MERIT Award Recipient: William H. Fenical, Ph.D.
Antitumor-Antibiotics from Marine Microorganisms
The overall goal of this project is to identify untapped resources for the discovery of new, naturally occurring anticancer agents. This project is built on a longer history of NIH support in which the field of marine medical microbiology was conceived and developed. Previous studies explored the fundamentals of how to sample the vast ocean microhabitats, where to look for unique microorganisms (sediments, water, surfaces, and the surfaces and internal tissues of plants and animals), how to cultivate them, and how to maximize their importance in the discovery of new cancer treatments. The result of previous work was the discovery that marine bacteria do, indeed, produce molecules of clinical relevance. One agent, called halimide, is produced by a marine fungal strain of the genus Aspergillus. This compound, which will be advanced to clinical trials in 2004, is a potent cytotoxin agent with a novel mechanism of action.
The Fenical laboratory's most important discovery to date, which will dramatically influence their approach for the next year, is the discovery that the deep sediments of the world's oceans (to approximately 1300 meters) contain diverse actinomycete bacteria. The terrestrial actinomycetes are, historically, well known producers of bioactive metabolites for cancer treatment (i.e., doxorubicin), and have been credited with the production of over 100 drugs in current use. Over the past 24 months, they have identified more than 10 new groups of true marine actinomycetes, and more than 4,000 strains have been isolated from the Atlantic, Pacific, and Indian Oceans. These new actinomycetes are exclusively marine-adapted, and because of their remote, isolated habitat, have never interacted with the terrestrial species. Thus, these new microorganisms, which may number in the hundreds of thousands, could represent the most important drug resource since Fleming's impacting discovery of penicillin from ordinary bread mold.
The Fenical laboratory has not yet examined the vast majority of these microorganisms, but their first examination of a member of the new genus Salinospora convincingly demonstrated that new drug leads could be effectively discovered. Salinospora strain CNB-392, when cultured in the laboratory, produces a series of highly potent cancer cell growth inhibitors, the salinosporamides, some of which show selective antitumor effects against cell lines derived from non-small cell lung cancer, central nervous system cancer, melanoma, and breast cancer. The major drug candidate within the group, salinosporamide A, shows activity as an authentic inhibitor of the intracellular proteasome protein complex, an appealing target for the development of anticancer drugs. Over the next year, and in the subsequent years of this project, the Fenical laboratory looks forward to developing the clinical potential of these new resources for the treatment of cancer.