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

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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.