Cancer Treatment Inspired by a Sea Creature

A rare toxin produced by a sea creature called Diazona angulata appears to hold promise for treating many different types of cancer while minimizing the harmful side effects of widely used chemotherapy drugs, according to a University of California, Los Angles study published in November 2016 in the journal Science Translational Medicine. The paper describes research on a synthetic version of a substance called diazonamide that prevents cell division and was isolated from the marine animal.

A release from the university notes that the research team was Led by Patrick Harran, UCLA’s Donald J. and Jane M. Cram Professor of Organic Chemistry. The team produced a synthetic form of diazonamide that, in rodents, appears to be effective in fighting breast cancer, colon cancer, and leukemia. The compound the scientists synthesized, DZ-2384, is more potent and lasts longer in the bloodstream than natural diazonamide.

And, when combined with a chemotherapy drug called gemcitabine (which is marketed under the brand name Gemzar), the compound is effective in rodents for combating advanced pancreatic cancer.

DZ-2384 works by disrupting a molecular machine called the mitotic spindle, which the cell uses to pull replicated chromosomes apart during division. There are numerous compounds that affect spindle function, including several FDA-approved cancer drugs. These agents, which are called anti-mitotics, have a typical pattern of toxicity associated with their use. DZ-2384 is an anti-mitotic that behaves differently.

In the study, researchers implanted or grew tumors in hundreds of rodents as models for various types of human cancer. They found that in animals receiving DZ-2384, tumors shrank as much as or more than when a conventional anti-mitotic was used, but with much less toxicity at effective doses.

Animals receiving DZ-2384 also had markedly less peripheral neuropathy — a type of debilitating nerve pain that often affects humans who take anti-mitotic drugs — than those that received docetaxel, a conventional anti-mitotic. Peripheral neuropathy is one of the chief side effects of anti-mitotic chemotherapy, and it’s often severe enough that doctors decide to stop administering chemotherapy, at least temporarily, in order to reduce patients’ pain. But that’s problematic as well, because once treatment is suspended, tumors tend to return, and often in forms that are resistant to drugs.

Harran said understanding the unique way DZ-2384 functions in animals wouldn’t have been possible without the cooperation of specialists from several fields over the past 15 years.

“One piece of the puzzle after another came into place over time,” Harran said. “Now, we have the chemistry, the biochemistry, the structural biology, the pharmacology and toxicology. We have a deep understanding of what this drug is doing.”