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© Oxford University Press 2006.
NEWS |
Scientists Are Searching the Seas for Cancer Drugs
Some cling to rocky shores and piers. Others spend their lives glued to coral reefs or buried within the sands of the ocean floors.
But, wherever they live, there is increasing evidence that many ocean organisms—including sponges, sea squirts, and microbes—produce potent chemicals that may be lethal to cancer cells. With seven marine-derived drugs now in clinical trials and others on the way, ocean products may be outstripping land-based plants as promising sources of potential cancer drugs.
"We've looked in many plants. The last commercialized anticancer drug that came directly from a plant was Taxol in 1972," said David Newman, D.Phil., acting director of the National Cancer Institute's Natural Products Branch Developmental Therapeutics Program. "What we have found is that if you look in plants, you find new variations on old themes. What we see in ocean organisms is novel chemistry that hasn't been seen before."
That chemistry has roots in the ocean environment, Newman said.
"These creatures want to avoid being food. They don't have teeth. They can't run. They don't have claws. The only thing they have is chemistry. So they secrete a toxin that doesn't affect them, but any pesky predator gets a mouthful of [it]. It's chemical warfare and because of the diluting effect of seawater, it has to be exquisitely potent."
Searching the Seas
Natural products from the land have been studied for thousands of years. The oceans, however, were largely overlooked until the late 1960s.
"Nobody knew anything about what was going on in the marine system. They knew everything about the terrestrial system," said William Fenical, Ph.D., director of the marine research division of the Cancer Biology Program at the Scripps Institution of Oceanography at the University of California in San Diego.
In December 2004, the Food and Drug Administration approved the first totally marine-derived drug, ziconotide (Prialt), to treat chronic and severe pain. The drug, manufactured by Elan Pharmaceuticals, is stronger than morphine and mimics the deadly venom of a cone snail found in the Indian and Pacific oceans.
Several other drugs are in clinical trials, and thousands more compounds are being studied in laboratories around the globe. The marine drug furthest along is Yondelis, also known as ET-743 or trabectedin, which the Spanish firm PharmaMar is testing with Johnson & Johnson Pharmaceutical Research and Development in New Brunswick, N.J. Originally derived from a sea squirt found in the Caribbean and Mediterranean seas, Yondelis is a chemotherapy agent that binds to parts of DNA, disrupting cell division and DNA repair and causing apoptosis. The drug is now in phase III trials for ovarian cancer and in phase IIb trials for soft-tissue sarcoma, as well as in phase II trials for prostate and breast cancers.
PharmaMar is developing another drug called Aplidin that was also originally isolated from a Mediterranean sea squirt. Aplidin is now in phase II trials in patients with hematological cancers. The compound works by inducing rapid apoptosis, inhibiting secretion of vascular endothelial growth factor, and blocking cell division.
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Also in phase II testing is a synthetic derivative of the natural compound halichondrin B, isolated from marine sponges by the Eisai Research Institute in Andover, Mass. The company presented results of a phase II trial of the compound, known by its Eisai number, E7389, at last December's San Antonio Breast Cancer Symposium. The trial included 71 heavily pretreated women with breast cancer.
Of 65 women evaluated, 10 had a partial response lasting between 4 and 11 months. Some women are maintaining partial responses a year after treatment. Two women had short-lived responses of about 2 months. Also, the drug had mild to moderate side effects, including limited gastrointestinal upset and neuropathy—a tingling in the fingers and toes that can sometimes worsen into a burning sensation.
"It may be best to use this in women earlier in their disease when they are less sick," said Sandra Silberman, M.D., Ph.D., oncologist and vice president of clinical research for Eisai.
The chemical suppresses the growth of cellular microtubules, essential for cell division. By doing so, the drug appears to stop the formation of new cancer cells and ultimately causes apoptosis.
The Next Frontier
Whereas much of the ocean discovery effort has focused on shallow waters, Harbor Branch Oceanographic Institution (HBOI) in Fort Pierce, Fla., has turned its attention to the deep sea. Last year, HBOI scientists went on two expeditions along the coast of Florida and in the Bahamas. On these expeditions, scientists went out on a 204-foot ship and used a small submarine to dive 3,000 feet below the ocean surface.
Deep-sea researchers collect mostly sponges and soft corals, said Amy Wright, Ph.D., director of the HBOI's Division of Biomedical Marine Research drug discovery group. They grind these samples up with alcohol and run tests on them to find out how chemically rich they are and if they can kill cancer cells.
"These primitive organisms make compounds that can, for example, block barnacles from settling on them, and these same compounds may have utility in human health," she said. "If we look long enough, using the right methods, we'll find things."
Since 1984, HBOI has collected ocean organisms for drug discovery and currently has about 30,000 samples in storage. The institution has researched several promising chemicals, including discodermolide, originally isolated by HBOI scientists from a Bahamian deep-sea sponge.
They recently started a program to look for ocean compounds that can specifically target cancer cells. One of their targets is the protein survivin, which inhibits cell suicide. This protein is usually found only in fetal tissue, but a large percentage of cancer cells express this protein.
"What we are trying to do is find something that selectively turns off the expression of that protein, so it will only work in cancer cells because no other cells have that protein," Wright explained.
The microbes that live within deep-water organisms may also prove useful. If a microbe living within an animal makes a chemical worth studying, researchers can isolate the microbe rather than work with the entire animal. In effect, the microbe would be like a small chemical factory cranking out drugs, Wright said.
Fenical has focused much of his recent work on microbes. He and his colleagues reported in the November 2005 issue of Cancer Cell that microbes living in ocean sediments as deep as 4,000 meters below the surface produce a compound lethal to cancer cells. Through gene sequencing, they discovered this particular group of organisms, which had never been seen before, and cultivated a strain in the lab. The chemical produced from this strain, NPI-0052, a proteosome inhibitor, will enter phase I clinical studies early this year in multiple-myeloma patients.
Turning on Genes
Eric Schmidt, Ph.D., is looking not only at the microbe but also at the genes within microbes that make specific compounds. Last summer, the University of Utah researcher and scientists from the Institute for Genomic Research in Rockville, Md., cloned the genes responsible for synthesizing patellamides. These are small peptides, thought to have anticancer properties, produced by microbes that live inside a sea squirt that lives in tropical Pacific waters.
To produce the peptides, the researchers inserted the cloned patellamide genes into Escherichia coli As the E. coli reproduced, it also produced patellamides. A separate research team from Australia and the United Kingdom used different methods and a similar tunicate from the Great Barrier Reef to devise a manufacturing method for the peptide.
Schmidt has since followed up on this initial work by taking all the genes thought to be involved in making patellimides and expressing them one at a time. Now, he and his colleagues know the minimum number of required genes to produce a substantial amount of the compounds and have been able to greatly increase the yield of patellamides.
Developing genetic engineering approaches may be the next step in moving ocean drug discovery and development forward, Schmidt believes. "Chemists may be able to use these genetic techniques in tandem with chemical synthesis to make complicated molecules with fewer steps," he said.
Problems remain
Although some ocean drugs are showing promise in clinical and preclinical studies and advances in the field may make getting such organisms easier, taking a compound from the ocean to clinical trials is still full of bumps, holes, and false starts. For example, the same potent chemistry that keeps a sea organism from being food can also make it too toxic for human use.
The journey also costs a lot of money. The NCI spent $350,000, plus $250,000 from the New Zealand government, just to isolate 300 mg of halichondrin, Newman said. That figure does not include the infrastructure needed to study the molecule.
"It is more laborious to get compounds from marine organisms than from land because at this moment, the only source you've got is a marine organism that produces the compound in very small amounts," he said. The NCI, a major sponsor of ocean drug discovery, collects about 500 samples—a kilogram each—of marine organisms per year. Each kilogram costs about $1,000 to collect.
Then there is the issue of having a renewable supply. Some companies initially tried aquaculture to reproduce compounds, but this process can be expensive. Scientists also devise synthetic versions of natural compounds. But coming up with just the right chemistry to develop a compound that mimics or improves upon what is found in nature can also be difficult. Eisai scientists, for example, evaluated more than 200 analogues before arriving at E7389. It took Fenical and others in his group nearly 10 years and an investment of $8 million–$9 million to determine how to culture ocean microbes.
Collecting specimens has its own set of challenges. The animals that harbor potentially promising chemicals may be in a particular spot one day, but gone tomorrow. And the collection of animals can be an emotionally charged or ethical issue for some.
"No one wants to see you whacking away at sponges with a knife and sticking them in a bag," Fenical said. "It's an emotional response."
Despite challenges, the oceans are expected to continue to attract researchers because of their unrivaled diversity. "It is almost impossible to find new species on land," Fenical said. "But you can find new species every day in the ocean."
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