ABT-869, a multi-targeted tyrosine kinase inhibitor, in combination with rapamycin is effective for subcutaneous hepatocellular carcinoma xenograft

Viraj J Jasinghe, Zhigang Xie, Jianbiao Zhou, Jiaying Khng, Lai-Fong Poon, Palaniyandi Senthilnathan, Keith B Glaser, Daniel H Albert, Steven K Davidsen, Chien-Shing Chen
Journal of Hepatology 2008, 49 (6): 985-97

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+/-20mm(3)), 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.

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