測(cè)試用以防止肺癌的藥物需要在成千上萬(wàn)的高危人群身上進(jìn)行試驗(yàn),，然后等待5、10或15年的時(shí)間才能發(fā)現(xiàn)這些受藥物處理的人是否會(huì)患上肺癌,，以評(píng)估哪些人可以從該治療中受益。現(xiàn)在,，科羅拉多大學(xué)癌癥中心的研究人員發(fā)現(xiàn)了一項(xiàng)新的研究結(jié)果,，他們提出了一個(gè)可能的新途徑，該方法可以極大地減少了測(cè)試肺癌預(yù)防藥物所需的患者數(shù)量和測(cè)試周期,。這篇文章發(fā)表在Cancer Prevention Research雜志上,。
CU癌癥中心的腫瘤學(xué)、醫(yī)學(xué)和病理學(xué)教授Fred R,。 Hirsch博士說(shuō)：“化學(xué)預(yù)防是一個(gè)重要的方法,，但是它的發(fā)展已經(jīng)遠(yuǎn)遠(yuǎn)落后于肺癌的發(fā)展。如果我們能找到一個(gè)肺癌死亡率的代理終點(diǎn)或一個(gè)中端,，就能讓研究人員更容易在更短的時(shí)間內(nèi)進(jìn)行較小的試驗(yàn),。”
這項(xiàng)研究的初衷是為了發(fā)現(xiàn)某些可以用來(lái)預(yù)測(cè)患者能否對(duì)潛在的化學(xué)預(yù)防藥物“Iloprost”發(fā)生反應(yīng)的microRNA，如果一種microRNA有特別高或低的表達(dá)水平,，能夠預(yù)測(cè)人們對(duì)預(yù)防性藥物的反應(yīng),，研究人員就能夠僅在這些受益人群中測(cè)試該藥物。不幸的是,，他們雖然發(fā)現(xiàn)有7種miRNAs的水平與肺癌的出現(xiàn)有關(guān),，但是沒(méi)有一種能夠預(yù)測(cè)患者對(duì)該藥物的反應(yīng)。
如果沒(méi)有microRNA-34c出現(xiàn)的話,，這很可能是一個(gè)沒(méi)有前途的研究,。
在藥物處理6個(gè)月后microRNA-34c表達(dá)水平的改變與該藥物效用之間的關(guān)系達(dá)到了驚人的程度。對(duì)于那些會(huì)因該藥物而受益的人來(lái)說(shuō),，藥物處理6個(gè)月后其體內(nèi)microRNA-34c的水平會(huì)下降,；對(duì)于那些對(duì)藥物不產(chǎn)生反應(yīng)的人來(lái)說(shuō)，microRNA-34c的水平則保持不變,。
“這樣,，不需要等到15年后,，在藥物處理6個(gè)月后我們就能潛在地發(fā)現(xiàn)該化學(xué)預(yù)防藥物的有效性。這將加速藥效檢測(cè)的步伐,，最終使新的化學(xué)預(yù)防藥物更快地進(jìn)入市場(chǎng),。”
Hirsch說(shuō)，這項(xiàng)發(fā)現(xiàn)是和來(lái)自CU癌癥中心的同事們一起獲得的,，但是它只是顯示出了microRNA-34c的一種潛力,，還需要更多的工作來(lái)驗(yàn)證其對(duì)化學(xué)預(yù)防反應(yīng)的這種預(yù)測(cè)能力。但是,，Hirsch和他的同事們都希望miRNA-34c不只是能作為一種預(yù)測(cè)性的手段，而在于用更尖端的技術(shù)來(lái)尋找它的下游靶基因,，通過(guò)對(duì)microRNA分子世界的理解來(lái)幫助它們尋找疾病的根源,。
Hirsch說(shuō)：“這種方法很新穎，因此需要進(jìn)行更多的探索,。”(生物谷Bioon.com)
doi: 10.1158/1940-6207.CAPR-12-0382
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Endobronchial miRNAs as biomarkers in lung cancer chemoprevention
Mascaux C, Feser WJ, Lewis MT, Baron AE, Coldren CD, Merrick DT, Kennedy TC, Eckelberger JI, Rozeboom LM, Franklin WA, Minna JD, Bunn PA Jr, Miller YE,Keith RL, Hirsch FR.
Lung cancers express lower levels of prostacyclin than normal lung tissues. Prostacyclin prevents lung cancer in a variety of mouse models. A randomized phase II trial comparing oral iloprost (a prostacyclin analogue) to placebo in high-risk subjects demonstrated improvement in bronchial histology in former, but not current, smokers. This placebo-controlled study offered the opportunity for investigation of other potential intermediate endpoint and predictive biomarkers to incorporate into chemoprevention trials. Matched bronchial biopsies were obtained at baseline (BL) and at 6 months follow-up (FU) from 125 high-risk individuals who completed the trial: 31/29 and 37/28 current/former smokers in the iloprost and placebo arm, respectively. We analyzed the expression of 14 selected miRNAs by qRT-PCR in 496 biopsies. The expression of seven miRNAs was significantly correlated with histology at BL. The expression of miR-34c was inversely correlated with histology at BL (p<0.0001) and with change in histology at FU (p=0.0003), independent of treatment or smoking status. Several miRNAs were also found to be differentially expressed in current smokers as compared with former smokers. In current smokers, miR-375 was up-regulated at BL (p<0.0001) and down-regulated after treatment with iloprost (p=0.0023). No miRNA at baseline reliably predicted a response to iloprost. No biomarker predictive of response to iloprost was found. MiR-34c was inversely correlated with BL histology and with histology changes. Mir-34c changes at FU could be used as a quantitative biomarker which parallels histologic response in formalin-fixed bronchial biopsies in future lung cancer chemoprevention studies.
