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Angiogenesis Inhibitors

The drugs in this section oppose the formation of new blood vessels (angiogenesis).  Tumors need to develop their own blood supply to support tumor growth.  Interfering with this process may decrease blood supply enough to retard growth or cause death of tumor cells.  Vascular endothelial growth factor (VEGF) is one primary stimulator of new blood vessel growth.  Therefore, VEGF and its receptors are drug targets.

For GIST, direct angiogenesis inhibition may be used:

  • as one function of a multiple-target tyrosine kinase inhibitor drug such as sunitiniib or sorafenib
  • as the only function of a drug  given together with tyrosine kinase inhibitors

Trent et al (2007) studied the levels of VEGF expression in GIST tumors from 53 GIST patients.  They found that 51% of tumors expressed VEGF and only 17% expressed high levels of VEGF by immunhistochemical staining.  The KIT mutational status of the tumors did not correlate with the levels of intratumoral VEGF expression.  Patients with tumors strongly positive for VEGF expression had an inferior median progression free survival on imatinib (7 months) compared to patients whose tumors were either negative or weakly positive for VEGF (29 months, P = 0.42).   Strong tumor VEGF expression also lead to a worse median overall survival.  Meanwhile, survival data for GIST testing weakly positive for VEGF expression were virtually identical to the data for tumors negative for VEGF.
 
Imatinib treatment has been shown to reduce VEGF production in some patient tumors or in laboratory GIST cell lines, but not in others.  Thus, a subset of VEGF-positive tumors regulate VEGF expression through signaling pathways targeted by imatinib, whereas others may not. Imatinib causes a decline in circulating VEGF in responding patients according to Joensuu et al in a 2002 ASCO abstract, although VEGF is not a direct target of imatinib.

Sunitiniib (Sutent) has anti-angiogenesis action, but case histories in which GISTs have been surgically removed following Sutent treatment do not usually show reduction of blood vessels; therefore, it is uncertain whether this action of sunitinib operates in GISTs.

Link below to pages for the following anti-angiogenesis drugs in clinical trials:

 

 

National Cancer Institute Tutorial on Angiogenesis

The National Cancer Institute website includes a tutorial on angiogenesis with numerous illustrations.

 



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