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Updated: Jul 5, 2026
Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
RAD001 (everolimus) inhibits tumour growth in xenograft models of human hepatocellular carcinoma
Hung Huynh1, K H Pierce Chow, Khee Chee Soo
1Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore. cmrhth@nccs.com.sg
Abstract:
Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and highly resistant to available chemotherapies. Mammalian target of rapamycin (mTOR) functions to regulate protein translation, angiogenesis and cell cycle progression in many cancers including HCC. In the present study, subcutaneous patient-derived HCC xenografts were used to study the effects of an mTOR inhibitor, RAD001 (everolimus), on tumour growth, apoptosis and angiogenesis. We report that oral administration of RAD001 to mice bearing patient-derived HCC xenografts resulted in a dose-dependent inhibition of tumour growth. RAD001-induced growth suppression was associated with inactivation of downstream targets of mTOR, reduction in VEGF expression and microvessel density, inhibition of cell proliferation, up-regulation of p27(Kip1) and down-regulation of p21(Cip1/Waf1), Cdk-6, Cdk-2, Cdk-4, cdc-25C, cyclin B1 and c-Myc. Our data indicate that the mTOR pathway plays an important role in angiogenesis, cell cycle progression and proliferation of liver cancer cells. Our study provides a strong rationale for clinical investigation of mTOR inhibitor RAD001 in patients with HCC.
Insights
RAD001, an mTOR inhibitor, effectively reduced hepatocellular carcinoma (HCC) tumor growth in patient-derived xenografts. This mTOR inhibition suppressed tumor cell proliferation and angiogenesis, supporting its clinical investigation for liver cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Hepatocellular carcinoma (HCC) is a prevalent and treatment-resistant cancer.
- The mammalian target of rapamycin (mTOR) pathway is crucial for cancer cell growth, proliferation, and angiogenesis.
Purpose of the Study:
- To investigate the efficacy of the mTOR inhibitor RAD001 (everolimus) in patient-derived HCC xenografts.
- To elucidate the molecular mechanisms underlying RAD001's anti-tumor effects in liver cancer.
Main Methods:
- Administration of RAD001 to mice bearing subcutaneous patient-derived HCC xenografts.
- Assessment of tumor growth, apoptosis, and angiogenesis.
- Analysis of downstream mTOR signaling pathway components, cell cycle regulators, and proliferation markers.
Main Results:
- RAD001 demonstrated dose-dependent inhibition of HCC tumor growth.
- Tumor growth suppression correlated with mTOR pathway inactivation, reduced VEGF, and decreased microvessel density.
- RAD001 treatment led to reduced cell proliferation and altered expression of key cell cycle regulators (p27Kip1, p21Cip1/Waf1, Cdks, cdc-25C, cyclin B1) and c-Myc.
Conclusions:
- The mTOR pathway is integral to HCC angiogenesis, cell cycle progression, and proliferation.
- RAD001 effectively targets the mTOR pathway, inhibiting tumor growth and angiogenesis in HCC.
- These findings provide a strong rationale for the clinical evaluation of RAD001 in HCC patients.
