Harvard and Japanese scientists say they’ve made a “landmark” discovery in cancer drug development. In a new study published Monday, they say they have finally found a way to synthesize in bulk a complex class of promising cancer-fighting molecules derived from sea sponges. Their new strategy has already helped speed up research into these molecules, including a planned clinical trial in humans.
Called halichondrins, the molecules were originally discovered by Japanese researchers in the mid-1980s in sea sponges. It became quickly apparent that they were capable of aggressively fighting tumors in both mice and lab dishes containing human cells, and in a way different from other existing treatments.
For decades, though, halichondrins were also a limited resource. They couldn’t be grown from sponges in any significant amount, and their sheer complexity made synthesizing them in a lab almost impossible. In the early 1990s, scientists were able to artificially make one of these molecules, called halichondrin B, but without not requiring more than 100 different steps. And as with the naturally made version, they could only produce a tiny amount at a time—roughly 1 percent of the total quantity of ingredients used to make it.
The discovery eventually led to the creation of a simpler compound based on halichondrin B, developed by the Japanese pharmaceutical company Eisai, that became an FDA-approved drug to treat advanced breast cancer (and later liposarcoma) in 2010.
The authors behind this new study—which include some of the original researchers to have synthesized halichondrin B—say their methods have now progressed to the point where they can at last make a relatively large supply of these molecules. Their work, detailed in Scientific Reports Monday, focuses on one particular halichondrin drug candidate, named E7130.
In the paper, they describe being able to produce just over 11 grams worth of E7130 at once, with more than 99 percent purity (meaning there’s little else beside the active ingredient). That might not seem like much, but it was more than enough to start larger animal trials of E7130 in mice. The same technique, they added, has since been licensed to Eisai to use in their ongoing Phase 1 clinical trial to evaluate whether E7130 is safe in humans.
“In 1992, it was unthinkable to synthesize a gram-quantity of a halichondrin, but three years ago we proposed it to Eisai,” senior author Yoshito Kishi, a Morris Loeb Professor of Chemistry at Harvard who also helped lead the research into halichondrin B, said in a release from the university. “Organic synthesis has advanced to that level, even with molecular complexity that was untouchable several years ago. We are very delighted to see our basic chemistry discoveries have now made it possible to synthesize this compound at large scale.”
According to Kishi and his team, their work might also uncover yet more hopeful news about the future of halichondrins as a cancer treatment. In the E7130 mice studies, they found evidence that halichondrins don’t just attack a tumor cell’s microtubules—the structures that give a cell its shape and stability—as previously thought; they might also promote some cells and inhibit others to prevent a tumor from growing.
That could mean these molecules can work in combination with existing drugs to boost the chances of successful chemotherapy. For now, though, they only plan to test out E7130 as a single drug for rare cancers such as angiosarcomas (a cancer of the inner lining of blood and lymph vessels), according to the team’s paper. Eisai also plans to start a second clinical trial of the drug, this time in the U.S.
Of course, we should somewhat temper our expectations of any experimental research, no matter how promising it sounds. But it’s almost surely a good step forward for the field of cancer drug development in general that scientists can now tackle challenges that would have been impossible 30 years ago.
17 June, 2019