Web Exclusives: PawPlus

November 22, 2006:

Edward Taylor and Alimta’s long road to success
Miriam Bocarsly '06 tells how a "shockingly good drug" was developed

Nearly three years ago, Edward Taylor was anxiously awaiting FDA approval of an anticancer drug that had spent about 12 years in clinical trials. Since its FDA approval, the drug, Alimta, has been a major success, stopping the growth of a variety of solid tumors while easing suffering and extending life. Taylor was recently the recipient of a Heroes in Chemistry award from the American Chemical Society, and royalties from Alimta will provide significant funding for the chemistry building that will soon begin construction next to Princeton Stadium.

The following piece, written nearly three years ago, reflects back on the time when Taylor was eagerly anticipating the impending FDA approval of Alimta. This piece was the winner of the University’s Pope Prize for Science Writing. The author, Miriam Bocarsly ’06, is currently working at Drexel University on a research project that addresses eating disorders, weight gain, and obesity in college freshmen.

By Miriam Bocarsly ’06

A veteran of more than a half-century of research, Edward Taylor sits in his office, swirling a pen between his hands. The office is immaculate, everything in its place, every book filed neatly on the floor-to-ceiling shelves. With a huge smile on his face, one of those ear-to-ear grins, Taylor is sitting, playing with his pen and waiting. He turns sideways every few minutes to take a quick glance at his e-mail, then returns to fiddling with his pen.

“Any moment now, any moment now,” he says checking his e-mail yet again, “but not yet.” Ted Taylor, professor emeritus of chemistry at Princeton University, has discovered what has proven to be a cancer treatment markedly more effective than any currently available drug. The list of cancers his new drug, Alimta, attacks is more than a foot in length, including virtually all solid tumors. Taylor is imminently expecting approval for Alimta from the U.S. Food and Drug Administration, the final hurdle standing between his drug and the market.

Taylor, a small-framed man, sitting cross-legged behind a large desk, is the definition of brilliance. But he’ll tell you, over and over again, that the success he has experienced is pure fate – a result of serendipity.

Equally serendipitous is the way that Taylor became a professor of chemistry. A much-younger Taylor attended Hamilton College in Clinton, N.Y., where he intended to major in English, a subject he loved. “I loved to write essays, learn poetry and debate,” he reminisces. “I had a good friend who would join me in this enterprise, and we would write essays on various topics we assigned to each other. It was nothing to do with our school work, it was just fun.” However, in order to fulfill a distribution requirement, he was forced to take a science class. “The only science I took in high school was physics, and I hated physics. So when I learned I had to take a science class, it was either biology or chemistry. So I flipped a coin, and ended up taking chemistry,” he explains. And something clicked. In two years Taylor had taken every chemistry course the school offered, and had to transfer to Cornell to continue his undergraduate education.

In 1946, nearly 60 years ago, Taylor began his Ph.D. work at Cornell. As was the custom and still is, he was looking around in multiple disciplines to see what the interesting problems were when a professor sent him down to the library to read a paper. The paper was a piece in Science Magazine about a strange compound that had been isolated from liver. As research continued, the same structure was also found in spinach leaves and fermentation broths, and was deemed an essential growth factor, or protein necessary for normal development of microorganisms.

What interested Taylor the most was that the strange compound he read about had a unique ring structure, a loop of carbon and hydrogen atoms, which had been seen before only in the wing pigments of butterflies. “Butterflies, imagine that!” he says, still fascinated and intrigued by the obscure relationship.

Taylor found himself entranced; there was something really bizarre about that ring system. “What is the connection between butterflies, liver, and spinach?” he asked. And before long, Taylor was in the lab, doing all he could to learn as much as possible about the recurring ring structure. He knew it wouldn’t be easy. He was tackling a problem that had already caused other scientists many headaches. “Just to figure out the ring structure in the butterfly took 50 years and frustrated two Nobel Prize winners,” he relates with a smile. And Taylor’s goal was to go farther and learn more than those scientists before him. Little did he know, his entire career, and a very successful one at that, would take flight from those butterfly wings.

While Taylor slaved away during those early years, attempting to understand everything he could about the structure and qualities of his much-beloved ring, other scientists also were working feverishly on the same ring system. In 1948, researchers at another institution determined that modifying the ring’s structure slightly could change it from being necessary for microorganism growth to a compound that could stop the growth of microorganisms. In other words, these scientists created an antibacterial agent. And by complete accident, while testing the antibacterial agent in patients, it was discovered that the chemical also brought about remissions of acute lymphoblastic leukemia, a lethal type of cancer in children.

“Now there is something that was really exciting, because you don’t cure leukemia with an antibacterial. Something else was happening here,” Taylor says, beaming like a child before opening a wrapped present.

The mysterious ring compound was named folic acid, and over the next 30 years, its role as a key component for life was elucidated. “It is now understood to be requisite for every form of life on this planet: microorganisms, birds, trees, mammals – man, the list keeps going,” Taylor says, explaining that it is necessary for DNA production, as well as a number of other cell functions.

Leaving Cornell with his Ph.D. and moving on to teach at the University of Illinois, and then transferring to Princeton University in 1954, Taylor expanded his repertoire from the single ring to an entire family of similar structures called heterocyclic compounds, on which he became the world’s recognized expert. As a matter of fact, to the right of his desk stand nearly 100 red-covered books – each edited by Taylor, and each exploring some aspect of heterocyclic compounds.

But no matter how far Taylor’s mind wandered, he kept on coming back to folic acid. “I just wanted to know what caused this cancer remission in the chemical derived from folic acid,” he says.

Even more importantly, however, the antibacterial that caused the cancer to go into remission was not only powerful, but also terribly toxic. It killed cancer cells very efficiently and effectively, but it also killed healthy body cells. There was very little distinction between an effective dose and a lethal dose; if the chemical were ever to be used in patients, something would have to be modified to make it less toxic. Taylor was ready to take on that challenge, and in the late 1970s, his lab developed a compound that looked as if it might be a more potent, less toxic anti-tumor agent.

At this point, Taylor realized that he couldn’t go about the task of developing a cancer treatment alone. “I am a trained synthetic organic chemist, and although I minored in biochemistry, that doesn’t make me a biochemist. And I knew I needed an expert,” he recalls.

Taylor contacted Eli Lilly, a pharmaceutical company located in Indianapolis, and asked them to evaluate the compound synthesized in his lab. Lilly scientists agreed to test his compound, but wrote back shortly thereafter saying that there was something wrong with their tests, and it must be the fault of a less-practiced summer crew. They asked Taylor to wait for the normal scientists to return in the fall. However, in the fall, when the normal crew returned, the results of the tests did not change.

As it turns out, Taylor’s compound was so efficient, powerful, and versatile that Lilly had never seen such positive results before, and was therefore convinced that there was a flaw in the tests. But the results were correct. And Lilly was willing to take a chance and embark on a collaborative mission with Princeton University in hope that Taylor might be on to something.

The beginning of the collaboration was exciting for Taylor, but in no way the end of his story. Rough roads and bumpy chemistry still paved the future. Taylor’s compound is horribly complicated to make. “It is like a rock, and how do you do chemistry on a rock?” he asks, referring to his compound. But rock-like compounds were the least of Taylor’s complications. He ran full-force into a major chemical problem: “There was a bugaboo,” he says, looking back with a smile. The compound was so insoluble, so rigid, and so difficult to work with that Taylor experienced a problem of geometry. Synthesis of his organic compound created two varieties, which were barely distinguishable, except for the fact that one worked to fight cancer, and the other didn’t. A chemist at Lilly was able to create a way to separate the active form from the inactive form, but it limited the amount of the compound that could be collected and would have made it as expensive as gold, Taylor explains.

But Taylor, a dedicated scientist, was not ready to give up, and decided to look at the problem in a different way. Instead of working to separate the two forms of the compounds, he decided to chemically eliminate the part of the molecule responsible for the geometric differences. Unfortunately, to do so would involve eliminating some of those features that had already been established as essential. “We took a chance; we figured, ‘Why not?’ ” It took years, and the new ring system seemed to be going off in a direction with no positive leads, but luck comes to those who least expect it. “We hit the jackpot,” Taylor quietly and simply states.

That is how Alimta, the summation of a decade of work, was born.

Whether it was luck or genius, or a delicate mixture of both, Taylor’s drug moved on to clinical trials. “The facts are sobering,” he says. Only one out of every 15,000 possible drug candidates makes it into clinical trails. Of those, only one out of five makes it through the first round of tests. By the time a drug makes it on to the market, it has cost about $1.7 billion in development costs. All that sums up to a lot of work, a lot of gambles, and a lot of money. “It’s tough out there,” Taylor says, but he was lucky; his drug survived.

While the compound was going through the first round of trials, Taylor’s lab went on to develop hundreds and hundreds of similar molecules, looking for an even more effective structure. But they couldn’t find one. “It was as if nature was sitting around waiting for us to find this molecule,” Taylor marvels.

Alimta is taken into cells by a specific protein that acts, like a car, as a transportation device. This protein happens to be over-expressed by all tumor cells, causing Alimta to be taken into tumor cells more frequently than normal cells. Once in the cell, the drug works by eliminating the function of folic acid in the host cell. "We are completely clobbering the folic acid in the cell, which is needed for cell survival," Taylor explains. But there was still one more hurdle to jump: Patients were still showing high levels of toxicity in normal cells. Through the work of hundreds of scientists and statisticians at Lilly, it was discovered that co-administering vitamin B12 with Alimta eliminates the toxic effects in normal cells. Yet, cancer cells are destroyed just as before, thus overcoming that final crucial hurdle.

Clinical trials have proven Alimta to work in a wide range of tumors – such as mesothelioma, cancer of the lining in the lungs – that have up until now resisted every type of therapy. The drug is administered intravenously for a 10-minute period only once every three weeks, making it more convenient than other chemotherapeutic agents. Additionally, while up to 50 percent of patients suffer life-threatening side effects with conventional cancer drugs, only 5 percent have similar adverse reactions to Alimta.

After 11 years of extensive clinical trials, six months ago the FDA approved Alimta for compassion use, meaning that seriously ill patients could obtain the drug free from Lilly before it had been approved for the market. So far the results of treatment with Alimta have been overwhelmingly positive. Mesothelioma, a cancer that kills most patients within six months of diagnosis, will be the first cancer for which Alimta is approved. In clinical trials, mesothelioma patients have survived up to three years with Alimta therapy – six times longer than expected. Moreover, patients report that when treated with Alimta, they feel better and can lead normal lives. “It is spectacularly successful,” Taylor says, “but it isn’t a cure. Nobody claims a cure, because the cancer can come back. But if you have someone who is supposed to be dead, and he is out mowing the lawn, or going on bike rides, that is a success.”

Although the imminent FDA approval will only authorize Alimta for treating mesothelioma, there are around a hundred clinical trials under way, and as the results come back, Taylor expects the drug to be approved for many more forms of cancer. Additionally, once the FDA has approved the drug for a single type of cancer, doctors can use it in any situation they think appropriate, a practice known as “off-label use.”

It has been a long road for Taylor, but one full of success and fulfillment. “In 1980, I started working on an idea, and it led to all this. And looking back now, I see it was a crappy idea, but what difference does it make? Find what is interesting and seems to be a curious phenomenon, and keep your eyes open and see what results. And what came out of it was an awful lot of neat stuff in chemistry,” Taylor says with excitement.

“It took a long time, and the fact that it turned out the way it did was serendipity, it was really luck. The luck would not have come if we were not working in the area, and we wouldn’t be working in this area if these hints pointing to something really important, weren’t there,” Taylor says. “It’s going to be a shockingly good drug.”

Now, nearly 60 years after it all started and six years after his retirement, Taylor still comes in to work every morning. He isn’t teaching classes or running a research lab, but he is still writing papers, consulting, and editing a series of books. “Once I discovered organic chemistry, that was it – I loved it. And I have loved it ever since. I still do it every day, even though I am retired.” Although Taylor has not been able to leave chemistry behind, he finds his farm in Vermont a much more relaxing environment for writing, and has scheduled plenty of time for family and grandchildren. And, Taylor added, he has more time to perfect one of his other loves: golf. Checking his e-mail one last time, Taylor hopes that he will hear from the FDA before leaving Monday with his wife Ginny, to play golf in Arizona. END