In 1971, Dr Judah Folkman published the “angiogenic hypothesis” suggesting that
ID: 96161 • Letter: I
Question
In 1971, Dr Judah Folkman published the “angiogenic hypothesis” suggesting that a tumor cannot grow beyond 1–2 millimeters without the development (angiogenesis) of new blood vessels that provide access to oxygen and nutrients. During the 1990s, it was discovered that vascular endothelial growth factor (VEGF) stimulates the proliferation and migration of the cells that form blood vessels, leading to the formation of new blood vessels. VEGF binds to receptor tyrosine kinases (RTKs) on the cell surface and causes the RTKs to dimerize and become active, thereby initiating an intracellular signaling cascade that stimulates cell division and inhibits apoptosis. Many cancer cells secrete high levels of VEGF. Increased VEGF expression in a tumor is correlated with a poor medical outcome for the patient. Some evidence suggests that blocking VEGF-dependent signaling may prevent the formation of new blood vessels and lead to the death of immature blood vessels without disturbing mature blood vessels. You work for a biotechnology company that seeks to create anticancer drugs that prevent the growth of tumors and/or cause tumors to shrink, while leaving normal cells relatively untouched. After learning about VEGF, you have a bright idea for a new mechanism of action for a potential anticancer drug. What is your idea?
Explanation / Answer
The vascular endothelial growth factor (VEGF) can be widely used as an anticancer target drug because it can be easily accessed as it circulates in the blood and acts directly on endothelial cells. Since VEGF-mediated angiogenesis occurs only during wound healing and female reproductive cycling, targeting the molecule would not affect other physiological processes. The tumor blood vessels formed under the influence of VEGF would be disorganized, tortuous and leaky with high interstitial pressure so, it would reduce the access for chemotherapies. By inhibiting VEGF, the vessel abnormality would increase the permeability of the tumor to chemotherapies. Therefore, targeting the receptors for VEGF and VEGF-targeting molecules would be ideal for treating cancer. The best approach to VEGF inhibition is the humanized monoclonal antibody bevacizumab (Avastin), which is the only anti-angiogenic agent approved for treatment of cancer.
VEGF inhibition would cause new tumor blood vessels, causing regression of the existing tumor vasculature, enhancing the anti-tumor immune response, and normalizes the vasculature thereby improving the delivery of chemotherapy.