By Cathy Dunn

Robert Gardner loved to wrestle with his two sons‚ Robbie and Chris. But four years ago‚ the playful family tussles became excruciating for Gardner‚ who thought an ulcer was causing the severe pain in his stomach.

“I procrastinated quite a while before I went to my physician‚” says Gardner‚ a 45–year–old welder from Bridgewater‚ Massachusetts. “I didn’t have an ulcer. I had a soft tissue sarcoma growing in my intestine.”

Gardner had surgery to remove the softball–sized growth‚ but despite follow–up chemotherapy‚ the cancer spread to his liver‚ lungs‚ and pelvis. That’s when he decided to participate in clinical trials at Massachusetts General Hospital‚ Boston‚ where he was treated with Yondelis™ (ecteinascidin–743 or ET–743)‚ one of a new group of cancer–fighting substances derived from tiny sea creatures.

Yondelis‚ foremost among the powerful antitumor agents in clinical trials worldwide‚ is derived from the Caribbean and Mediterranean sea squirt Ecteinascidia turbinata. Yondelis shows promise in treating advanced‚ pretreated soft tissue sarcoma and is also being tested as a treatment for other cancers in clinical trials under way in Europe and the United States.

Soft tissue sarcoma‚ which typically develops in connective tissue‚ is notoriously difficult to treat. About 7‚500 new cases are diagnosed in the United States each year‚ which makes the disease fairly rare when compared with the more than 400‚000 cases of breast‚ ovarian‚ and prostate cancer diagnosed annually. Yondelis is also being tested in the treatment for these more prevalent cancers.

Searching the Seas for New Treatments
“The marine ecosystem has long been of interest as a source for effective clinical compounds‚” says José Jimeno‚ MD‚ vice president of scientific development for PharmaMar‚ the Spanish pharmaceutical firm developing Yondelis.

“The discovery of new anticancer entities developed from natural products adds greater dimension to the ocean’s therapeutic potential‚” says Dr. Jimeno. “The usefulness of the marine ecosystem in cancer treatment was established many years ago when Ara–C proved to be effective against acute myeloid leukemia. This agent is still the gold standard of treatment for this disease.”

Researchers at PharmaMar began studying the tubelike sea squirts in 1987‚ led by biochemist and company president José María Fernández Sousa–Faro‚ PhD. The tiny creatures used to produce Yondelis grow on coral reefs and are part of a class called tunicates‚ because their tough membranes resemble tunics.

Sea squirt toxin—100 times more powerful than Taxol® (paclitaxel)‚ a natural cancer treatment derived from the Yew tree—is so potent that a mere 0.05 ounce is enough to treat 100 patients. Only moderate numbers of sea squirts are needed to provide the raw material for Yondelis. In fact‚ only 15 to 29 milligrams of the drug are needed to treat one patient for up to six cycles.

Through their marine farms in the Mediterranean‚ PharmaMar has raised enough sea squirts to satisfy the demands of clinical trials.

Replicating Nature in the Lab
“An industrially feasible semisynthetic version of Yondelis has been developed by our chemists and will soon be incorporated into the clinical setting‚” Dr. Jimeno notes. “The drug has been referred to as one of the most complex molecules ever made on a commercial scale.”

The complexity of the substance appears to be what makes it so effective‚ according to Bruce Chabner‚ MD‚ chief of hematology and oncology at Massachusetts General Hospital.

“Yondelis attaches to the minor groove of a DNA molecule‚ then interacts with certain transcription factors that regulate genes in cancerous cells‚” says Dr. Chabner. “This interaction appears to stimulate apoptosis [cell death] and to block the MDR1 gene‚ which causes drug resistance in tumor cells.”

When given to patients with advanced soft tissue sarcomas‚ Yondelis produced encouraging results. In U.S. phase II trials‚ 47% of patients with advanced tissue sarcoma who had undergone prior chemotherapy treatment either experienced long–lasting tumor shrinkage or stabilization of the disease. In addition‚ 47% of patients who had not received prior chemotherapy also experienced stabilization or tumor regression.

In initial tests to determine dosage‚ Yondelis caused reversible liver damage in some patients. The drug’s other side effects include nausea and fatigue‚ but changing the dosage schedule in future studies may reduce these effects‚ notes Dr. Chabner.

“My side effects with Yondelis were mild compared to what I’d gone through with traditional chemotherapy‚” says Gardner‚ who continued to work full–time during his treatment course.

Gardner’s cancer did not respond to treatment with Yondelis‚ but his disease has stabilized as a result of his involvement with other clinical trials.“My positive experience with the Yondelis clinical trial gave me the courage to participate in other drug studies. Ultimately‚ Gleevec proved to be the right medication for me.”

It Takes Two: Powerful Combinations That Fight Cancer
“Typically‚ patients with soft tissue sarcoma are treated with doxorubicin as the first line of defense‚” says Dr. Chabner. “Only about 15% respond to the treatment initially and the cancer often recurs in a more drug–resistant form.
“We clearly need a better treatment and we’re encouraged by these findings‚” he says‚ adding that Yondelis trials are being expanded to include other types of cancer. “We’re very interested in testing the drug in combination with other treatments‚ too. Phase I studies combining Yondelis with conventional therapies such as taxanes‚ anthracyclines‚ and platinum salts are now under way.”

“It’s unlikely that a single entity will control a particular type of solid tumor‚” adds Dr. Jimeno. “But drugs like Yondelis paired with other therapies may prove to be relevant in successfully treating soft tissue sarcomas and other tumors in the future. Based on results to date‚ Johnson & Johnson will perform further clinical studies in the United States.”Meanwhile‚ PharmaMar and other pharmaceutical companies continue to search the seas for new compounds that may one day use natural substances to revolutionize cancer treatment.