測試用以防止肺癌的藥物需要在成千上萬的高危人群身上進行試驗,，然后等待5,、10或15年的時間才能發(fā)現這些受藥物處理的人是否會患上肺癌，以評估哪些人可以從該治療中受益?，F在,，科羅拉多大學癌癥中心的研究人員發(fā)現了一項新的研究結果，他們提出了一個可能的新途徑,，該方法可以極大地減少了測試肺癌預防藥物所需的患者數量和測試周期,。這篇文章發(fā)表在Cancer Prevention Research雜志上。
CU癌癥中心的腫瘤學,、醫(yī)學和病理學教授Fred R,。 Hirsch博士說：“化學預防是一個重要的方法，但是它的發(fā)展已經遠遠落后于肺癌的發(fā)展,。如果我們能找到一個肺癌死亡率的代理終點或一個中端,，就能讓研究人員更容易在更短的時間內進行較小的試驗。”
這項研究的初衷是為了發(fā)現某些可以用來預測患者能否對潛在的化學預防藥物“Iloprost”發(fā)生反應的microRNA,，如果一種microRNA有特別高或低的表達水平,，能夠預測人們對預防性藥物的反應,，研究人員就能夠僅在這些受益人群中測試該藥物,。不幸的是，他們雖然發(fā)現有7種miRNAs的水平與肺癌的出現有關,，但是沒有一種能夠預測患者對該藥物的反應,。
如果沒有microRNA-34c出現的話，這很可能是一個沒有前途的研究,。
在藥物處理6個月后microRNA-34c表達水平的改變與該藥物效用之間的關系達到了驚人的程度,。對于那些會因該藥物而受益的人來說，藥物處理6個月后其體內microRNA-34c的水平會下降,；對于那些對藥物不產生反應的人來說,，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個月后我們就能潛在地發(fā)現該化學預防藥物的有效性。這將加速藥效檢測的步伐,，最終使新的化學預防藥物更快地進入市場,。”
Hirsch說,，這項發(fā)現是和來自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驗證其對化學預防反應的這種預測能力,。但是，Hirsch和他的同事們都希望miRNA-34c不只是能作為一種預測性的手段,，而在于用更尖端的技術來尋找它的下游靶基因,，通過對microRNA分子世界的理解來幫助它們尋找疾病的根源。
Hirsch說：“這種方法很新穎,，因此需要進行更多的探索,。”(生物谷Bioon.com)
doi: 10.1158/1940-6207.CAPR-12-0382
PMC:
PMID:
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.
