Long-term collaboration yields cancer-fighting compound

By Steven Schultz

Princeton NJ -- When Princeton chemist Edward C. Taylor reflects on the projects and discoveries that have filled his 57-year career, he traces many of them to his fascination with two peculiar rings of atoms.

Professor Edward C. Taylor stands in front of a blackboard with the chemical diagram of Alimta, a drug that could offer doctors an important new option in treating cancer.

He has published a book on the subject and written more than a hundred papers that chase these loops of carbon and nitrogen into the far reaches of chemistry and biology. For thousands of cancer patients around the world, however, there is another product of Taylor's fascination: hope.

Taylor, Princeton's A. Barton Hepburn Professor of Organic Chemistry Emeritus, invented an experimental cancer drug in collaboration with the pharmaceutical company Eli Lilly. After 13 years of additional scientific work and testing, the company recently began the process of filing for approval to market the drug. The drug, called Alimta, could offer doctors an important new option in treating cancer as early as next year.

Alimta appears to reduce or eliminate a wide range of solid tumors. Initially, it is targeted to slow the progress of malignant pleural mesothelioma, a lethal and painful cancer of the chest wall often caused by asbestos. If approved, Alimta would be the first drug marketed specifically for that cancer, which generally does not respond to other drugs. Alimta does not cure mesothelioma, which typically kills patients in nine months or less. However, according to studies, it increases patients' lives by an average of three months and greatly reduces their pain.

That degree of improvement is significant for such a devastating disease, said Dr. Nicholas Vogelzang of the University of Chicago, who led a major clinical trial of Alimta for mesothelioma. "The quality of life during those extra months is very impressive. (Patients) can do things. They can visit their families."

"We could not have imagined that the drug would be this effective," Vogelzang said, noting that in a few cases patients have lived six or nine months longer than expected. One patient, he said, has survived 34 months following treatment with the drug.

On the strength of Vogelzang's study and others, the U.S. Food and Drug Administration has -- in advance of actual approval -- allowed doctors to prescribe Alimta to mesothelioma patients as part of an expanded access, or compassionate use, program. So far, more than 400 patients have received the drug through that program. In all, more than 3,000 patients already have received the drug as part of studies, and the number is growing as Lilly tests it as a treatment for pancreatic, breast, ovarian, colorectal, bladder and other solid-tumor cancers.

For Taylor, the enormity of the change from academic investigation to cutting-edge medicine hit home when he learned that a relative of his wife's college roommate was diagnosed with mesothelioma and was receiving Alimta. It is a terrible diagnosis, he said, but, without the drug, there would be no hope of relief at all. "It is a thrill to realize that there is a drug of choice for him, and that it is our drug," said Taylor. "It's real."

A half-century of research

Taylor's search for cancer drugs began more than 50 years ago when he learned of the link between the disease and the particular area of chemistry that was capturing his imagination as a young scientist.

Taylor began his undergraduate education at Hamilton College in Clinton, N.Y., where a chemistry course caught his attention and changed his plan of majoring in English. He took every chemistry course Hamilton offered, moved to Cornell University to finish his undergraduate degree and, in 1946, entered Cornell's graduate program.

That same year, Taylor saw an article in Science magazine that set his research agenda for the rest of his career. It described a chemical compound that had been found in yeast, liver and spinach leaves, and that was an essential growth factor for some microorganisms. It also possessed the same unusual ring system that, just a few years earlier, had been found in some butterfly wing pigments.

"That was such a remarkable, bizarre situation -- an essential growth factor for microorganisms had a resemblance to butterfly wing pigments," he said. "That is what fascinated me, and I never let go of it."

Starting at the University of Illinois and then moving to Princeton in 1954, Taylor studied and became the world authority on these compounds and their many variations, all with a characteristic two-ring structure of six carbon and four nitrogen atoms. Some of these turned out to be variations of folic acid, one of the essential B vitamins. These folic-acid-related compounds, known as enzyme cofactors, are now recognized as critical for building DNA and RNA in cells and are necessary for all known forms of life on Earth, Taylor said.

An important link came in 1948 when research at other institutions revealed that one of these two-ring compounds, a synthetic variant of folic acid, not only could kill microorganisms, but also brought about remissions of acute lymphoblastic leukemia in children. This synthetic compound stopped cancer because it interfered with the mechanisms by which natural folic acid is converted into enzyme cofactors that are necessary for cell division. Unfortunately, this compound, as well as other related derivatives, had serious side effects because they also damaged healthy cells. Taylor and his graduate students began looking for new compounds that would disrupt the processing of folic acid only in cancer cells.

"In retrospect, we realized that we had started with a very naïve idea," he said. Over the years, Taylor's research group devised and tested many hundreds of compounds. In the 1980s, one emerged as a promising candidate. Having already worked as a consultant to Lilly, Taylor brought his compound to the company, which embarked on testing it, first in the laboratory, then in human clinical trials.

A convoluted series of steps

Taylor delights in recounting the long and convoluted series of steps that his lab had initially devised for synthesizing the first drug candidate. He noted mischievously that the person at Lilly charged with repeating his synthesis found it to be one of the most difficult projects of his career.

Licensing the compound to Lilly was far from a simple hand-off. Lilly and Princeton researchers collaborated closely, consulting and visiting each other other's labs, as they looked for new molecules that might be even more effective. In 1989, this joint effort succeeded with Taylor's discovery of the compound that was to become Alimta.

"It is a wonderful example of a long-term relationship between an academic lab and an industrial lab that benefited both," said George McLendon, chair of Princeton's chemistry department. In honor of that relationship, Lilly recently endowed a graduate fellowship in chemistry at Princeton in Taylor's honor (see box on this page).

The decade of collaboration yielded a candidate that has more benefits than anyone expected. Research has shown that one reason for Alimta's effectiveness is that it inhibits as many as five separate parts of the folic acid system that are necessary for cell division and tumor growth. This multiple-target action also appears to make cancers less capable of developing resistance to the drug.

In another unanticipated development, researchers at Lilly found they could greatly reduce side effects of the drug by giving patients folic acid and vitamin B12, which, for reasons that are still unclear, help protect healthy cells but not cancerous ones from the toxic effects of Alimta.

A magical compound

Today Lilly has hundreds of staff scientists and other employees working on Alimta. In addition, doctors in more than 19 countries have been involved in scores of clinical studies. Many more studies currently are under way or are being planned.

"This is an enormous investment," said Homer Pearce, a former vice president for cancer research at Lilly who led much of Alimta's development. "When a drug comes along that has special properties like Alimta, it really is remarkable."

Pearce, now a research fellow at Lilly, and Taylor recently gave a joint presentation on the drug to a Princeton graduate seminar on drug development taught by McLendon and Professor Martin Semmelhack.

"In drug development, many are called, but few are chosen," Pearce told the class. Only one of about 10,000 candidate compounds makes it all the way through the development process to the commercial market, he said, noting that the average cost of successful development is more than $800 million.

Now almost six years into his retirement, Taylor remains fascinated with the twists and turns of chemistry and the many serendipitous discoveries that led to the drug. He steps to a blackboard, smiling, to sketch those hexagonal rings and explain their journey from butterflies to cancer treatment.

Recently, he explained, researchers at Albert Einstein College of Medicine identified a protein in mesothelioma cells that latches onto Alimta and carries it into the cell. Nothing else seems to be carried by this protein, not even folic acid. What's more, the protein seems tailor-made to shepherd more Alimta into cells just as the dose is wearing off, naturally smoothing the administration.

"It's magic!" Taylor said. "Alimta was not designed that way to start with, but it's as though nature was waiting for this compound."

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