Ocean Organisms a Source of New Anticancer Drugs

NEW YORK--The earth's oceans are yielding a multitude of new sourcesof anticancer and anti-HIV agents, possibly with unique mechanismsof action (see illustration on page 1). In only 8 years of operation,Pharma Mar, s.a. (Madrid, Spain) has developed a library of morethan 20,000 marine samples and has isolated some 350 novel marine-basedcompounds, including 40 that have been patented.

Jose Jimeno, MD, vice president of clinical research at PharmaMar, s.a., Spain's only biotech company, spoke to Oncology NewsInternational while visiting the United States to review withthe National Cancer Institute (NCI) several Pharma Mar productsundergoing trials there.

Also interviewed were Pharma Mar, s.a. president and CEO MichaelRosen, and vice president of preclinical research Glynn Faircloth,PhD. Dr. Faircloth is also chief operating officer of Pharma Mar,U.S.A. (Cambridge, Mass).

In addition to collaborations with the NCI, the company is workingwith the Pasteur Institute, Paris, the European Organization forResearch and Treatment of Cancer (EORTC), the EORTC's New DrugDevelopment Office (NDDO), and 29 research laboratories and universitiesaround the world.

"The NCI and EORTC are only interested in working with uniquecompounds with new mechanisms of action," Mr. Rosen said,"and all of the compounds that we are bringing forward appearto have potent and unique mechanisms."

Pharma Mar has developed methods for primary screening for anticancercompounds using a range of human tumor cell lines. "We screenin a disease-oriented way as opposed to a mechanistic approach,"Dr. Faircloth said.

The company first determines that a compound has anticancer activityand only later delves into possible mechanisms of action. "Ithink this is the opposite approach to some biotech firms wholook first at mechanisms of action and then test to see if theagent is effective," he added.

Dr. Faircloth said that the company has about 30 compounds inthe pipeline at various stages of development, "two in pre-INDthat should proceed to phase I clinical trials in the near future,and one currently in clinical trials."

"By 1996, we want to have five drugs in clinical trials atvarious stages," Mr. Rosen added.

The agent in clinical trials (phase II) is didemnin B (DB), developedfrom a tunicate (a marine invertebrate) found in the Caribbean.In studies of patients with previously treated non-Hodgkin's lymphoma,the agent achieved a 37% response rate, Dr. Jimeno said.

Didemnin B has shown activity in patients with HIV-related lymphoma,as well as prostate cancer.

According to Dr. Jimeno, neurotoxicity (fatigue and weakness)is the most important adverse effect seen to date with DB, buthas not been universal in the studies of non-Hodgkin's lymphoma.

DB may have two mechanisms, one through the immune system andone that directly affects the protein synthesis rate of oncogeneproducts.

Dr. Faircloth said that a recent study by Craig Crews, PhD, ofHarvard, has shown that DB binds to elongation factor-1-alpha(EF-1-alpha), at the ribosome level. EF-1-alpha enhances the translationrate of amino acids to growing proteins, and by blocking thisfactor, DB brings the translation rates down to normal. "Soone of its putative anticancer effects may be to slow down themachinery that induces cancer to make its own proteins,"Dr. Faircloth said.

In the non-Hodgkin's lymphoma studies, DB appeared to enhancethe proliferation of natural killer cells, an indirect immunosuppressanteffect that may correlate with its anticancer effect, he said.

DDB Has Similar Structure

While DB was isolated from a tunicate in the Caribbean, dehydrodidemninB (DDB) was developed from another tunicate found off the coastof Spain in the Mediterranean. Although the two organisms areof a different genus and species, the two agents derived fromthem have a similar chemical structure.

"It seems odd that the two different organisms conserve thestructure of this compound," Dr. Faircloth said, "soit must be important to them, and the small difference in structurehas shown itself to be important."

DDB has demonstrated strong antitumor activity against Lewis lung(one of the experimental models for non-small-cell lung cancer,or NSCLC), Dr. Faircloth said. The agent appears to have a goodtherapeutic index, and the optimal dose is "quite potent,"he added.

DDB is also currently being assessed at the Pasteur Institutefor it immunomodulation properties. The drug has been shown toinhibit apoptosis of T lymphocytes in the peripheral blood ofHIV-infected patients and seronegative donors. This could preventthe gradual depletion of these cells in HIV patients.

Phase I trials appear imminent for ecteinascidin-743 (ET-743),part of a family of eight ecteinascidins derived from tunicates.ET-743 has shown very strong preclinical activity in melanoma,ovarian cancer, and NSCLC. In vivo studies of human tumors ofthose cancer types are now underway in both chemosensitive andmarginally chemoresistant tumors, Dr. Faircloth said.

ET-473 appears to be much more potent than standard agents, hesaid. "When we compared the panel of in vivo activity toET-743 with the known standards such as fluorouracil and cyclophosphamide,we found an optimal dose for ET-743 in the range of 12.5 to 50mcg/kg. The optimal doses for the standard drugs were about 500to 1,000 times higher, so the potency of this compound is veryhigh."

In comparative studies performed at the NCI, ET-743 was extremelyeffective in inhibiting tumor growth in both early- and late-stagehuman mammary xenografts (MX-1), he said. Although pre-IND toxicologystudies on the compound are continuing, it appears to be effectivein the nontoxic dosing range, he said.

Mr. Rosen said that the company plans to file INDs this year forET-743 and DDB in both Europe and the United States, and hopefullyto go into phase I trials before the end of the year.

The company is seeking to establish a corporate alliance witha major pharmaceutical company in order to "push forwardmore compounds faster," Mr. Rosen said. "The issue rightnow is financial, but if we can establish a strategic alliancewith a major corporation, we will accelerate the development ofa number of these compounds," he said.

Collecting Samples From the Sea

Pharma Mar collects some 4,000 marine samples each year--invertebrates(such as algae, mollusks, sponges, and tunicates) and microorganisms(bacteria and actinomycetes).

"We have our own scientific expeditions using a researchvessel located in Spain and scuba divers to collect representativesamples," Dr. Faircloth said. Pharma Mar also has an investmentpartner, Pescanova, a Spanish company with a large fishing fleetthat collects organisms from all the earth's oceans.

When effective agents are identified, Pharma Mar has a numberof techniques to produce enough material for development. Marinemicroorganisms are being produced by fermentation methods, andseveral compounds in the Didemnin family, for example, have beensuccessfully synthesized.

When smaller quantities are required, the company may simply collectmore samples from the same location as the original. If significantamounts are involved, an environmental impact study is done first.

The company has also been successful in culturing organisms. Ecteinascidiaturbinata and several other tunicates are now routinely grownin aquaculture.