Harvard and Japanese scientists say they have made a "historic" discovery in the development of anti-cancer drugs. In a new study released Monday, they say they have finally found a way to mass synthesize a complex class of promising cancer-fighting molecules derived from sea sponges. Their new strategy has already accelerated research on these molecules. including a planned clinical trial in humans.
The molecules are called halichondrins and were discovered by Japanese researchers in the mid-1980s in sea sponges. It quickly became clear that halichondrins were able to aggressively fight tumors in mice and laboratory boxes containing human cells, and in a different way from other existing treatments.
For decades, however, halichondrins were also a limited resource. They could not be developed with sponges significantly, and their complexity made their synthesis in a laboratory almost impossible. In the early 90s, scientists were able to artificially manufacture one of these molecules, called halichondrin B, without requiring more than 100 different steps. And as for the naturally made version, they could only produce a small amount at a time – about 1% of the total amount of ingredients used to make it.
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The discovery eventually led to the creation of a simpler compound based on Halichondrin B, developed by the Japanese pharmaceutical company Eisai, which has become an FDA approved drug for treating advanced breast cancer ( and later liposarcoma).
The authors of this new study – which includes some of the original researchers who synthesized the B-halichondrin – claim that their methods have now progressed to the point where they can finally get a relatively large supply of these molecules. Their work, detailed in Scientific Reports Monday, focuses on a particular drug candidate, called halichondrin, called E7130.
In this article, they describe their ability to produce just over 11 grams of E7130 at a time, with more than 99% purity (ie there is nothing else beside of the active ingredient). This might not seem like a lot, but it was more than enough to start testing on more important animals of the E7130 in mice. The same technique, they added, has since been licensed to Eisai for use in the ongoing phase 1 clinical trial to assess the safety of E7130 use in humans.
"In 1992, it was unthinkable to synthesize a quantity of gram of halichondrin, but we proposed it three years ago at Eisai," senior writer, Yoshito Kishi, professor of chemistry at Morris Loeb at Harvard. , who also contributed to the research on the B. halichondrine, said in a statement from the university. "Organic synthesis has reached this level, even with molecular complexity untouchable many years ago. We are pleased to see that our discoveries in basic chemistry have made it possible to synthesize this compound on a large scale. "
According to Kishi and his team, their work could also reveal even more optimistic information about the future of halichondrins as a cancer treatment. In the E7130 mouse studies, they found evidence that halichondrins did not only attack the microtubules of a tumor cell – the structures that give it its shape and stability – as previously thought; they could also promote certain cells and inhibit others in order to prevent the growth of a tumor.
This could mean that these molecules can work in combination with existing drugs to increase the chances of successful chemotherapy. For the moment, however, they are only planning to test the E7130 as a single drug for the treatment of rare cancers such as angiosarcomas (a cancer of the lining of the blood and lymphatic vessels), according to the team's paper. Eisai also plans to launch a second clinical trial of the drug, this time in the United States.
Of course, we should somewhat temper our expectations for experimental research, as promising as it may seem. But this is surely a good step forward for the development of cancer drugs in general: scientists can now face challenges that would have been impossible 30 years ago.