FRONTLINE CANCER: Cancer discovery on the high seas
By Scott M. Lippman
Question: When can you say, “You’re all wet,” and it’s taken as a compliment?
Answer: When you’re talking to a scientist from the Scripps Institution of Oceanography, or SIO, in La Jolla. From Darwin’s epic voyage aboard the HMS Beagle (1831-1836) to Craig Venter’s on-going Global Ocean Sampling Expedition, science has a long tradition of seeking out nature’s secrets wherever they may reside. For SIO cancer researchers, that means combing the seas to discover natural agents that control and prevent cancer.
These first-class scientists are also first-class seamen and scuba divers. Collecting specimens from the high seas for later examination in the lab isn’t for landlubbers or the faint of heart (or stomach). SIO researchers and their students have faced many dangers below and above the water, including shark attacks and hurricanes.
Using scuba and other methods, SIO researchers gather an amazingly diverse group of microorganisms to cultivate and explore chemically. These organisms grow prolifically in the deep ocean, defined as deeper than one mile. Sailing out aboard one of SIO’s fleet of research vessels, scientists position themselves over a promising deep-ocean location and then send remote collection devices attached to the end of deep ocean fishing reels, where they scoop up bottom sediments for investigation. Next stop is the laboratory in La Jolla.
These samples are amazingly rich in microbes ‒ a sample the size of a small sugar cube contains an estimated one billion microscopic organisms. Coming from the bottom of the sea, these microbes are generally new to science. At 75 percent of the Earth’s surface, the ocean bottom is a massive resource that will take several centuries to fully explore.
After processing, bottom samples yield hundreds of pure microorganisms, typically bacteria, that can be cultured in laboratory flasks. Often, these bacteria produce chemical compounds that help them to adapt to their harsh environments. SIO researchers can apply these same chemical compounds to the discovery of new drugs for cancer treatment and prevention.
Step one is to identify bacterial cultures that produce potentially useful compounds. A good sign are microbial cultures that cause cancer cells in the same dish to die. Only one in a thousand cultures has this capacity. But killing cancer cells isn’t enough to generate a drug. It must selectively target cancer cells and leave normal cells alone.
At this point, SIO researchers often collaborate with the National Cancer Institute (NCI) to decide if a potential drug is truly promising. NCI collaborators use sophisticated tests to differentiate “toxins” from compounds with new-drug potential. The NCI helps SIO researchers to evaluate discoveries in terms of practical use to treat diverse cancers.
This pioneering, ocean-going research is the workaday world of William Fenical, Ph.D., and colleagues at SIO. They search the ocean for new chemical molecules that can be applied to treat the most dangerous cancers. To find these molecules, they exploit the evolution of chemical defenses in marine life.
Within the past 10 years, SIO researchers have discovered 12 unique natural marine-origin drugs. Two of these are in mid- to late-stage human clinical trials. These trials are showing significant benefit in patients with breast and ovarian cancers, multiple myeloma, lymphoma and other complex cancers. A third is in earlier-stage development.
The researchers worked with local biotech company Nereus Pharmaceuticals to develop marizomib from the deep sea bacterium Salinispora. Clinical trials are showing that marizomib is highly active against several cancers. Indeed, it completely cured one patient with cutaneous marginal zone lymphoma.
SIO researchers and Nereus Pharmaceuticals also discovered and developed Plinabulin, a derivative of the natural marine product halimide. Plinabulin selectively targets the blood vessels in breast and other solid cancers, thus disrupting the flow of blood to them. This drug is benefiting patients with non-small-cell lung cancer in clinical trials.
Another important discovery involves melanoma. A unique marine bacterium, Serinicoccus, produces a novel drug called Seriniquinone that targets several melanoma cell lines in the lab; it is particularly hostile to one dangerous form of metastatic melanoma. Seriniquinone has a unique way of inducing apoptosis, or natural cell death. It inactivates the recently discovered target dermcidin in melanoma cells, prompting natural defenses that cause the cells to kill themselves.
Seriniquinone is still in early development, but its unique, selective way of attacking a deadly, rapidly spreading melanoma highlights the growing importance of the oceans in cancer research. Lucky for us, scientists like Bill Fenical get wet to keep the rest of us high, dry and healthy.
—Scott M. Lippman, MD, is Director of UC San Diego Moores Cancer Center. His column on medical advances from the front lines of cancer research and care appears in the La Jolla Light the fourth Thursday of each month. You can reach Dr. Lippman at email@example.com
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