The Hunt for Better Cancer Fighters

Taxol was the most important new cancer drug of the last decade, becoming the first line of defense against breast, ovarian and lung solid tumors.

Since 1995, when Bristol-Myers Squibb found a way to make Taxol without harvesting it from its natural source, the Pacific yew, sales of the drug have grown to more than $1 billion per year.

Despite its success, Taxol has some problems. Tumors often develop resistance to it, and about 2% of patients suffer severe--in rare cases, fatal--allergic reactions to a compound added to Taxol to make it soluble in the bloodstream.

Some researchers believe they have found an exciting potential successor to Taxol in a chemical called epothilone. Naturally secreted by a soil bacterium, epothilone acts through the same mechanism as Taxol to prevent cancer cells from dividing. It appears to be effective against more types of tumors and against tumors that are Taxol-resistant--and it doesn’t have as many side effects.

“It’s a new experimental drug with a demonstrated ability to kill tumor cells that are Taxol-resistant, and that’s very exciting. You can imagine how useful it would be in treating cancer,” said chemist K.C. Nicolaou of the Scripps Research Institute and UC San Diego.

But getting enough of the drug to test has proved difficult. Harvesting epothilone from its natural source is nearly impossible. The bacterium that produces it secretes only minuscule amounts. Moreover, these bacteria grow so slowly that growing enough of them to harvest the drug--a process known as fermentation--is impractical.

Companies in Race With Big Stakes

These holdups have spawned a fierce competition among drug companies to produce enough of the drug for human trials and eventually, commercial use. While Novartis, Bristol-Myers Squibb and others pour resources into traditional chemical methods, a small Hayward company, Kosan Biosciences, has taken an entirely new, biological approach. Whoever comes out on top will have performed a great feat, both medically and financially.

“It’s a tight race, but the quality . . . of our product, the strength of our team and our collaboration with the National Cancer Institute puts us in a leadership position. By no means is it going to be an easy race to win,” said Gregory Vite, group leader at Bristol-Myers Squibb.

During the race, researchers have already produced variations of epothilone that are more stable and less toxic than epothilone itself in animal studies.

Samuel Danishefsky’s bioorganic chemistry lab at the Sloan-Kettering Institute was the first to reproduce the natural compound, a ring of 16 atoms with a tail. Through total synthesis, chemists built the molecule from scratch, starting with simple building blocks and adding to them in sequential step reactions. In the case of epothilone, it takes about 20 steps.

“There are several points in the molecule where the 3-D structure is critical. We found certain regions where beneficial changes could be made,” Danishefsky said. He and his colleagues found that a precursor to epothilone was better tolerated by dogs than epothilone but had the same anti-tumor effect. “We are confident that our product is safer than anything out there, although, obviously, it remains to be tested in humans,” he said. He expects to begin testing this compound in humans in January.

Nicolaou’s lab also synthesized epothilone and then used combinatorial synthesis to yield hundreds of analogs, or “cousins,” of the compound. By combining the building blocks for the chemical in every possible way, analogs can be produced that may be more potent than the natural compound. A problem with this method, which Nicolaou calls the “human genome of chemists,” is that it may take years to screen the huge number of compounds for drug activity.

Bristol-Myers has used a combination of fermentation and synthesis to produce an epothilone analog that is effective against human tumors. The company tested both Taxol-sensitive and resistant cancers and presented its findings at a meeting of the American Assn. for Cancer Research in April.

Their compound, named BMS247550, inhibited growth of ovarian, colorectal, breast and pancreatic human tumors that had been grafted onto mice. More significant, the epothilone derivative was effective against tumors that were resistant to a broad variety of drugs, including Taxol.

Human safety testing of the compound has begun in the U.S. and Europe. “We are cautiously optimistic,” Vite said. “Of course we don’t want to create false hope in patients . . . but we’re very hopeful.”

A Genetic Approach to Manufacturing

Chemical synthesis has allowed researchers to make enough epothilone to test its effects on cancer in the test tube, in animal models and in preliminary patient tests. But making epothilone in the lab is neither cheap nor easy and yields only a few grams at a time.

Kosan is hoping to solve this problem with an entirely new genetic approach to manufacturing and modifying epothilone. In January, the company induced other bacteria to make larger quantities of the drug. Dr. Daniel Santi, CEO at Kosan, applauded chemists’ efforts but pointed out a remaining concern: “They’ve gotten a lot of good information on which part of the molecule is doing what, but they still haven’t solved the production problem.”

Kosan researchers succeeded in transferring a complete set, or cluster, of eight genes responsible for the synthesis of epothilone into a “fermentation-friendly” organism. This new bacterium grows 10 times faster than the natural host and can be easily manipulated by scientists.

Each gene in the cluster encodes an enzyme. These enzymes string together chemical building blocks in a bacterial cell assembly line to produce epothilone. The scientists at Kosan discovered how to modify epothilone, the end product, by changing the order or number of enzymes on the assembly line. This can be done simply by moving, duplicating or knocking out genes in the cluster, researchers say.

Kosan project director Leonard Katz explained that this “chemistry by genetics” approach is a novel way to produce drugs and is largely untested. He also pointed out that this approach permits modifications to atoms buried deep within the molecule that are inaccessible to chemists. Chemists argue that these fermentation methods cannot produce the hundreds or even thousands of analogs that might be more effective than the natural substance.

Nicolaou conceded, however, that “these approaches will most likely be complementary to each other.” Indeed, it’s not hard to imagine that a change discovered to be beneficial by a chemist could one day be genetically engineered into the assembly line of enzymes of a bacterium. In this way, a drug that is superior to the natural compound could be produced easily and inexpensively by large vats of bacteria.

So the race continues to find the best variant of epothilone. “At the end of the day,” Katz concluded, “it’s not the first molecule [that counts], it’s the best.”

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Kendall Powell can be reached by e-mail at kendall.powell@latimes.com.

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Growing a New Drug

Researchers are experimenting with a way to mass-produce epothilone, a potential cancer drug that promises to be more effective than Taxol with fewer side effects.

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1. A set of eight genes responsible for the synthesis of the drug is transferred from its natural host, a soil bacterium, to a laboratory strain of bacteria that grows 10 times faster. The gene set instructs the bacterial cells on how to make a set of enzymes that construct epothilone one step at a time.

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2. The enzymes act as an assembly line. Each adds on a building block to the growing chemical chain. At the end of the assembly line, the final reaction closes the chain into the 16-carbon ring structure of epothilone.

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3. Scientists may want to change the structure of epothilone to improve its cancer-fighting ability. They can change one of the genes in the set, altering the order of enzymes and yielding a slightly different product.

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4. Once the preferred form of epothilone is formulated, huge batches of bacteria can be grown. The drug will then be collected for use in clinical trials.

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Source: Kosan Biosciences Inc.