Yale biologist Craig M. Crews has discovered how a promising cancer medication, now in clinical trials, starves tumors by cutting off their blood supply. The discovery, for which the University is seeking a patent, will enable pharmaceutical firms to search for other effective agents in a new class of anti-cancer drugs called angiogenesis blockers.
The drugs block the growth of new blood vessels that supply oxygen and nutrients to growing tumors, often causing them to shrink dramatically and preventing the spread of cancer cells to other organs. In addition, few tumors develop resistance to the blockers, as they can in conventional cancer therapies.
The first of eight promising angiogenesis blockers now undergoing Federal Drug Administration testing could reach the market as early as next year. How most of them stop blood vessel growth is unknown.
"The beauty of these medications is that they block the same basic mechanism, which makes them effective against a wide range of tumors, including lung, brain, prostate and breast tumors," says Mr. Crews, who is assistant professor of molecular, cellular and developmental biology. "They also appear to be far less toxic to patients than radiation or chemotherapy and could even make surgery unnecessary in some cases." His research appears in the June 10 issue of the Proceedings of the National Academy of Sciences.
Professor Crews and his colleagues have 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 is blocked by a potential cancer medication called TNP-470, new blood vessels fail to grow, he says. The drug, which is a product of molds, is now in the final phase of clinical trials necessary for FDA approval. It is being developed jointly by Takeda Pharmaceuticals of Japan and Illinois-based Abbott Pharmaceuticals.
Collaborating on the research to determine how the drug blocks angiogenesis were graduate students Lihao Meng and Margaret Q.W. Wang; postdoctoral fellows Ny Sin and James J. Wen; and William G. Bornmann of Memorial Sloan-Kettering Cancer Center. The research was funded by the Donaghue Medical Research Foundation and the Association for the Cure of Cancer of the Prostate, CaPCURE.
Search for new agents
"Now that one of several key proteins needed for blood vessel growth has been identified, pharmaceutical firms can 'challenge' the protein with thousands of new agents as they search for medications even more effective than TNP-470," says Professor Crews, who is also affiliated with the Yale Cancer Center. The University and the protein's discoverers could receive royalties or licensing fees for any new drugs that block MetAP-2, if Yale's patent application is approved.
In addition, scientists may be able to determine the three- dimensional chemical structure of the protein so a drug can be specially designed to bind with it, like two meshing puzzle pieces, he says. The protein's gene already has been identified.
Angiogenesis blockers starve 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 for wound healing and menstruation, note researchers.
Among the many angiogenesis blockers now being studied is thalidomide, which in the 1960s caused some children to be born with missing limbs. This unexpected side-effect of a drug 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 1970s that blocking blood vessel growth would starve tumors.
Professor Crews pinpointed the key protein in the process of angiogenesis as part of his exploration of basic cell functions using drugs that are known to disrupt those functions. "My approach has been to take naturally occurring agents such as extracts of tree bark, plant secretions and microorganisms to probe the machinery of the cell cycle," he explains. "We attach the chemically active agents -- many of which are known to have anti-cancer properties -- to a resin or bead to immobilize them. We then pass a mixture of proteins over them to see which ones stick, or bind naturally, to each agent."
He and his colleagues also are interested in signal transduction, or how cells interpret signals from outside the cell, such as their response to growth factors.