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MicroRNAs As Modifiers Of Drug Resistance In Esophageal Cancer: Impact of Modulation Of Resistance-Relevant MicroRNAs And Their Direct Targets On Chemotherapy

MicroRNA 作为食管癌耐药性的修饰剂：耐药相关 MicroRNA 及其直接靶标的调节对化疗的影响

基本信息

批准号：
234635071
负责人：
Privatdozent Dr. Richard Hummel
金额：
--
依托单位：
Department of Surgery
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2013
资助国家：
德国
起止时间：
2012-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/234635071?language=en
关键词：
MicroRNAs Modifiers Drug Resistance Esophageal

项目摘要

The dismal overall outcome of esophageal cancer patients and the variable response to chemo- or radiochemotherapy highlights the urgent need for new molecular biomarkers for diagnostic response prediction and, even more important, for effective therapeutic targets to overcome potential drug resistance. MicroRNAs are very promising candidates in this context, and we could previously generate a database of microRNAs (including potential targets) which inform about response prediction and control of chemotherapy in esophageal adenocarcinoma and squamous cell carcinoma in-vitro and in-vivo. Furthermore, we provided first evidence, that modification of microRNAs (namely miR-148a) affects response to anticancer treatment in both cancer subtypes, and that microRNA signatures in human biopsies indeed correlate with response to anticancer treatment. With this current proposal, we now aim to continue this work by assessing whether or not a selection of 9 microRNAs from the above mentioned database (i.e. let-7e, miR-27b, miR-130a, miR-125a-5p, miR-148a, miR-181b, miR-200b, miR-222, miR-1226) actually affect cellular sensitivity to chemotherapy to cisplatin and 5-FU (the two most commonly used chemotherapeutic drugs in the treatment of this disease) in esophageal adenocarcinoma and squamous cell carcinoma, and whether these 9 microRNAs are epigenetically regulated via DNA methylation. In addition, we aim to investigate if these 9 microRNAs directly target genes such as KRAS, CYP3A4, MAP4K4 and others impacting thereby on relevant genetic pathways that are involved in drug resistance. Finally, we aim to extend and finalize the initiated clinical multicentre trial on biopsy-derived microRNAs as predictors of response to anticancer treatment in clinical settings.

食管癌患者的总体结局令人沮丧，对化疗或放化疗的反应多变，这突出表明迫切需要新的分子生物标志物用于诊断反应预测，更重要的是，需要有效的治疗靶点来克服潜在的耐药性。在这种情况下，microRNA是非常有前途的候选者，我们可以预先生成一个microRNA数据库（包括潜在的靶标），这些数据库可以在体外和体内提供有关食管腺癌和鳞状细胞癌化疗反应预测和控制的信息。此外，我们提供了第一个证据，即microRNA（即miR-148 a）的修饰影响两种癌症亚型对抗癌治疗的反应，并且人类活检中的microRNA特征确实与抗癌治疗的反应相关。根据目前的建议，我们现在的目标是通过评估是否从上述数据库中选择9种microRNA来继续这项工作。（即let-7e、miR-27b、miR-130a、miR-125a-5p、miR-148a、miR-181b、miR-200b、miR-222、miR-1226）实际上影响细胞对顺铂和5-FU化疗的敏感性（治疗这种疾病最常用的两种化疗药物）在食管腺癌和鳞状细胞癌中，以及这9种microRNA是否通过DNA甲基化进行表观遗传调控。此外，我们的目标是研究这9种microRNA是否直接靶向KRAS、CYP 3A 4、MAP 4K 4等基因，从而影响与耐药性相关的遗传途径。最后，我们的目标是扩展和完成启动的临床多中心试验，活检衍生的microRNA作为临床环境中抗癌治疗反应的预测因子。