Nintedanib Backgrounder

10.05.2012

1. Overview BIBF 1120* is a triple angiokinase inhibitor that blocks three growth factor receptors simultaneously: vascular endothelial growth factor receptors (VEGFR 1-3), platelet-derived growth factor receptors (PDGFR alpha and beta) and fibroblast growth factor receptors (FGFR 1-3).¹ All three receptors are crucially involved in the formation and maintenance of new blood vessels (angiogenesis); their blockade may lead to the inhibition of angiogenesis, which plays a critical role in tumour growth and spread.^2,3
BIBF 1120* is currently being investigated in patients with a number of various solid tumours including advanced non-small cell lung cancer (NSCLC), ovarian cancer, hepatocellular cancer, renal cancer, and colorectal cancer.

2. Mechanism of action
Angiogenesis is an essential process for normal growth and development occurring in the body. For example, angiogenesis occurs in important functions such as embryogenesis, wound healing and restoring blood flow to damaged tissues. However, it is also vital in enabling tumours to grow and metastasise to other organs. Continued growth of a tumour beyond a certain size requires the recruitment of new blood vessels, which supply the tumour with additional oxygen and nutrients, encouraging growth and spread (metastasis).⁴

The process of tumour angiogenesis is tightly regulated and controlled by growth factors released by cancerous tumour cells. The subsequent signalling is driven from activated growth factor receptor tyrosine kinases. Angiokinase inhibitors, such as BIBF 1120*, interfere with steps in the angiogenesis signalling cascade thereby preventing tumour growth and spread.

Unlike other angiogenesis inhibitors available today, BIBF 1120* targets all three receptor classes involved in angiogenesis simultaneously:

• VEGFR -activation stimulates endothelial cells to grow, divide, resist apoptosis and migrate.⁵
• PDGFR -control the migration and adherence of cells and provide support and stability to vessel walls.⁶
• FGFR -signalling also promotes the migration and adherence of cells and thus plays a role in the development and stabilisation of new blood vessels.

Inhibiting VEGFR and FGFR is thought to have an impact on the formation of new tumour blood vessels and inhibition of FGFR and PDGFR may hinder vessel maturation and maintenance of the vascular integrity.^7-9

 

*BIBF 1120 is an investigational compound. Its safety and efficacy have not yet been fully established.

 

1. Hilberg F et al. BIBF1120: Triple angiokinase inhibitor with sustained receptor blockade and good anti-tumor efficacy. Cancer Research 2008;68(12): 4774-4782.
2. Folkman N. Clinical Applications of Research on Angiogenesis. New England Journal of Medicine 1995;333: 1757-1763.
3. Ellis, L.M. and Hicklin, D.J. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nature Reviews Cancer 2008;8: 579-591.
4. Weidner N et al. Tumor Angiogenesis: A New Significant and Independent Prognostic Indicator in Early-Stage Breast Carcinoma. Journal of the National Cancer Institute 1992;84: 1875-1887.
5. Ferrara N et al. The biology of VEGF and its receptors. Nature Medicine 2003;9(6): 669-676.
6. Andrae J et al. Role of platelet-derived growth factors in psychology and medicine. Genes & Development 2008;22: 1276-1312.
7. Yu J et al. J Biochem Mol Biol. 2003;36: 49-59.
8. Hicklin D.J et al. Role of the Vascular Endothelial Growth Factor Pathway in Tumor Growth and Angiogenesis. Journal of Clinical Oncology 2005;23(5): 1011-1027.
9. Heldin C.H et al. High interstitial fluid pressure - an obstacle in cancer therapy. Nature Reviews Cancer 2004;4: 806-813.