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Expert Opinion on Investigational Drugs Apr 2011Angiogenesis inhibition represents a rational therapeutic strategy in the management of solid tumors. Brivanib is a dual tyrosine kinase inhibitor with selectivity... (Review)
Review
INTRODUCTION
Angiogenesis inhibition represents a rational therapeutic strategy in the management of solid tumors. Brivanib is a dual tyrosine kinase inhibitor with selectivity against VEFGR-2 and FGFR.
AREAS COVERED
This review provides an updated summary of preclinical and clinical experience with brivanib in cancer. Data presented in abstract form from international conferences or journal articles found with a PubMed search of published literature up to December 2010 are described in this review.
EXPERT OPINION
Brivanib appears tolerable and exhibits favorable pharmacokinetic and pharmacodynamic profiles with evidence of target inhibition in surrogate tissues. Clinical and pharmacodynamic data support an oral once daily administration at 800 mg. Brivanib shows promising activity as single agent in hepatocellular carcinoma and in combination with cetuximab in colorectal cancer. Further evaluations with cytotoxic chemotherapy and in other solid tumors are currently ongoing.
Topics: Alanine; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Clinical Trials as Topic; Drug Screening Assays, Antitumor; Humans; Neoplasms; Pyrroles; Receptor, Fibroblast Growth Factor, Type 1; Triazines; Vascular Endothelial Growth Factor Receptor-2
PubMed: 21391890
DOI: 10.1517/13543784.2011.565329 -
Pharmacological Research Aug 2021Dengue virus (DENV) is the most prevalent arthropod-borne viral disease of humans and has a major impact on global public health. There is no clinically approved drugs...
Dengue virus (DENV) is the most prevalent arthropod-borne viral disease of humans and has a major impact on global public health. There is no clinically approved drugs for DENV infection. Since intracellular VEGFR2 is increased in DENV infected patients, we thus hypothesized that VEGFR2 participated DENV proliferation and its inhibitors could be served as antivirals against DENV. Actually our results showed that VEGFR2 was induced by DENV infection. Also the agonist of VEGFR2, VEGF-A, promoted DENV proliferation. Therefore, we screened the inhibitors of VEGFR2 and found that brivanib alaninate (brivanib) showed the best anti-DENV ability with the lowest cellular cytotoxicity. Mechanically, our results indicated VEGFR2 directly interacted with PTP1B to dephosphorylate AMPK to provide lipid environment for viral replication. However, this effect could be inhibited by brivanib, which significantly reversed the reduction of AMPK phosphorylation caused by DENV infection, thus improving the cellular lipid environment. Moreover, the antiviral effect of brivanib could be reversed by AMPK inhibitor, Compound C. In addition, oral administration of brivianib (20-50 mg/kg/day) clearly improved the survival rate of DENV2 infection, and this effect was abolished in accompanied with Compound C (10mg/kg/day). Collectively, our study disclosed the mechanism of VEGFR2 in DENV2 and evaluated the antiviral ability of brivanib, which deserved more attention for clinical usage in DENV infection.
Topics: AMP-Activated Protein Kinases; Alanine; Animals; Antiviral Agents; Cells, Cultured; Dengue; Dengue Virus; Disease Models, Animal; Endothelial Cells; Host-Pathogen Interactions; Humans; Mice; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Signal Transduction; Triazines; Vascular Endothelial Growth Factor Receptor-2; Virus Replication
PubMed: 34116207
DOI: 10.1016/j.phrs.2021.105721 -
Journal of Cellular Physiology Feb 2020In age-related macular degeneration (AMD), choroidal neovascularization (CNV), a major pathologic feature of neovascular AMD (nAMD), affects 10% of patients, potentially...
In age-related macular degeneration (AMD), choroidal neovascularization (CNV), a major pathologic feature of neovascular AMD (nAMD), affects 10% of patients, potentially causing serious complications, including vision loss. Vascular endothelial growth factor receptor 2 (VEGFR2) and fibroblast growth factor receptor 1 (FGFR1) contribute to the pathogenesis of CNV. Brivanib is an oral selective dual receptor tyrosine kinase (RTK) inhibitor of FGFRs and VEGFRs, especially VEGFR2 and FGFR1. In this study, brivanib inhibited zebrafish embryonic angiogenesis without impairing neurodevelopment. In a mouse CNV model, brivanib intravitreal injection blocked phosphorylation of FGFR1 and VEGFR2 and reduced CNV leakage, area, and formation without causing intraocular toxicity. Moreover, brivanib oral gavage reduced CNV leakage and area. Accordingly, brivanib remained at high concentrations (above 14,000 ng/ml) in retinal/choroidal/scleral tissues following intravitreal injection. Similarly, brivanib remained at high concentrations (over 10,000 ng/ml) in retinal/choroidal/scleral tissues following oral gavage. Finally, in vitro cell experiments demonstrated that brivanib inhibited the proliferation, migration and tube formation of microvascular endothelial cells. In conclusion, our study suggested that brivanib treatment could be a novel therapeutic strategy for nAMD.
Topics: Alanine; Angiogenesis Inhibitors; Animals; Cell Movement; Cell Proliferation; Choroidal Neovascularization; Disease Models, Animal; Endothelial Cells; Lasers; Male; Mice; Mice, Inbred C57BL; Protein Kinase Inhibitors; Triazines; Wet Macular Degeneration; Zebrafish
PubMed: 31270802
DOI: 10.1002/jcp.29041 -
Future Oncology (London, England) Sep 2012The development of new agents in oncology has focused on disrupting key pathways in oncogenesis. Both malignant angiogenesis and peptide growth factor signaling have... (Review)
Review
The development of new agents in oncology has focused on disrupting key pathways in oncogenesis. Both malignant angiogenesis and peptide growth factor signaling have been studied extensively and have been validated for cancer treatment. While antibody-directed therapeutics offer increased specificity, small-molecule tyrosine kinase inhibitors often have the ability to hit multiple targets. Brivanib alaninate (BMS582664) is an oral, potent selective inhibitor of both the FGF and VEGF family of receptors. It is a first-in-class FGF/VEGF inhibitor now in late-phase clinical trials. Besides its antiangiogenic activity from blocking VEGF receptor 1-3, its ability to disrupt FGF receptors 1-3 has been suggested to add additional antiangiogenic activity, overcome resistance from VEGF blockade, and block FGF-dependent tumor proliferation. In this review, we will discuss the preclinical science driving brivanib's development and the clinical data generated to date.
Topics: Alanine; Angiogenesis Inhibitors; Animals; Clinical Trials as Topic; Drug Screening Assays, Antitumor; Humans; Neoplasms; Treatment Outcome; Triazines
PubMed: 23030483
DOI: 10.2217/fon.12.104 -
Molecular Pharmaceutics Nov 2019Brivanib, a promising tyrosine kinase inhibitor, is currently undergoing advanced stages of clinical evaluation for solid tumor therapy. In this work, we investigated...
Brivanib Exhibits Potential for Pharmacokinetic Drug-Drug Interactions and the Modulation of Multidrug Resistance through the Inhibition of Human ABCG2 Drug Efflux Transporter and CYP450 Biotransformation Enzymes.
Brivanib, a promising tyrosine kinase inhibitor, is currently undergoing advanced stages of clinical evaluation for solid tumor therapy. In this work, we investigated possible interactions of this novel drug candidate with ABC drug efflux transporters and cytochrome P450 (CYP450) drug-metabolizing enzymes that participate in cancer multidrug resistance (MDR) and pharmacokinetic drug-drug interactions (DDIs). First, in accumulation experiments with various model substrates, we identified brivanib as an inhibitor of the ABCB1, ABCG2, and ABCC1 transporters. However, in subsequent combination studies employing 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-tetrazolium bromide proliferation assays in both Madin-Darby canine kidney II (MDCKII) and A431 cellular models, only ABCG2 inhibition was revealed to be able to synergistically potentiate mitoxantrone effects. Advantageous to its possible use as MDR antagonist, brivanib's chemosensitizing properties were not impaired by activity of any of the MDR-associated ABC transporters, as observed in comparative viability assay in the MDCKII cell sublines. In incubation experiments with eight recombinant CYP450s, we found that brivanib potently inhibited CYP2C subfamily members and the CYP2B6 isoform. Finally, in induction studies, we demonstrated that brivanib upregulated and messenger RNA levels in systemic cell models, although this interaction was not significantly manifested at a functional level. In conclusion, brivanib exhibits potential to cause clinically relevant pharmacokinetic DDIs and act as a modulator of ABCG2-mediated MDR. Our findings might be used as an important background for subsequent in vivo investigations and pave the way for the safe and effective use of brivanib in oncological patients.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; Alanine; Animals; Biotransformation; Cell Line; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dogs; Drug Interactions; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Madin Darby Canine Kidney Cells; Neoplasm Proteins; Triazines
PubMed: 31633365
DOI: 10.1021/acs.molpharmaceut.9b00361 -
Anticancer Research Nov 2010The process of neo-vascularisation from pre-existing blood vessels (angiogenesis) plays a critical role in both tumour growth and dissemination in multiple cancer types.... (Review)
Review
The process of neo-vascularisation from pre-existing blood vessels (angiogenesis) plays a critical role in both tumour growth and dissemination in multiple cancer types. Tumour angiogenesis is an attractive target for cancer treatment, and the VEGF/VEGF-R and FGF/FGF-R systems have been identified as key factors for neo-angiogenesis. Several active compounds have been developed so far and some of them are already widely used in clinical protocols. However, currently, only very few drugs have been shown to act synergistically with VEGF. Brivanib (BMS-582664) is a novel, orally available and selective receptor tyrosine kinase inhibitor that targets the key angiogenesis receptors VEGF-R2 and FGF-R1 and -2. The drug is currently under clinical evaluation and published data as well as data on biomarker studies with brivanib are reviewed and discussed.
Topics: Alanine; Clinical Trials as Topic; Humans; Neoplasms; Pyrroles; Receptor, Fibroblast Growth Factor, Type 1; Triazines; Vascular Endothelial Growth Factor Receptor-2
PubMed: 21115896
DOI: No ID Found -
British Journal of Cancer Mar 2019Sorafenib 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...
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.
Topics: Alanine; Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Drug Resistance, Neoplasm; Electrophoresis, Polyacrylamide Gel; Gene Knockdown Techniques; Hep G2 Cells; Humans; Liver Neoplasms; Liver Neoplasms, Experimental; MCF-7 Cells; Molecular Targeted Therapy; Proteomics; RNA, Small Interfering; Rats; Rats, Wistar; Receptor, Notch3; Triazines; Two-Dimensional Difference Gel Electrophoresis
PubMed: 30765875
DOI: 10.1038/s41416-018-0375-4 -
Journal of Clinical Oncology : Official... Oct 2013
Topics: Alanine; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Drug Resistance, Neoplasm; Female; Humans; Liver Neoplasms; Male; Niacinamide; Palliative Care; Phenylurea Compounds; Protein Kinase Inhibitors; Salvage Therapy; Sorafenib; Triazines
PubMed: 23980088
DOI: 10.1200/JCO.2013.49.7941 -
European Journal of Cancer (Oxford,... Oct 2019Brivanib is a selective inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signalling. We performed a phase II randomised discontinuation... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Brivanib is a selective inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signalling. We performed a phase II randomised discontinuation trial of brivanib in 7 tumour types (soft-tissue sarcomas [STS], ovarian cancer, breast cancer, pancreatic cancer, non-small-cell lung cancer [NSCLC], gastric/esophageal cancer and transitional cell carcinoma [TCC]).
PATIENTS AND METHODS
During a 12-week open-label lead-in period, patients received brivanib 800 mg daily and were evaluated for FGF2 status by immunohistochemistry. Patients with stable disease at week 12 were randomised to brivanib or placebo. A study steering committee evaluated week 12 response to determine if enrolment in a tumour type would continue. The primary objective was progression-free survival (PFS) for brivanib versus placebo in patients with FGF2-positive tumours.
RESULTS
A total of 595 patients were treated, and stable disease was observed at the week 12 randomisation point in all tumour types. Closure decisions were made for breast cancer, pancreatic cancer, NSCLC, gastric cancer and TCC. Criteria for expansion were met for STS and ovarian cancer. In 53 randomised patients with STS and FGF2-positive tumours, the median PFS was 2.8 months for brivanib and 1.4 months for placebo (hazard ratio [HR]: 0.58, p = 0.08). For all randomised patients with sarcomas, the median PFS was 2.8 months (95% confidence interval [CI]: 1.4-4.0) for those treated with brivanib compared with 1.4 months (95% CI: 1.3-1.6) for placebo (HR = 0.64, 95% CI: 0.38-1.07; p = 0.09). In the 36 randomised patients with ovarian cancer and FGF2-positive tumours, the median PFS was 4.0 (95% CI: 2.6-4.2) months for brivanib and 2.0 months (95% CI: 1.2-2.7) for placebo (HR: 0.56, 95% CI: 0.26-1.22). For all randomised patients with ovarian cancer, the median PFS in those randomised to brivanib was 4.0 months (95% CI: 2.6-4.2) and was 2.0 months (95% CI: 1.2-2.7) in those randomised to placebo (HR = 0.54, 95% CI: 0.25-1.17; p = 0.11).
CONCLUSION
Brivanib demonstrated activity in STS and ovarian cancer with an acceptable safety profile. FGF2 expression, as defined in the protocol, is not a predictive biomarker of the efficacy of brivanib.
Topics: Aged; Alanine; Antineoplastic Agents; Biomarkers, Tumor; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasms; Prognosis; Survival Rate; Triazines; Withholding Treatment
PubMed: 31522033
DOI: 10.1016/j.ejca.2019.07.024 -
PloS One 2014Brivanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR) tyrosine kinases, which are both...
BACKGROUND AND AIMS
Brivanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR) tyrosine kinases, which are both involved in mechanisms of liver fibrosis. We hypothesized that inhibition of VEGFR and FGFR by brivanib would inhibit liver fibrosis. We therefore examined the effect of brivanib on liver fibrosis in three mouse models of fibrosis.
METHODS
In vivo, we induced liver fibrosis by bile duct ligation (BDL), chronic carbon tetrachloride (CCl4), and chronic thioacetamide (TAA) administration. Liver fibrosis was examined by immunohistochemistry and Western immunoblotting. In vitro, we used LX-2 human hepatic stellate cells (HSCs) to assess the effect of brivanib on stellate cell proliferation and activation.
RESULTS
After in vivo induction with BDL, CCl4, and TAA, mice treated with brivanib showed reduced liver fibrosis and decreased expression of collagen Iα1 and α-smooth muscle actin in the liver. In vitro, brivanib decreased proliferation of HSCs induced by platelet-derived growth factor (PDGF), VEGF, and FGF. Brivanib also decreased stellate cell viability and inhibited PDGFBB-induced phosphorylation of its cognate receptor.
CONCLUSION
Brivanib reduces liver fibrosis in three different animal models and decreases human hepatic stellate cell activation. Brivanib may represent a novel therapeutic approach to treatment of liver fibrosis and prevention of liver cancer.
Topics: Alanine; Animals; Carbon Tetrachloride Poisoning; Cell Line; Cell Proliferation; Cell Survival; Collagen Type I; Collagen Type I, alpha 1 Chain; Fibroblast Growth Factors; Hepatic Stellate Cells; Humans; Immunohistochemistry; Liver Cirrhosis; Liver Neoplasms; Mice; Platelet-Derived Growth Factor; Protein Kinase Inhibitors; Signal Transduction; Triazines; Vascular Endothelial Growth Factor A
PubMed: 24710173
DOI: 10.1371/journal.pone.0092273