|
Sub-category:
Translational research
Category:
Pancreas, Small Bowel, and Hepatobiliary Tract
Meeting:
2009 Gastrointestinal Cancers Symposium
Session Type and Session Title:
General Poster Session C
Abstract No:
140
Author(s):
B. Blechacz, R. Smoot, S. Bronk, N. Werneburg, A. E. Sirica, G. J. Gores
Abstract:
Introduction and Aims: Cholangiocarcinoma (CCA) is a devastating neoplasm with no proven medical therapy. Sorafenib, a multikinase inhibitor (known to inhibit b-Raf, VEGF, c-Kit and PDGFR), is FDA approved for the treatment of hepatocellular carcinoma. However, the potential efficacy of this agent for treating cholangiocarcinoma is unknown. Our aims were to evaluate Sorafenib for treatment of CCA, a malignancy driven by JAK/STAT signaling pathways. Methods: Morphologic quantification of apoptosis was evaluated in human cholangiocarcinoma cell lines HuCCT-1 and KMCH-1 by DAPI-staining and fluorescence microscopy. STAT3-phosporylation and nuclear translocation were evaluated by immunoblot analysis and immunofluorescence studies, respectively. For in vivo efficacy analysis, the recently described syngeneic rat model with BDEneu cells was employed (Sirica AE et al. Hepatology 2008; 47: 1178-1190). Results: STAT3, a transcription factor, is constitutively phosphorylated (activated) in HuCCT-1 cells. Sorafenib (10 µM) completely abrogates STAT3 phosphorylation without altering total cellular STAT3 levels. Mcl-1, a potent antiapoptotic member of the Bcl-2 family, is a direct transcriptional target of STAT3. Consistent with its inhibition of STAT3 activity, Sorafenib treatment reduced cellular levels of Mcl-1. Furthermore, Sorafenib mediated Mcl-1 downregulation sensitized TRAIL-resistant CCA cells to TRAIL-induced apoptosis. Finally, we employed an in vivo model where BDEneu cells are orthotopically injected into a bile duct ligated segment of a syngeneic Fisher rat. Seven days later, the animals were treated with vehicle or drug. Sorafenib treatment (30 mg/kg daily, i.p. × 7 days) was associated with a significant tumor suppressive effect in the BDEneu rat CCA model, reduction in liverweight/bodyweight ratio of 0.06 to 0.04 (p <0.05) in untreated vs. treated animals, respectively. Complete tumor regression was achieved in 22.2% of animals vs. 0% in untreated rats. Conclusions: In cholangiocarcinoma cells, Sorafenib interferes with the STAT3 signaling pathway, reduces cellular expression of Mcl-1, and sensitizes cells to TRAIL-mediated apoptosis. Sorafenib maybe useful for treating human cholangiocarcinoma.
Faculty Disclosures
Abstract Disclosures
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy
and are designated with a caret symbol (^) here and in the print version.
 Associated Presentation(s):
Other Abstracts in this Sub-Category:
Abstracts by B. Blechacz:
Presentations by B. Blechacz:
Educational Book Manuscripts by B. Blechacz:
|
