测试用以防止肺癌的药物需要在成千上万的高危人群身上进行试验，然后等待5、10或15年的时间才能发现这些受药物处理的人是否会患上肺癌，以评估哪些人可以从该治疗中受益。现在，科罗拉多大学癌症中心的研究人员发现了一项新的研究结果，他们提出了一个可能的新途径，该方法可以极大地减少了测试肺癌预防药物所需的患者数量和测试周期。这篇文章发表在Cancer Prevention Research杂志上。
CU癌症中心的肿瘤学、医学和病理学教授Fred R。 Hirsch博士说：“化学预防是一个重要的方法，但是它的发展已经远远落后于肺癌的发展。如果我们能找到一个肺癌死亡率的代理终点或一个中端，就能让研究人员更容易在更短的时间内进行较小的试验。”
这项研究的初衷是为了发现某些可以用来预测患者能否对潜在的化学预防药物“Iloprost”发生反应的microRNA，如果一种microRNA有特别高或低的表达水平，能够预测人们对预防性药物的反应，研究人员就能够仅在这些受益人群中测试该药物。不幸的是，他们虽然发现有7种miRNAs的水平与肺癌的出现有关，但是没有一种能够预测患者对该药物的反应。
如果没有microRNA-34c出现的话，这很可能是一个没有前途的研究。
在药物处理6个月后microRNA-34c表达水平的改变与该药物效用之间的关系达到了惊人的程度。对于那些会因该药物而受益的人来说，药物处理6个月后其体内microRNA-34c的水平会下降；对于那些对药物不产生反应的人来说，microRNA-34c的水平则保持不变。
“这样，不需要等到15年后，在药物处理6个月后我们就能潜在地发现该化学预防药物的有效性。这将加速药效检测的步伐，最终使新的化学预防药物更快地进入市场。”
Hirsch说，这项发现是和来自CU癌症中心的同事们一起获得的，但是它只是显示出了microRNA-34c的一种潜力，还需要更多的工作来验证其对化学预防反应的这种预测能力。但是，Hirsch和他的同事们都希望miRNA-34c不只是能作为一种预测性的手段，而在于用更尖端的技术来寻找它的下游靶基因，通过对microRNA分子世界的理解来帮助它们寻找疾病的根源。
Hirsch说：“这种方法很新颖，因此需要进行更多的探索。”(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.
