Colonies of Ecteinascidia turbinata, the species from which Yondelis® is derived. (Photos: PharmaMar, SA)
By Dolores García Grávalos
Scientists the world over are searching for the next wonder drug that may cure cancer or treat tuberculosis. Dolores García Grávalos, the author of this article, is cited as co-inventor on the US patent for Kahalalide F 1, a compound derived from a sea algae, currently in phase II clinical trials for the detection of prostate cancer.
The discovery of penicillin in 1928 triggered a systematic search for other terrestrial micro-organisms that could be used in new antibiotics, leading to the discovery of drugs such as streptomycin, neomycin, chlorophenocol and chlorotetracyclin. For many years, research focused on terrestrial plants and micro-organisms, mainly because specimens are easy to obtain. But a growing proportion of today’s promising pharmaceutical research focuses on the sea, where marine organisms have evolved biologically unique molecules.
Life began in the sea, and three-quarters of the Earth’s surface is covered by water. Innumerable organisms, displaying rich biodiversity, populate the ocean depths. There are extremely diverse species of invertebrates – fixed or sessile – many in plant form and others capable of slow, primitive movement. These invertebrates possess no physical defenses such as protective shells or spines; instead, they have developed biologically active molecules – secondary metabolic substances – that they use to attack prey or defend their habitat. The fascinating variety of marine organisms hints at a myriad of new possibilities for drug discovery.
Exploration of the sea and its organisms is still at a relatively early stage. Although the oceans contain much greater biodiversity than is found on land, efforts to exploit this biodiversity by identifying new chemical compounds have hardly begun: at present, there are some 11,000 marine-derived natural products compared with more than 155,000 natural, terrestrial products.
Sponges became the focus of many studies after the discovery, in 1959, that some produced active antimicrobial substances. Research soon revealed that other invertebrates, such as tunicates, ascidians, echinoderms, bryozoans, corals and molluscs, produced similar substances. Biologists and chemists worldwide began searching for natural products of marine origin, leading to a boom in marine bio-prospecting – the search for aquatic organisms for the research and development of new therapeutic products. The discovery in the 1980s of various marine-derived compounds with the ability to inhibit cell culture growth stimulated the interest of the pharmaceutical industry.
There are several phases in marine product research: specimen collection; establishing taxonomy; extracting possible active molecules; using screening techniques to evaluate therapeutic activity; identifying and isolating the structure responsible for the activity; and using organic synthesis to ensure a supply. Patent applications are immediately filed for promising molecules. These molecules are then tested and, if the results are positive, studies are carried out on human subjects in clinical trials. Once this last phase has been completed, the product is registered as a new drug and brought to market.
Treatment for soft tissue sarcoma
Yondelis®, the first treatment for soft tissue sarcoma to be released on the market in 30 years, offers an excellent example of the kind of drugs that can be developed through marine organism research. PharmaMar, a Spanish biopharmaceutical subsidiary of the Zeltia Group, was established in 1986 with the primary goal of investigating marine resources for new active ingredients that could have an application in the treatment of cancer. The company’s pioneering research in this area was rewarded in 2007, when both the European Medicines Agency (EMEA) and the European Commission authorized the marketing of Yondelis (trabectedine). The agent is the first marine-derived anti-tumoral drug developed by a Spanish company. Its approval confirms the sea’s potential as a source of new drugs.
The drug was derived via extraction from the ascidian Ecteinascidia turbinata (popularly referred to as sea squirt). The need to collect large quantities of ascidian from the sea to isolate active ingredients led to the development of mariculture techniques and organic synthesis of the product. The drug can now be obtained via hemi-synthesis from cyanosafracine, a metabolic substance of the bacteria Pseudomonas fluorescens.
Ascidians (Ascidiacea) are benthic invertebrates that live at the bottom of the sea in solitary or colonial forms. They belong to the class of tunicates, so named because their body wall secretes a covering, or tunic, composed of a cellulosic substance called tunicin. The ascidian Ecteinascidia turbinata is found in the tropical and sub-tropical Atlantic, from the Mediterranean coast to northern Brazil and the Caribbean. The species is present in all coastal ecosystems from inter-tidal beds to outer reefs.
Other marine-derived products
Ecteinascidia turbinata
Other pharmaceutical companies – such as Novartis, Aventis, Eli Lilly, Inflazyme Abbott, Wyeth and Taiho Pharmaceuticals Co. – have marine-derived therapeutic products in the pipeline. The examples that follow concern products currently in the clinical research phase.
Didemnin, the first marine compound subjected to phase II human clinical trials for the treatment of certain cancers, was isolated by the Rinehart Group at the University of Illinois from the tunicate Trididemnum solidum. It proved so toxic that it was rejected as a therapeutic drug source. Nevertheless, its development laid the foundation for large-scale cultivation and extraction of marine organisms, which proved essential for the development of other drugs from the sea. Didemnin has now been replaced by aplidin, manufactured by PharmaMar. Aplidin is obtained from the tunicate Aplidium albicans and is structurally quite similar to didemnin but less toxic. Aplidin, currently in phase II of clinical development, was granted orphan drug status* by the US Food and Drug Administration (FDA) in 2004 for the treatment of multiple myeloma and acute lymphoblastic leukaemia.
Bryostatin was discovered at Arizona State University, where researchers isolated it from the bryozoan Bugula neritina. The first clinical trial was conducted by the US National Cancer Institute (NCI). It was necessary to collect 13 metric tonnes of the organism to derive 18 grams of the compound. Bryostatin is being developed by GPC Biotech in Germany and is in phase II of clinical testing as a treatment for esophageal cancer for which it was granted FDA orphan drug status in 2001. It has further served as a model for the preparation of many synthetic analogues.
Numerous bioactive peptides have been derived from the sea hare Dolabella auricularia, including the anti-tumoral dolastatin 10, discovered at Arizona State University. Even though this compound, which is currently undergoing phase II clinical trials, has shown insufficient activity against various tumors, it has served as a model in the preparation of several synthetic analogues under development by different companies and research centers, some of which have entered the clinical research phase.
Kahalalide F, a cyclic depsipeptide, is produced by algae of the Bryopsis genus, albeit in minute quantities (5 mg derived from 3 kg of algae). A more adequate source can be found in the sea mollusc Elysia rufescens, which feeds off algae, concentrating the compound (2.1 g derived from 216 g of mollusc). This compound, which has already been patented, is currently in phase II clinical trials for the detection of prostate cancer.
Despite the potential of marine organisms as a source of bioactive compounds, several challenges remain. The regulatory framework for access to and use of marine genetic resources from the high seas is unclear. And, as the examples of Yondelis and Bryostatin show, the difficulty in dealing with these organisms is the enormous amounts of raw material needed to yield usable quantities of compounds. This problem, in turn, has led to advances in mariculture techniques and organic synthesis.
* The orphan drug designation allows a pharmaceutical company exclusive marketing rights for the drug for the indicated treatment in the US for seven years following marketing approval by the FDA. The designation also enables the company to apply for research funding, tax credits on certain research expenses and a waiver from the FDA's application user fee.
Acknowledgement Anja Von Der Ropp, WIPO Life Sciences and Public Policy Section
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