3-D Structure of Key Protein Targeted by Promising Cancer Drug Could Lead to Discovery of Better Drugs that Starve Tumors

Yale and Cornell University biochemists have unveiled the three-dimensional chemical structure of a key protein that is the target of TNP-470, an experimental drug that shows promise for starving cancerous tumors. The discovery could help pharmaceutical firms find or design more effective medications in a new class of anti-cancer drugs called angiogenesis blockers, which appear to work by blocking the growth of blood vessels that supply oxygen and nutrients to tumors.

“The beauty of these medications is that they all block the same basic mechanism – blood vessel growth – which makes them effective against a wide range of tumors, including lung, brain, prostate and breast tumors,” said Yale biologist Craig M. Crews “They also appear to be far less toxic to patients than radiation or chemotherapy.”

TNP-470 and several other angiogenesis blockers currently are involved in more than 20 clinical trials to test their effectiveness in treating cancer. None has been approved by the Federal Drug Administration, although the first blockers could reach the market next year. Early tests have shown that some of the compounds can shrink tumors or slow their growth dramatically while preventing the spread of cancer cells to other organs and causing few side effects. Unlike the drug resistance that plagues conventional cancer therapies, resistance to the blockers is rare.

No one knows exactly how the blockers work. However, in 1997 Crews and his colleagues identified a key mammalian protein called methionine aminopeptidase (MetAP-2), which they believe enables endothelial cells in the lining of blood vessels to respond to chemicals called growth factors. When the protein was blocked by TNP-470, new blood vessels failed to grow.

In research published in the Nov. 13 issue of the journal Science, Crews and his colleagues captured a three-dimensional “snapshot” of a molecule of human MetAP-2 alone and bound to fumagillin, the parent compound of TNP-470. Crews collaborated with Shenping Liu, Joanne Widom, and Jon Clardy of Cornell, and Christopher W. Kemp of Kemp Biotechnologies Inc.

“Knowing how the drug binds with its target is an important step in tweaking the chemical structure, like carving a key to mesh with a lock, in order to make future versions of fumagillin-based drugs even more effective,” said Crews, who explained that the detailed “snapshot” was captured through a process called X-ray crystallography.

A product of molds, fumagillin is being developed for cancer treatment jointly by Takeda Pharmaceuticals of Japan and Illinois-based Abbott Pharmaceuticals in the form of the fumagillin analog TNP-470.

TNP-470 and other angiogenesis blockers force tumors into dormancy by starving the inner cells, so the tumors continually collapse inward upon themselves. But the drugs seldom kill the tumors entirely, which means that discontinuing treatment can allow tumors to grow back. Thanks to the lack of drug resistance, treatment could be discontinued when a tumor is dormant and resumed if it starts to grow again, making cancer treatable as a chronic disease.

Long-term use of the blockers could cause complications, however, because blood-vessel growth is critical during fetal development, for wound healing and for menstruation.

Among the many angiogenesis blockers now being tested against cancer is thalidomide, which in the 1960’s caused some children to be born with missing limbs. This unexpected side-effect of the drug, which was prescribed for morning sickness, may have been related to its ability to block blood vessel growth, scientists now believe. Other angiogenesis blockers are secreted by the tumor itself, perhaps to control the growth rate of metastasized tumors, according to Dr. Judah Folkman of Harvard Medical School, who first suggested in the early 1970’s that blocking blood vessel growth would starve tumors.

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