1.In 1971, Dr. Judah Folkman published the “angiogenic hypothesis” suggesting th
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Question
1.In 1971, Dr. Judah Folkman published the “angiogenic hypothesis” suggesting that a tumor cannot grow beyond 1–2 millimeters without the development of new blood vessels (angiogenesis) that provide access to oxygen and nutrients. During the 1990s, it was discovered that vascular endothelial growth factor (VEGF) stimulates migration and proliferation 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 and increased VEGF expression in a tumor is correlated with a poor medical outcome for the patient. You work for a biotechnology company that seeks to create anti-cancer drugs that prevent growth of tumors and/or cause tumors to shrink, while leaving normal cells relatively untouched. Your company has purchased the rights to therapeutic uses of VEGF derived proteins as anti-tumor drugs. You have found that the VEGF protein has 2 domains, one involved in receptor binding, the other is required for dimerization of VEGF. You propose to make mutant versions of the protein that will act as antagonists of the receptor to be given to patients as an IV treatment as a way to inhibit the endogenous VEGF secreted by the tumor.
a.Which of the 2 domains should you mutate (receptor binding or dimerization)?
b. How do you expect the introduction of the mutant protein into the bloodstream of patients to block tumor progression (in other words, why did you change the domain in part a)?
Explanation / Answer
Please find the answers below:
Part a) VEGF binds to the surface receptors of the cells which makes them undergo dimerization and onset of intracellular signalling cascades such as angiogenesis which promotes tumor growth. Thus, targeting a therapeutic strategy which prevents binding of VEGF to its receptor either by blocking the receptor or changing the interaction between VEGF and its receptor will be a better strategy to design anti-cancerous drugs. Infact, such biotechnological approaches are presently being utilized for treating VEGF-mediated signal transduction and disease progression in many other disease models as well such as pulmonary edema formation, cerebral edema formation etc.
Part b) If a mutant protein is introduced in the blood stream, it will bind to all the VEGF receptor sites non-specifically to all the organs. This will indeed prevent progression of tumor formation but simultaneously also prevent normal VEGF-mediated signalling in other organs as well. Thus, althoug a pathological effect will be down-regulated, but a common physiological process to shall be affected. Thus, it is not recommended to change the domain of the VEGF in part a).
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