸納為兩個方向,即二甲雙胍、他汀類調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。

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生率和肝臟衰竭或肝移植率[8]。伴有糖尿病的肝癌手術患者術后使用二甲雙胍能夠有更好的總體生存率和無復發生存率[9]。一項系統評價結果表明,對比其他降血糖手段,二甲雙胍能夠最優效地降低罹患肝癌的風險[10]。該藥物的抗腫瘤效應可能通過激活肝癌細胞中的腺苷酸活化蛋白激酶(adenosine monophosphate activated protein kinase,AMPK),下調哺乳動物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR),從而抑制細胞增殖,降低體內成瘤率[11]。

本次ASCO會議中,二甲雙胍被認為在中晚期卵巢癌、輸卵管癌、原發腹膜癌、多發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局[15]。對P53缺失的Li-Franmeni綜合征患者服用二甲雙胍后行代謝組學研究顯示,干預組患者的三羧酸循環產物增加,同時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合其他干預(如運動和其他通路阻斷劑)的臨床療效。一項旨在探索二甲雙胍和生活方式干預對子宮內膜癌高危人群(絕經后肥胖女性)作用的初步結果表明,每日服用1 700 mg二甲雙胍同時對生活方式干預可減輕體重,并對血清學指標變化(如脫氫表雄酮)有積極效果[17]。一項納入139例Ⅰ～Ⅲ期結直腸癌或乳腺癌患者的Ⅱ期多中心臨床試驗表明,運動和服用二甲雙胍均能顯著改善結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合蛋白1(insulin-like growth factor-binding protein 1,IGFBP1)等水平并潛在協同作用于瘦素水平[18]。二甲雙胍聯合依維莫司治療晚期腫瘤患者的生存分析結果顯示,盡管不少患者不能耐受兩藥的聯合治療,但是耐受患者相對不耐受患者生存期更久[19]。體內和體外實驗也證明,二甲雙胍對血管內皮生長因子(vascular endothelial growth factor,VEGF)阻斷劑的抗腫瘤作用有正向調節作用[20]。de Censi等[21]比較了結腸組織和血漿中二甲雙胍的濃度,發現二甲雙胍在結腸組織中濃度聚集的現象,從藥物動力學上闡釋了二甲雙胍的抗癌作用。該研究組同時發布了一項Ⅰ～Ⅲ期結直腸癌患者使用二甲雙胍和阿司匹林獨立或協同抗癌作用的臨床試驗簡要方案[22]。

雖然不少研究表明二甲雙胍的抗腫瘤效應,但是一項在實體瘤中聯合mTOR抑制劑(西羅莫司)和二甲雙胍的臨床試驗因對初期結果分析發現首要終點指標無差異而被中止[23]。此外,意大利的研究團隊基于先前研究結論的擴大樣本分析(280例)提示,對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促進腫瘤進展和索拉菲尼的耐藥[24-25]。作者分析認為,這樣的促腫瘤現象可能是由于藥效或藥物動力學上的轉運基因或轉錄因子的分子改變從而導致聯合用藥的失敗。

總之,目前不少回顧性隊列研究和病例對照研究均顯示出二甲雙胍的抗腫瘤作用,而少數持相反觀點的研究結論均來自對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格設計的前瞻性隨機對照研究進行檢驗,同時需明確二甲雙胍對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)是三羧酸循環中的關鍵酶之一,分為IDH1、IDH2等,可將異檸檬酸轉化為α-酮戊二酸。

一項對384例急性髓系白血病(acute myelocytic leukemia,AML)患者的研究發現,其中13例(3.4%)和27例(7%)發生了IDH1/2突變,均低于文獻報道[26]。來自美國MD Anderson的科學家對334例多種腫瘤組織二代測序數據的分析結果顯示,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型構象轉換為R型對映異構體的積聚。Sim等[28]研究發現膠質瘤組織中R/S比例能夠有效區分是否有IDH突變,此現象可為臨床實時決策(如術中切緣)提供幫助。同樣在膠質瘤中,經Toca511和Toca FC治療(Toca511為逆轉錄病毒復制載體藥物,Toca FC為5-Fu的緩釋劑型)的患者其IDH1突變情況和客觀反應相關[29]。我們既往研究發現IDH1在肝內膽管癌中也存在一定的突變率[30]。AG120是目前正在試驗的靶向IDH1突變實體瘤的口服藥物。會議摘要編號4015的研究報道了該藥物的Ⅰ期臨床試驗初步結果[31]。截至2016年底,73例患者接受AG120治療,僅2例患者出現3級不良反應,但無因不良反應而中斷治療的情況發生。這些患者中,4例確認部分緩解,56例患者維持病情穩定,達到6個月無進展生存比例為40%。因此,AG120對IDH1突變的膽管癌患者顯示出一定安全性并能延長疾病穩定期。該藥物的Ⅲ期臨床試驗(ClarIDHy)簡要方案同期公布[32]。

IDH2抑制劑AG221在復發難治的AML Ⅰ期臨床試驗中顯示出較好的耐受性并能誘導疾病完全緩解[33]。即使產生AG221相關的分化綜合征等并發癥,系統性激素治療、密切血流動力學管理及羥基脲的及早使用仍是有效的[34]。

他汀類調脂藥 他汀類藥物通過抑制內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,減少胞內膽固醇合成并反饋性促進胞膜低密度脂蛋白受體數量和活性增加,從而清除血清膽固醇,達到降脂目的。

針對Framingham隊列的一項研究發現,是否達到指南中他汀藥物的適應證可篩選出高患癌風險和癌死亡風險人群[35]。另2個隊列研究也發現他汀類藥物能降低食管腺癌、結腸癌的患癌風險或癌死亡風險[36-37]。Rutledge等對10 868例服用他汀類調脂藥的絕經后女性分析發現,服用他汀類藥物和晚期結直腸癌診斷率的下降顯著相關[38]。此外,阿比特龍治療去勢抵抗前列腺癌患者聯合他汀類藥物治療對疾病預后有正向作用[39]。一項納入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的保護作用,但這種作用僅在隨訪的前4年中可觀察到[40]。通過對7 298例姑息治療的老年非小細胞肺癌患者分析發現,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,本次會議對其他代謝分子抑制劑也有報道。葉酸受體在肺腺癌等眾多腫瘤中高表達,而在絕大多數正常組織中表達量低。EC1456為靶向葉酸受體的小分子化合物。一項EC1456的Ⅰ期劑量爬坡臨床試驗初步結果顯示大部分患者對藥物耐受良好[42]。通常情況,癌細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鍵轉運酶。英國研究團隊報道了靶向MCT1藥物AZD3965劑量探索臨床試驗結果:最大耐受劑量為每天20 mg[43]。SM88是一種選擇性增加癌細胞代謝氧化應激的抗癌藥物,本次會議上報道了其Ⅱ期臨床試驗的簡要方案[44]。

靶向代謝聯合免疫治療 雖然有關腫瘤免疫檢查點抑制劑的研究是當前熱點,但臨床實踐發現,對一些患者使用已批準的免疫檢查點抑制劑,其臨床效果甚微。聯合免疫檢查點藥物的靶向代謝治療有望能使部分患者獲益。有研究表明,癌細胞能夠通過代謝使得腫瘤微環境和免疫調節受體發生改變,從而抑制效應T細胞[45]。Beckermann等[46]致力于闡明腎細胞癌中代謝狀態如何抑制T細胞發揮抗腫瘤作用。運用皮下瘤接種模型研究發現,腫瘤浸潤CD8淋巴細胞處于失衡的代謝狀態,即活性氧和線粒體損傷水平而非糖代謝水平被上調,是免疫治療的障礙。來自中美兩國的聯合研究團隊同樣利用肺腺癌小鼠模型研究程序性細胞死亡1(programmed cell death-1,PD1)抑制劑耐藥機制,發現PD1抑制劑耐藥組中脂質代謝通路高度富集。脂質代謝網絡通過免疫抑制細胞的積聚來驅動PD1抑制劑耐藥[47],故聯合靶向脂質代謝通路的抑制劑可能是PD1耐藥后續治療的選擇之一。

基于代謝原理的腫瘤顯像技術目前臨床實踐中運用最廣泛也最成熟的代謝顯像技術是氟18標記的脫氧葡萄糖正電子發射計算機斷層顯像(18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography,18F-FDG PET/CT)。本次會議中2篇摘要報道了該技術能早期預測納武單抗治療非小細胞肺癌患者的效果及預后[48-49]。早期代謝反應評估預測治療效果同樣適用于局部高級別鼻咽癌、彌漫性大B細胞淋巴瘤和HER2陽性的轉移性乳腺癌[50-52]。Huang等[53]報道了早期PET掃描用于評估局部晚期食管鱗癌新輔助放化療一個療程的預測效果。雖然結果與預期不符,但是作者分析時發現化療后標準攝取最大值(maximum of standard uptake value,SUVmax)是這些患者無進展生存時間和總體生存時間的獨立預測因子。作者進一步分析預測失敗的原因可能是選取終點指標不夠完善。一項來自日本的研究通過對18例患者分析發現PET/MRI聯合檢測對婦科腫瘤淋巴結轉移有較高的診斷價值[54]。PET結合彌散加權成像(diffusion weighted image,DWI)序列可以提供比這兩種方法單獨診斷更高的準確率。PET/MRI 最大優勢在于 PET 與 MRI 掃描同時進行,較 PET/CT 能縮短時間并簡化步驟。

本次大會公布了聯合影像學和液體活檢技術用于聯合診斷的探索研究結果。因目前暫無有效的生物預測指標反映瑞戈非尼治療轉移性結直腸癌患者的預后,Woff等[55]將基線細胞游離DNA(cell free DNA,cfDNA)結合腫瘤代謝體積及體重指數用來預測瑞戈非尼治療轉移性結直腸癌患者的預后,并顯示了良好的預測效能。來自西班牙的研究團隊通過基因表達芯片技術在71例不同組織類型的轉移性腫瘤患者中進行測試,從13例患者中篩選出葡萄糖攝取環節關聯基因,結合SUV發現909個探針有意義,基于這909個探針的構建了PLS-3模型,并對比發現其能夠準確預測SUV[56]。

代謝分子在腫瘤發生發展中的作用和機制代謝通路及通路涉及的分子紛繁復雜。但正是由于對關鍵分子的不斷探索,二甲雙胍、他汀類等藥物才有機會在抗癌治療中得到實踐。Millis等[57]回顧分析1 781例前列腺癌患者全基因組數據發現延胡索酸脫氫酶基因變異率為3%,且大部分位于C末端結合區域,對進一步藥物研發有提示作用。復旦大學附屬腫瘤醫院的研究團隊報道了FOXC1通過在轉錄水平調控糖酵解通路中關鍵酶二磷酸果糖酶(fructose-bisphosphatase 1,FBP1)并形成反饋軸,增強了腫瘤Warburg效應,參與結直腸癌的惡性進展[58]。Trapp等[59]研究發現乳腺癌循環腫瘤細胞可能通過肝激酶B1(liver kinase B1,LKB1)的上調表達,對早期內滲階段代謝壓力進行反饋,從而促進轉移。因此,LKB1有望成為捕獲循環腫瘤細胞、防止轉移的新治療靶點。Hu等[60]基于先前發現Kras突變的雜合性缺失(loss of heterozygosity,LOH)和Redd1表達上調相關,對比基因工程小鼠來源的Kras突變和Kras-LOH胰腺癌細胞,發現Kras-LOH使得胰腺癌細胞嗜糖酵解并通過Redd1促進增殖和侵襲。

臨床營養方案和營養評估癌癥患者,特別是癌癥晚期患者,因疾病本身或相關治療易導致惡病質[61],故臨床實踐中有效的營養方案和恰當的評估很有必要。

Li等[62]公布的食管癌同期放化療患者行腸內營養的隨機對照臨床試驗結果顯示,對存在高營養不良風險的患者群體給予腸內營養能夠提升個體營養狀態,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素也能更好地維持體重,獲得更優的生存質量和治療耐受性[63]。992例Ⅲ期結腸癌患者的CALGB 89803研究證明,遵從ASCO腫瘤患者營養及運動指南的結腸癌患者能獲得更長的無疾病進展期和總體生存期[64]。該研究還得出另一個有趣的結論:更多堅果的食用可能和結腸癌患者更低的復發和死亡率有關[65]。除了有效的營養方案,恰當的評估也十分重要。Herrera等[66]將包含血清白蛋白水平和總淋巴細胞數的預測營養指數(prognostic nutrition index,PNI)用于91例胃癌術后患者的營養評估,結果發現PNI低于38.7的患者總體生存率更低(46個月vs.25個月,P=0.009)。這種評估方案同樣適合乳腺癌患者[67]。

結語腫瘤代謝和營養支持與目前的臨床實踐密切相關,且在實踐中可嘗試二甲雙胍、他汀類藥物及營養素攝入等干預手段。在靶向腫瘤代謝的基礎研究中,除mIDH抑制劑外的大多數藥物仍停留在Ⅰ或Ⅱ期臨床試驗階段。隨著新技術和算法的應用,基于腫瘤代謝的腫瘤顯像不斷取得進展。對于其他傳統或新興治療耐藥的患者,聯合靶向代謝治療初現優勢。

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