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Purpose: Sorafenib has proved survival benefit for patients with advanced hepatocellular carcinoma (HCC). This study explored whether the efficacy of sorafenib can be improved by adding the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor CI-1040 to vertically block the Raf/MEK/ERK pathway. Experimental Design: The growth inhibitory effects of sorafenib and CI-1040 were tested in HCC cell lines (Huh-7 and Hep3B) and human umbilical vascular endothelial cells (HUVEC). The potential synergistic growth inhibitory effects were measured by median effect analysis. Apoptosis was measured by flow cytometry. The effects on ERK phosphorylation and levels of apoptosis regulatory proteins were measured by Western blotting. The in vivo antitumor activity of sorafenib and CI-1040 were tested in xenograft HCC models. Results: Combination of sorafenib and CI-1040 synergistically inhibited ERK phosphorylation and cell growth and induced apoptosis in both HCC cells and HUVECs. Increased expression of Bim protein, which correlated with the extent of ERK inhibition, was found in both HCC cells and HUVECs. Knockdown of Bim expression by small interfering RNA partially abrogated the synergistic proapoptotic effects of sorafenib and CI-1040. Combination therapy inhibited tumor growth significantly better than either single agent in the xenograft models. Conclusion: The antitumor effects of sorafenib in HCC can be improved by vertical blockade of Raf/MEK/ERK signaling with CI-1040. (Clin Cancer Res 200915(18):5820-8) Molecular targeted therapy has emerged as a new treatment for advanced hepatocellular carcinoma (HCC; ref. 1). Sorafenib, an oral multitargeted kinase inhibitor targeting Raf kinase, vascular endothelial growth factor receptor-2 (VEGFR-2), VEGFR-3, and platelet-derived growth factor receptor (2), is approved for the treatment of advanced HCC because of its survival benefit shown in two randomized, placebo-controlled trials (3, 4). Sorafenib prolonged the overall survival of advanced HCC patients from 7.9 months to 10.7 months in the Western trial and from 4.2 to 6.5 months in the Asian trial.The success of the sorafenib trials represents a major breakthrough in the treatment of advanced HCC. However, several important issues remain unresolved. First, most patients who received sorafenib treatment had tumor progression within relatively short periods. The median time-to-tumor progression was 5.5 and 2.6 months in the Western and the Asian trials, respectively. Therefore, combination with other systemic therapy to improve the efficacy of sorafenib is needed. Second, the role of Raf kinase as the molecular target of sorafenib treatment remains controversial. Sorafenib can inhibit Raf-1 and both wild-type and mutant B-Raf kinase activity, but in preclinical models, the antitumor activity of sorafenib did not correlate completely with its inhibitory effect on extracellular Sorafenib can induce apoptosis of cancer cells through regulation of multiple proapoptotic and...

Objectives To assess the respective diagnostic value of Sonazoid™ and SonoVue® for characterizing FLLs as benign or malignant and the corresponding safety. Methods This prospective Phase 3 study was conducted at 17 centres in China and Korea (May 2014 to April 2015); 424 patients (20 to 80 years) with at least 1 untreated focal liver lesion (FLL) (< 10 cm in diameter) underwent a contrast-enhanced ultrasound (CEUS) examination (218 received Sonazoid of 0.12 μL microbubbles/kg; 206 received SonoVue of 2.4 mL). Three independent blinded readers evaluated pre- and post-contrast images characterising the FLLs as benign or malignant. Results Sonazoid-enhanced and SonoVue-enhanced ultrasound provided a statistically significant improvement in specificity for all 3 readers comparing to unenhanced ultrasound (for Sonazoid: p = 0.0093, < 0.0001, 0.0011; for SonoVue: p = 0.002, 0.03, 0.12, respectively). Difference in accuracy improvement between the 2 groups was within the pre-specified non-inferiority margin of 20% for all 3 readers (6.1%, 95% CI: − 5.0 to 17.2; − 7.5%, 95% CI: − 18.4 to 3.5; − 0.3%, 95% CI: − 11.3 to 10.7). The diagnostic confidence level for all 3 readers increased with post-contrast images relative to pre-contrast images. Both contrast agents were well tolerated. Conclusion Results showed a similar efficacy for Sonazoid™ and SonoVue® in diagnosing FLLs as benign or malignant, and underlined the benefit of CEUS imaging over unenhanced ultrasound imaging in reaching a confident diagnosis without having to refer patients for additional imaging exams.