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. 2014 Aug;21(8):607-15.
doi: 10.1002/jhbp.107. Epub 2014 Apr 15.

Hedgehog Pathway as a Potential Treatment Target in Human Cholangiocarcinoma


Hedgehog Pathway as a Potential Treatment Target in Human Cholangiocarcinoma

Dorothee Riedlinger et al. J Hepatobiliary Pancreat Sci. .


Background: Innovative treatment concepts targeting essential signaling pathways may offer new chances for patients suffering from cholangiocarcinoma (CCC). For that, we performed a systematic molecular genetic analysis concerning the Hedgehog activity in human CCC samples and analyzed the effect of Hh inhibition on CCC cells in vitro and in vivo.

Methods: Activation of the Hh pathway was analyzed in 50 human CCC samples using quantitative polymerase chain reaction (qPCR). The efficacy of Hh inhibition using cyclopamine and BMS-833923 was evaluated in vitro. In addition, the effect of BMS-833923, alone or in combination with gemcitabine, was analyzed in vivo in a murine subcutaneous xenograft model.

Results: Expression analysis revealed a significant activation of the Hh-signaling pathway in nearly 50% of CCCs. Hh inhibition resulted in a significant decrease in cell proliferation of CCC cells. Moreover, a distinct inhibition of tumor growth could be seen as a result of a combined therapy with BMS-833923 and gemcitabine in CCC xenografts.

Conclusion: The results of our study suggest that the Hh pathway plays a relevant role at least in a subset of human CCC. Inhibition of this pathway may represent a possible treatment option for CCC patients in which the Hh pathway is activated.

Keywords: Cholangiocarcinoma; Gemcitabine; Hedgehog proteins; Molecular targeted therapy; Sonic Hedgehog inhibitor.

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