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Intrahepatic cholangiocarcinoma (ICC) is the second most common liver cancer. Conventional chemotherapy and radiotherapy have only a marginal impact on the natural history with a median survival of 12 months. Encouraging results obtained on ICC cell lines prompted us to evaluate the antitumor activity and mechanism of action of ET-743 on an ICC patient-derived xenograft (PDX) model, currently representing an innovative tool to personalize cancer therapy. The antitumor activity of ET-743 was tested on a cohort of mice carrying an ICC PDX. At the achievement of about 150 mm3 of volume, mice were randomized in two arms (n=7) of therapy in three independent experiments: 150 mg/Kg/weekly i.v. of ET-743 or drug vehicle for three administrations. Tumors were monitored weekly. Mean volumes of treated and untreated xenografts were compared by two-way Anova, considering a p-value ET-743 slowed tumor growth of PDX-treated compared to PDX-untreated mice in a statistically significant manner (p=0.04). Interestingly, we found a decrease in the number of proliferating cells (p=0.05) and a significant decrease in the number of new vessel formation (p=0.007). Upon ET-743 treatment, 1346 differentially expressed probes were found: 628 down-regulated and 718 up-regulated in ET-743 treated vs control PDX mice. Gene Ontology analysis revealed that the most significant deregulated processes were biological and cell adhesion, tissue development and inflammatory/immune response. Among the 20 most down-regulated genes, we found TFF3, MUC5B, MUC6A, WISP1, previously associated with cholangiocarcinoma. miRNA profiling revealed a deregulation of 6 miRNAs, 3 up-regulated and 3 down-regulated. Using the Mirpath program, we found that the down-regulated miRNAs affect important cancer related pathways (p53, Akt-PI3K, MAPK pathways) in a statistically significant way. In conclusion, ET-743 is able to control tumor growth, inhibiting proliferation and neoangiogenesis; moreover ET-743 perturbs gene and miRNA profiling affecting important cancer related pathways. Taken together these data are a strong rational for the design of a clinical trial to evaluate the activity of ET-743 in ICC patients. Citation Format: Caterina Peraldo Neia, Giuliana Cavalloni, Giovanna Chiorino, Paola Ostano, Massimo Aglietta, Francesco Leone. Antitumor activity, gene and miRNA modulation upon ET-743 treatment in an intrahepatic cholangiocarcinoma patient-derived xenograft model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5551. doi:10.1158/1538-7445.AM2014-5551