Eduardo Martinez (left) and E.J. Corey use a “stick” model and diagram to show the chemical structure of phthalascidin, a potent new cancer drug that they synthesized. Staff photo by Kris Snibbe. 
A cut-away drawing of a sea squirt.

Sack-like sea squirts living on the sea floor make a complex anti-tumor drug hundreds to thousands of times more powerful than any cancer potion now in use. For the past six years, chemists have been trying to do the same thing more efficiently and without the ecological mayhem involved in scraping the squirts off Caribbean coral reefs in large numbers.

Researchers at Harvard University have finally succeeded.

“I believe it’s the most complicated molecule ever made on a commercial scale,” says Elias J. Corey, winner of the 1990 Nobel Prize in chemistry, in whose laboratory the compound was first fashioned. Called ecteinascidin (ek-TIN-aside-in), the drug is being tested on terminally ill patients suffering with cancers of the blood vessels, tendons, muscles, and other soft tissues. “That’s the most striking result so far,” adds Corey. “There hasn’t been effective chemotherapy for such cancers.”

A newer method of producing ecteinascidin, recently developed by Corey and graduate student Eduardo Martinez, “should speed up and simplify mass production of the anti-tumor substance, potentially making the drug more available to patients,” according to the American Chemical Society.

Ecteinascidin is so powerful that a mere 11 pounds of it should be enough to satisfy the present world demand for an entire year, Corey estimates.

To top that, Corey and Martinez have now come up with a simpler and less expensive version of ecteinascidin called phthalascidan (THAL-aside-in).

Outdoing the Squirts

 

Kenneth Rinehart of the University of Illinois first discovered the drug while diving on reefs in the West Indies in the late 1980s. He collected samples of a sea squirt known to biologists as Ecteinascidia turbinate and checked their tissues for substances having anti-tumor activity. Rinehart wasn’t just amusing himself; he had a research vessel and a National Institutes of Health grant to see what medicines he could find in the sea.

Despite the potential of the drug, purifying it turned out to be laborious and expensive. Ten pounds of sea squirts yielded only millionths of an ounce of ecteinascidin. A Spanish company, Pharma Mar, has tried growing the sea squirt on underwater farms in Puerto Rico and Spain, but with only limited success. Rinehart, who knew Corey when both were professors at the University of Illinois, asked him whether he could help overcome these difficulties.

In 1994, Corey instructed David Gin, a post-doctoral fellow at Harvard, to see if he could make the drug synthetically. Two years later, Gin completed the task. Corey calls that synthesis “a notable achievement,” one that launched Gin into a high-orbit scientific career.

To obtain enough ecteinascidin for tests with humans, however, a simpler, more efficient process was needed for making it. Under Corey’s guidance, Martinez developed such a process. “It’s a very elegant and efficient synthesis,” Corey says.

Harvard patented the method, and licensed it to Pharma Mar which supplies it for human tests now underway at Massachusetts General Hospital in Boston, the M.D. Anderson Cancer Center in Houston, Sloan-Kettering Cancer Center in New York City, and in Europe. Hundreds of patients are involved.

“It’s one of the most promising drugs being tested,” says Bruce Chabner, a Harvard professor of medicine in charge of the tests at Massachusetts General Hospital. “We see [good] responses among patients with soft-tissue sarcomas (cancers) and among those with breast cancer and melanoma (lethal skin cancer). However, it’s not clear yet what the future of the drug will be. Compounds with this kind of early success record have eventually failed in the past. We just can’t be sure.”

If the drug does live up to promise, it could be on the market in five years. In that case, Pharma Mar will need to produce only pounds rather than tons of the drug, because patients are responding positively to exceedingly small doses of ecteinascidin. A course of treatment consists of nine injections or a total of less than 14 milligrams of the drug. (A single aspirin contains 325 milligrams.)

There are about 7,000 new cases of soft-tissue cancer in the United States each year and many more in the world. So far, human tests are “demonstrating the exquisite sensitivity of these tumors to minute amounts of ecteinascidin,” Corey notes. “It’s 100-to-500 times more potent that paclitaxel (Taxol), a drug commonly used against breast and ovarian cancers.”

How the drugs work

With so much potential, Corey decided to design a drug that is structurally simpler, easier to make, and comparable to ecteinascidin in potency. He and Martinez came up with phthalascidin on their second attempt. Martinez continued the work, making more than 60 other versions, but none of them proved easier to make or more potent than phthalascidin.

Corey calls the result “a striking discovery.”

Harvard has applied for a patent on phthalascidin. Pharma Mar and many other drug companies have expressed interest in licensing it.

Both drugs work by interacting with DNA and an unknown protein in cancer cells. “We’re trying to identify the protein and determine the specifics of this interaction,” Martinez notes.

The drugs do not kill tumor cells; rather, they prevent them from reproducing and growing. Most drugs now used in chemotherapy kill both cancerous and healthy cells, resulting in punishing side effects. “We expect ecteinascidin and phthalascidin to be better tolerated by patients,” Corey states.

Another closely watched drug, called endostatin, is undergoing human tests in various centers around the country. It works by blocking the development of blood vessels that bring oxygen and sustaining nutrients to tumors. “If endostatin works as well as expected, presumably we could use it together with ecteinascidin or phthalascidin,” Corey says.

To demonstrate the potential and potency of the latter drugs for treatment of other cancers, Martinez and Corey tried them on drug-resistant colon, lung, melanoma, and prostate tumor cells growing in laboratory dishes. In all cases, phthalascidin effectively destroyed these cells. Corey adds that “the costs of the new compounds should not be prohibitively high.”

If phthalascidin works as well in patients as it does in lab dishes – and that’s still a big “if” – Corey will add to his Nobel reputation as a master of developing innovative ways to make laboratory versions of complex substances found in nature.

“I love to discover new chemistry, and to help my students achieve major research goals,” Corey says. “It’s especially satisfying when this leads to medically useful compounds that benefit people who are ill.”