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Updated: Jan 29, 2026
Murine Bioluminescent Hepatic Tumour Model
Published on: July 17, 2010
Brivanib in combination with Notch3 silencing shows potent activity in tumour models
Catia Giovannini1,2, Anna Maria Salzano3, Michele Baglioni4
1Center for Applied Biomedical Research (CRBA), S.Orsola-Malpighi University Hospital, Bologna, Italy. catia.giovannini4@unibo.it.
Background:
Sorafenib is the first targeted agent proven to improve survival of patients with advanced hepatocellular carcinoma (HCC) and it has been used in first line treatments with heterogeneous response across patients. Most of the promising agents evaluated in first-line or second-line phase III trials for HCC failed to improve patient survival. The absence of molecular characterisation, including the identification of pathways driving resistance might be responsible for these disappointing results.
Methods:
2D DIGE and MS analyses were used to reveal proteomic signatures resulting from Notch3 inhibition in HepG2 cells, combined with brivanib treatment. The therapeutic potential of Notch3 inhibition combined with brivanib treatment was also demonstrated in a rat model of HCC and in cell lines derived from different human cancers.
Results:
Using a proteomic approach, we have shown that Notch3 is strongly involved in brivanib resistance through a p53-dependent regulation of enzymes of the tricarboxylic acid (TCA), both in vitro and in vivo.
Conclusion:
We have demonstrated that regulation of the TCA cycle is a common mechanism in different human cancers, suggesting that Notch3 inhibitors combined with brivanib treatment may represent a strong formulation for the treatment of HCC as well as Notch3-driven cancers.
Insights
Notch3 inhibition combined with brivanib shows promise for treating hepatocellular carcinoma (HCC) by targeting the tricarboxylic acid (TCA) cycle, offering a new therapeutic strategy for resistant cancers.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Sorafenib, a targeted therapy, offers limited survival benefits for advanced hepatocellular carcinoma (HCC) due to heterogeneous patient responses and resistance.
- Many promising agents for HCC have failed in clinical trials, highlighting the need for molecular characterization to understand resistance mechanisms.
Purpose of the Study:
- To investigate the role of Notch3 in brivanib resistance in hepatocellular carcinoma (HCC).
- To explore the therapeutic potential of combining Notch3 inhibition with brivanib treatment in various cancers.
Main Methods:
- Proteomic analysis using 2D Difference Gel Electrophoresis (2D DIGE) and Mass Spectrometry (MS) to identify proteomic signatures.
- In vitro studies using HepG2 cells and cell lines from various human cancers.
- In vivo studies using a rat model of HCC.
Main Results:
- Notch3 inhibition, in combination with brivanib, demonstrated therapeutic potential in HCC and other cancers.
- A proteomic approach revealed Notch3's significant role in brivanib resistance via p53-dependent regulation of tricarboxylic acid (TCA) cycle enzymes.
- This mechanism was confirmed both in vitro and in vivo.
Conclusions:
- Tricarboxylic acid (TCA) cycle regulation is a conserved mechanism across different human cancers.
- Combining Notch3 inhibitors with brivanib presents a potential therapeutic strategy for HCC and other Notch3-driven cancers.
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