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Title: ABT-869, a multi-targeted tyrosine kinase inhibitor, in combination with rapamycin is effective for subcutaneous hepatocellular carcinoma xenograft
Authors: Jasinghe, V.J. 
Xie, Z. 
Zhou, J. 
Khng, J.
Poon, L.-F. 
Senthilnathan, P. 
Chen, C.-S. 
Albert, D.H.
Davidsen, S.K.
Keywords: ABT-869
Hepatocellular carcinoma
mTOR pathway
Tyrosine kinase inhibitor
Issue Date: 2008
Citation: Jasinghe, V.J., Xie, Z., Zhou, J., Khng, J., Poon, L.-F., Senthilnathan, P., Chen, C.-S., Albert, D.H., Davidsen, S.K. (2008). ABT-869, a multi-targeted tyrosine kinase inhibitor, in combination with rapamycin is effective for subcutaneous hepatocellular carcinoma xenograft. Journal of Hepatology 49 (6) : 985-997. ScholarBank@NUS Repository.
Abstract: Background/Aims: Receptor tyrosine kinase inhibitors (RTKIs) and mTOR inhibitors are potential novel anticancer therapies for HCC. We hypothesized that combination targeted on distinctive signal pathways would provide synergistic therapeutics. Methods: ABT-869, a novel RTKI, and rapamycin were investigated in HCC pre-clinical models. Results: Rapamycin, but not ABT-869, inhibited in vitro growth of Huh7 and SK-HEP-1 HCC cells in a dose dependant manner. However, in subcutaneous Huh7 and SK-HEP-1 xenograft models, either ABT-869 or rapamycin can significantly reduce tumor burden. Combination treatment reduced the tumors to the lowest volume (95 ± 20 mm3), and was significantly better than single agent treatment (p < 0.05). Immunohistochemical staining of tumor shows that ABT-869 potently inhibits VEGF in HCC in vivo. In addition, the MAPK signaling pathway has been inhibited by significant inhibition of phosphorylation of p44/42 MAP kinase by ABT-869 in vivo. Rapamycin inhibits phosphorylation of p70 S6 kinase and 4E-BP-1, downstream targets of mTOR, and decreases VEGF. Combination treatment showed synergistic effect on expression levels of p27 in vivo. Dramatic inhibition of neo-angiogenesis by ABT-869 was also demonstrated. Conclusions: HCC could potentially be treated with the combination treatment of ABT-869 and rapamycin. Clinical trials on combination therapy are warranted. © 2008 European Association for the Study of the Liver.
Source Title: Journal of Hepatology
ISSN: 01688278
DOI: 10.1016/j.jhep.2008.08.010
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