Research / Clinical
Summary
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Diseases/Research Topics
Chemical Biology
Other Leadership Roles:
Director, Center for Marine Biotechnology and Biomedicine (CMBB)
Scripps Institution of Oceanography
The goal of CMBB is to provide research opportunities for staff and faculty from SIO and the UCSD campus to participate in the areas of marine medicine and biotechnology. CMBB does this by establishing facilities and resources directly relevant to the world’s oceans and their biota.
Our group conducts research relevant to defining the roles and biomedical applications of the unique organic molecules produced by marine life. Programs are integrated to isolate and define chemical compounds which function as chemical defenses and molecules used for communication, and to assess the potential of these same compounds in the treatment of human and animal diseases. In drug discovery, a major focus is upon cancer, inflammatory diseases and in the discovery of new anti-infectives. Research support from the National Cancer Institute, the National Science Foundation, the National Sea Grant Program, the California BioStar Program and various pharmaceutical companies provide financial support for these studies.
A major portion of our research program focuses on the discovery and preclinical development of new natural products useful in the treatment of cancer. An emphasis is placed upon the discovery of anticancer agents which show selective inhibition of various difficult cancers, especially those of the lungs, colon, breast, pancreas, prostate, ovaries and skin. With funding from the NCI, our group explores selected classes of marine animals and microorganisms with the goal to discover new potential drug candidates with improved capabilities in clinical treatment. This program has recently focused on several new mitotic inhibitors from marine invertebrates of the class Ascidiacea (sea squirts or tunicates). These animals possess novel chemical formulations which show potent activities against HCT-116 human colon carcinoma (the preliminary test cell line). Working with Drs. Gerrit Los and Stephen Howell from the UCSD Cancer Center, they were able to define the pharmacological mechanisms of action of two new drugs, diazonamide A and tamandarin A. Diazonamide A continues to be of interest for preclinical study at the NCI.
A major portion of this program explores marine microorganisms, bacteria and fungi, as an unexplored source for chemical diversity. This study has illuminated an entirely new source for new, naturally produced anticancer drugs. Over the past year, studies of sargassamide, halimide and avrainvillamide have shown that these molecules may have clinical utility. All three new drugs are produced by marine fungi found growing on the surfaces of tropical marine algae. When cultivated under laboratory conditions, the fungal strains produce these compounds in high yield. The three new molecules all show selective inhibition of certain cancer cell lines and possess in vivo activity in early preclinical models (P-388 lymphocytic leukemia). Most important, each of these molecules possesses unique features, i.e. avrainvillamide is selectively active against LN-Cap progesterone-dependent prostate cancer. Two of the three new drug candidates mentioned above have been licensed to the pharmaceutical industry and are in preclinical development.
A major developmental project continues on the Taxol®-mimic eleutherobin. Eleutherobin was discovered in 1995 and, through a collaborative program with Bristol-Myers Squibb, this molecule was demonstrated to be qualitatively and quantitatively identical to Taxol, the recently approved (and mechanistically novel) anticancer drug for breast and ovarian cancer. Because of the clear importance of this discovery, the development of eleutherobin will be a major effort of our group for several years to come.
Other Biomedical Research:
Other areas of drug discovery are integral to our interests in cancer. We have focused our interests on inflammatory diseases and the discovery of anti-infectives particularly antiviral drug discovery for Herpes simplex. In inflammation, our efforts target the discovery of new drugs which inhibit the arachidonic acid pathway. Several new agents, cyclomarin A, exumolides, and avrainamide show inhibition of edema and control of pain at levels equivalent to existing drugs (Indocin, Hydrocortisone).
In a new anti-infectives program, my colleagues and I are exploring marine compounds for their effects on methacillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, amphoterocin-resistant Candida albicans and upon the replication of Herpes simplex. A new class of antivirals with entirely novel mechanisms of antiviral action, the halovirs, has been recently discovered.
Chemical Studies of the Ocean:
Our NSF-sponsored research program aspires to define the roles of organic compounds in the marine environment. In this project, the molecules produced by marine organisms (invertebrates, plants and microbes) are evaluated for their effects on competitors, predators and pathogens. The roles of these molecules as agents of chemical defense and communication have illustrated the differences (between land and sea) and complexity of the marine environment. These studies are highly integral with those mentioned above. Fortuitously, many chemicals that function in defense also show promising effects in cancer and other diseases. This study highlights the value of understanding the fundamental roles that chemistry plays in survival and evolution.
Keywords: marine anticancer agents, marine microorganisms, natural products chemistry, drug discovery, compound isolation, structure elucidation, marine microorganism cultivation, pharmaceutical screening
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