Fishing for Therapeutics
Marine Microorganisms Show Promise as New Cancer Drugs
Admit it—everyone harbors a secret hope that the cure for cancer is obscured only by the ocean depths, and that some day, science will find a way to harvest nature’s undersea pharmacopeia.
The ocean was once thought to be too deep, dangerous and difficult to explore, but marine scientists now have the tools to reel in and analyze some of the vast, previously untapped potential of marine microorganisms. It turns out that the ocean contains a plethora of dynamic molecules that have shown great potential as cancer drugs and new antibiotics.
“Over the last 60 years, microbes have provided a massive source for antibiotics and for cancer drugs; the first statins came from microbial sources,” said marine chemist Dr. William Fenical, director, Center for Marine Biotechnology & Biomedicine of the Scripps Institution of Oceanography at UCSD, who delivered the John Daly Memorial Lecture recently in Masur Auditorium. “It really was based on the fact that microorganisms are diverse, unique and the chemistry of the products produced by them tends to be highly bioactive.”
If Alexander Fleming could discover penicillin from a fungus, what medicines might lurk inside tiny organisms in the ocean? There’s a great deal we still don’t know. So far, scientists have found a variety of molecules, including thousands of bacteria strains—notably cultured marine actinomycetes—the source of many of our antibiotics, said Fenical, who started his NIH-funded research into therapeutic marine organisms 25 years ago. Some of the greatest potential, he noted, may lie in the deep ocean, where sediments have a billion bacterial cells per cubic centimeter.
“These marine bacteria are producing metabolites we haven’t seen before,” Fenical said. “They’re unprecedented; a lot of them have very interesting bioactivities including in the areas we need them now—cancer and infectious diseases.”
Scientists can isolate the sediments and cultivate the samples in large scale. The initial challenge was bringing them to shore. To reach ocean bottom, researchers developed powerful fishing reels with snapping or coring devices that can freefall thousands of meters then collect and bring up samples.
Fenical’s team discovered two drugs derived from marine microorganisms that are currently in clinical trials for cancer treatment. Marizomib first showed successful results in targeting multiple myeloma and lymphomas when investigators determined another promising sign—the drug passes the blood-brain barrier. Now it’s in phase 2 trials for treating glioblastoma, among other cancers. Another drug they found, Plinibulin, is in phase 3 trials for lung cancer.
“In cancer research, today’s challenge is really to find ways to discover treatments—new drugs—that are highly selective…to specific types of cancer—something that is selective for melanoma, selective for breast cancer—so that you minimize the side effects of these drugs,” said Fenical.
As his team set out to find marine molecules that would target new biochemical pathways and proteins specific to cancer cells, they developed an approach to label and tag the proteins using immunofluorescent probes and confocal microscopy. They screen all microbial collections against cancer cell lines, exploit only the molecules showing specific cell selectivity and label inhibitors with fluorescent tags that show exactly where the protein binds in the cell.
Using this approach, they found a bacterium in shallow waters in the Bahamas that contains 2 unusual metabolites—ammosamides A and B—found to be effective against several neuroblastoma cell lines. When they incubated ammosamide B with colon carcinoma, it glowed, an intense blue fluorescence exclusively in the cytoplasm. Then they found their target: the large protein myosin, which transports tubulin and other proteins in the cell and might be a target for a tubulin inhibitory drug.
Another example is seriniquinone, a bright orange gram-positive bacterium collected in shallow waters off of Palau, which showed excellent selectivity against melanoma. When seriniquinone was introduced to melanoma cells, said Fenical, the cells began to die within hours. They also found their protein target, dermcidin, which is overexpressed in advanced melanoma.
A strain of Streptomyces, extracted from deep waters off of southern California, yielded 2 compounds—chlorizidines A and B, which target enolase, an enzyme present in all living cells that seems to regulate production of several proto-oncogenes. Further study is needed to uncover the potential of enolase as a cancer target. “There are targets that people don’t think are of any use, however they result in rapid cell kill and offer some new opportunities,” said Fenical.
“Chlorizidines are structurally unprecedented types of molecules, which is what we hope to find all the time,” said Fenical. “[We look for] things that are new, that offer opportunities not only in biomedical discovery but also open up opportunities for more effective patenting and more effective drug development, giving the pharmaceutical industry confidence that they have effective [intellectual property].”