Background and Aims: Considerable evidence suggests that TGF-? triggers tumor progression in hepatocellulyr carcinoma (HCC) by modulating the tissue microenvironment. For this reason, a phase II clinical trial with a selective inhibitor of the TGF-? kinase-(K)I receptor is currently ongoing in patients with advanced HCC. Galunisertib has been shown to be effective in different in vitro experimental models but so far no data are available in a mouse model. Aim of this study is to investigate the effectiveness of galunisertib on the tissue microenvironment in in vivo models. Methods: We established an orthotopic model of HCC in NOD/SCID mice, whereby HepG2 cells directly implanted into the liver were treated with galunisertib administered by gavage or delivered in nano-micelles intravenously, two weeks after evidence of tumor implantation. In particular, 1 × 106/40 ?L HepG2-Luc cells were orthotopically injected into the liver of NSG female mice; 16 days after tumor cells injection, mice were randomly assigned to three groups each of 15 mice : vehicle (Group 1), vs Group 2 and Group 3 treated with LY215799 (150 mg/Kg p.o. and 1.5 mg/Kg i.v. respectively). Weekly tumor growth observations were carried out with the IVIS Spectrum (PerkinElmer), after intraperitoneal administration of D-Luciferin (Sigma, 150 mg/10 mL/kg). Results: Galunisertib did not affect tumor growth in the groups receiving the drug orally or intravenously, compared to controls. However, a statistically significant reduction ( p = 0.003) was observed between the LY215799-treated groups and the control group in terms of cancer dissemination. TGF-?1, TGF-?RI and TGF- ?RII, investigated by means of qRT-PCR, were significantly ( p < 0.001) down-regulated in animals treated both with orally or nanocarrier- delivered Galunisertib, compared to controls. Conclusions: This study is the first proof-of-concept demonstrating that targeting the TGF-? pathway with Galunisertib is effective in reducing HCC progression in in vivo preclinical models, thus providing the rationale for future clinical trials.
A TGF-B RECEPTOR I KINASE INHIBITOR, GALUNISERTIB (LY2157299) INHIBITS HEPATOCELLULAR CARCINOMA PROGRESSION IN IN VIVO EXPERIMENTAL MODELS
Hanafy N;Leporatti S;
2016
Abstract
Background and Aims: Considerable evidence suggests that TGF-? triggers tumor progression in hepatocellulyr carcinoma (HCC) by modulating the tissue microenvironment. For this reason, a phase II clinical trial with a selective inhibitor of the TGF-? kinase-(K)I receptor is currently ongoing in patients with advanced HCC. Galunisertib has been shown to be effective in different in vitro experimental models but so far no data are available in a mouse model. Aim of this study is to investigate the effectiveness of galunisertib on the tissue microenvironment in in vivo models. Methods: We established an orthotopic model of HCC in NOD/SCID mice, whereby HepG2 cells directly implanted into the liver were treated with galunisertib administered by gavage or delivered in nano-micelles intravenously, two weeks after evidence of tumor implantation. In particular, 1 × 106/40 ?L HepG2-Luc cells were orthotopically injected into the liver of NSG female mice; 16 days after tumor cells injection, mice were randomly assigned to three groups each of 15 mice : vehicle (Group 1), vs Group 2 and Group 3 treated with LY215799 (150 mg/Kg p.o. and 1.5 mg/Kg i.v. respectively). Weekly tumor growth observations were carried out with the IVIS Spectrum (PerkinElmer), after intraperitoneal administration of D-Luciferin (Sigma, 150 mg/10 mL/kg). Results: Galunisertib did not affect tumor growth in the groups receiving the drug orally or intravenously, compared to controls. However, a statistically significant reduction ( p = 0.003) was observed between the LY215799-treated groups and the control group in terms of cancer dissemination. TGF-?1, TGF-?RI and TGF- ?RII, investigated by means of qRT-PCR, were significantly ( p < 0.001) down-regulated in animals treated both with orally or nanocarrier- delivered Galunisertib, compared to controls. Conclusions: This study is the first proof-of-concept demonstrating that targeting the TGF-? pathway with Galunisertib is effective in reducing HCC progression in in vivo preclinical models, thus providing the rationale for future clinical trials.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
