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Abstract
Angiogenesis is one of the major mechanisms controlling tumor proliferation and metastatic spreading. Targeting of pro-angiogenic factors and their downstream effectors represents an appealing therapeutic option in the treatment of different cancer types. Linifanib (ABT-869) is a novel tyrosine-kinase inhibitor (TKI) inhibitor and its anti-angiogenic activity has been explored in numerous clinical trials. Here, we review preclinical development of linifanib focusing on its pharmacodynamic and pharmacokinetic characteristics and briefly summarize its evaluation in clinical trials. Linifanib selectively targets VEGFR and PDGFR and has low off-target inhibitory activity. Preclinical and early-phase trials have been showing promising efficacy results However, although signals of anti-tumor activity have been proven in some malignancies, linifanib late-phase development has been facing some challenges due to limited efficacy and increased toxicities. New strategies aimed at finding biomarkers of response and minimizing toxicities are needed to allow the further development of a promising compound.
Acknowledgements
The authors wish to thank Associazione Italiana per la Ricerca sul Cancro (AIRC) special program molecular oncology 5 X 1000 2010 Ref. 9970 and Investigator Grant IG-2013 Ref. 14451.
Financial & competing interests disclosure
F Montemurro has served as member of Speaker’s Bureau for Astra Zeneca and for Hoffmann La Roche SPA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Angiogenesis promotes tumor growth and progression and is widely investigated as therapeutic target.
VEGFR and PDGFR are components of major pathways involved in neovascularization.
Linifanib (ABT-869) is a novel oral inhibitor, selective for VEGFR and PDGFR and has undergone preclinical development proving anti-angiogenic efficacy both in vitro and in vivo.
Phase I and II trials investigated the role of linifanib in treating different cancer types, including breast cancer, acute myeloid leukemia, colorectal cancer, non-small-cell lung cancer, renal cell cancer and hepatocellular cancer.
A Phase III trial compared linifanib with sorafenib in patients with hepatocellular cancer.
Linifanib proved notable anti-tumor activity in early phase trials and proved activity in renal cell cancer and non-small-cell lung cancer in the subsequent clinical development. However, it has faced efficacy issues in other neoplasms and is characterized by an increased toxicity profile.
A deeper understanding of the angiogenesis network, with regard to tumor microenvironmental heterogeneity and the identification of predictive biomarkers, still represents a major need for a better application of promising compounds, such as linifanib.