Angiogenesis inhibitors / VEGF & mTOR inhibitors
Role of VEGF and mTOR in angiogenesis
Cancer cells can stimulate angiogenesis, thereby facilitating their own growth. A key component of the intracellular signaling pathways is mTOR, which is involved in growth of both the cancer and the vascular cells. |
|
|
Most angiogenesis inhibitors work by decreasing the actions of substances that promote angiogenesis, particularly VEGF and mTOR. The only exception is INTERLEUKIN 12, which increases the actions of a native angiogenesis inhibitor |
 |
- mTOR is an intracellular serine/threonine kinase that plays a central role in the control of cell growth and proliferation
- mTOR senses changes in availability of growth factors and/or energy sources, and induces synthesis of proteins necessary for angiogenesis, cell growth/survival and nutrient uptake
- proteins regulated by mTOR include cell cycle regulators (cyclin D1), amino acid and glucose transporters, proangiogenic factors (transcriptional regulators of VEGF and PDGF), and enzymes required for DNA repair
- the mTOR pathway is frequently activated in cancer cells as part of the process that leads to uncontrolled proliferation
- VEGF-R is a tyrosine kinase receptor that activates mTOR in order to promote angiogenesis
- a core concept is that increased mTOR activity in cancer cells can lead to secretion of VEGF and PDGF, which promote angiogenesis by increasing mTOR activity in vascular cells
- therefore, decresing the activity of VEGF-R and mTOR can result in a synergistic kill of cancer cells
- strategies to block VEGF/VEGF-R and mTOR are a major focus of drug development