New Frontiers in Marine Drug Discovery

Agenda

*Presentation times are subject to change.

Abstracts

SESSION I: What is Marine Biomedicine?

The Multidisciplinary Nature of Marine Biotechnology Stimulates Innovation and Creativity

William Gerwick, Scripps Institution of Oceanography and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA

Marine biotechnology is inherently multidisciplinary, involving such fields as marine biology, analytical and organic chemistry, biochemistry and chemical biology, material science, genomics and proteomics, chemical ecology, pharmaceutical biology and agrochemical sciences, as well as many other diverse areas of science. A natural consequence of this is that individual studies are enriched by their drawing on various scientific methodologies and interesting aspects from these different fields of inquiry. For example, there are numerous opportunities to borrow scientific techniques common to one discipline and apply them innovatively to other areas and questions. As an illustration, in my research laboratory, we are integrating a phylogenetic and biological understanding of different marine cyanobacteria to help select the most promising species for pharmaceutical drug discovery efforts, and then using a genomics and molecular biological approach to understand how their unique natural products are created at a genetic and biochemical level. Ultimately, we hope to harness and capture these biochemical systems so as to possess a ready source of the natural products as well as to create novel molecular entities through genetic engineering of their biosynthetic pathways. In these regards, marine biotechnology is also enhanced through the integration of basic scientific investigations with those that have real world applications, as for marine pharmaceutical drug discovery efforts or development of proteins of industrial value. It is at the confluence of these various disciplines that new discoveries are frequent, and this continues to advance the field forward as well as keep it scientifically vigorous and rich in vitality.

From the Oceans to the Clinic

George R. Petitt, Arizona State University, Tempe, AZ

The most tragic death toll in the United States, and on a much larger scale, internationally will not be reduced until more generally affective and curative anticancer drugs are discovered and developed. Although a relatively small number of anticancer drugs are now available that have greatly improved cancer treatment and provided various levels of curative treatment for some 20‐25 types of human cancer, 12 of the major types of human cancer are usually refractory to current anticancer drugs and urgently require discovery and development of routinely curative anticancer drug treatments. As in the past, and certainly far into the future, the vast array of living organisms available for new anticancer discovery and for other lethal diseases across the medical spectrum is in the tens of millions. Currently we have over‐whelming evidence that marine organisms represent a fabulous array of opportunities for discovery of such new drugs.

Our pioneering research directed at evaluating a broad selection of marine organisms from diverse ocean areas in 1965 forward has certainly helped accelerate interest in exploring marine microorganisms, invertebrates, and vertebrates as new sources of improved drugs for a great variety of indications. Even now, less than 0.5 percent of the marine animals for example, have received even a cursory effort to detect antineoplastic constituents. Thus, the most important marine animal and microorganism anticancer drug still await discovery. Furthermore, these natural products are a result of 3.8 billion years of evolutionary biosynthetic organic reactions aimed at even more specific molecular design and targeting. The net result of these trillions and trillions of biologically‐directed organic reactions (biosynthetic combinatorial processes) is an astronomical number of candidates for use as anticancer drugs and as drugs necessary across most medical indications. But they need to be discovered and developed to the clinic. Especially with the discovery of anticancer drugs our research group has been very fortunate to detect anticancer drug candidates in a variety of marine invertebrates and microorganisms.

Today’s summary will be focused on our discoveries of the Bryostatins, Dolastatins, Auristatins and current status in human cancer clinical trials. In addition a rapid summary of the preclinical status of the spongistatins, cephlostatins and two examples from marine microorganisms will be reviewed. The discovery of new drugs based on marine organism constituents represents an exceedingly productive and exciting Frontier for making great advances in medicine.

SESSION II: New Frontiers of Sea Product Discovery

New Paradigms for Marine Natural Product Discovery and Development

Shirley A. Pomponi, PhD, Harbor Branch Oceanographic Institute-Florida Atlantic University, Fort Pierce, FL

Sessile marine invertebrates have evolved sophisticated chemical mechanisms that may be used for communication, defense, reproduction, anti-fouling, regulation of calcium and sodium, and control of potential microbial pathogens. Their value as drugs is based on the fact that they interact with proteins that have been conserved throughout evolutionary history and that are involved in human disease processes, e.g., cell division and apoptosis, immune and inflammatory responses. In general, the roles of marine-derived compounds in the organisms that are producing them are not known. Better understanding of how and why these compounds are produced, as well as evaluation of marine natural products in non-traditional disease targets (i.e., other than cancer, inflammation, and infectious diseases) could lead to innovative approaches for the discovery of novel drug leads. Recent advances in sequencing one sponge genome may provide insights into such alternative approaches to the identification of novel targets for drug discovery. Research in our laboratory on sponge cell cycling and gene expression profiles offers another approach to the discovery of novel products, as well as the sustainable (in vitro) production of known products and the possibility for development of a marine invertebrate model for transgenic expression of other marine (non-sponge)-derived natural products.

Genomics-Inspired Discovery and Bioengineering of Marine Microbial Natural Product Drug Leads

Bradley S. Moore, Scripps Institution of Oceanography & Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, San Diego, CA

The natural product discovery process has not fundamentally changed in decades whereby new bioactive metabolites are identified through bioassay-guided isolation schemes. While this approach has been essential to the discovery and development of many important clinical agents that have helped shape modern medicine, it is hampered by its own success in which known agents are rediscovered at a higher frequency than new chemical entities. The genomics revolution has recently provided an orthogonal approach to the discovery of natural product drug leads in which sequenced genomes are “mined” for biosynthetic pathways. Not only does this method provide a rational basis for guiding the isolation of new chemical entities, it also enables synthetic biology platforms to genetically reengineer biosynthetic pathways to extend nature’s chemistry. While promising, this emerging technology faces its own challenges. This seminar will focus on the status, challenge and future potential of genome mining in the natural product discovery process in relation to marine microbial systems.

Genomic Approaches to Animal Marine Natural Products

Eric W. Schmidt, PhD, Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT

Marine invertebrate animals provide a robust source for the discovery of bioactive small molecules with the potential to treat human diseases. More than 20,000 such compounds have been discovered, an amazing total that is due in part to the immense biodiversity of marine invertebrates and in part to a large variation in compounds even within seemingly identical animals. Metagenomics affords an efficient and inexpensive method to capture this chemical diversity. Such methods have already been applied to discover and supply new “invertebrate” compounds from tiny animals that are not accessible through chemical means, to provide a renewable supply of coral reef animal products, and to engineer variants for preclinical evaluation. In addition, metagenomics is providing renewed insights into what chemical diversity means and how it originates in the ocean.

Anticancer Leads from Marine Cyanobacteria: Novel Chemistry and Biology

Hendrik Luesch, PhD, Department of Medicinal Chemistry, University of Florida, Gainesville, FL

Marine cyanobacteria dedicate a significant portion of their genome to the production of secondary metabolites, especially antiproliferative natural products, some of which are selectively cytotoxic against cancer cells over nontransformed cells and therefore suitable candidates for anticancer drug development. The microtubule agent dolastatin 10, produced by cyanobacteria of the genus Symploca, had reached phase II clinical trials. More recently we discovered the cancer cell selective compound largazole from another Symploca collection, which is at the preclinical stage and targets a different protein. The key to advancing lead compounds for drug development is not only solving the supply problem, but also identifying the molecular target and mechanism of action. Largazole is the most potent natural histone deacetylase inhibitor known to date and shows promising activity against a variety of cancer cell types, but also efficacy for other disease indications. A structure-based approach resulted in the identification of largazole’s target. For other prioritized compounds that result from our marine drug discovery efforts, we apply genomic and proteomic profiling techniques to gain insight into how they act globally on the molecular and cellular level, which has led to the identification of novel mechanisms of action.

SESSION III: From the Sea to the Bedside: Lessons from Pioneering Successes of Marine Biomedicine

Lessons Learned Developing Bioactive Marine Compounds into Cancer Drugs

Paul G. Grothaus, PhD & David J. Newman, Natural Products Branch, Developmental Therapeutics Program, National Cancer Institute, Frederick, MD

Will discuss the methods used initially to develop compounds such as didemnin B and the dolastatins and how the lessons learned from these early preclinical and clinical trials led to changes ranging from acquisition of compounds to novel delivery systems. Several of the other speakers represent companies and organizations with whom the NCI Natural Products Branch has collaborated to advance marine compounds to the clinic. Their compounds will only be mentioned en passant.

The Success of Marine Microbiology as a Source for New Anticancer Agents

G. Kenneth Lloyd¹, Kim S. Lam¹, Barbara Potts¹, Michael Palladino¹, Matthew Spear¹, William Fenical², Paul Jensen², Yoshio Hayashi^3
1Nereus Pharmaceuticals Inc, San Diego, CA
²Scripps Institution for Oceanography, UCSD, San Diego, CA
³Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan

Marizomib (salinosporamide A, NPI-0052) is a potent (IC50 of 1-10 nM), novel, selective pan-inhibitor of the 20S proteasome. Extensive work showed that the natural product appeared to be the most appropriate development candidate, and that fermentation of the marine actinomycete, salinispora tropica, was the most efficient route of synthesis. Preclinical profiling suggested hematological malignancies as the primary clinical target and trials are undergoing in multiple myeloma and lymphomas. Proof of concept has been demonstrated with marked proteasome inhibition in patients at doses that are well tolerated. Efficacy is suggested by decreases in biological markers for multiple myeloma and by the complete response in a patient with cutaneous marginal zone lymphoma.

Plinabulin (NPI-2358) is a highly selective tumor vascular disrupting agent with marked activity in several tumor models. Extensive analogue efforts of the natural product discovered from a marine fungus greatly enhanced both the potency and the physical chemical characteristics of the natural product, and plinabulin, a synthetic analogue was selected for development. In Phase 1 studies, plinabulin was demonstrated to reduce tumor blood flow at well tolerated doses, and development progressed to Phase 2 studies in non-small cell lung cancer in combination with the standard-of-care agent docetaxel. Preliminary results are very encouraging both from efficacy and tolerability perspectives .

Thus, marine microbiology has been demonstrated to be a viable resource for potential anticancer agents. As this is a renewable resource that does not leave an environmental footprint, marine microbiology appears to be an exciting new frontier in marine drug discovery.

From Halichondrin B to Eribulin

Melvin J. Yu, PhD on behalf of the Eribulin Team, Eisai Inc., Andover, MA

Breast cancer represents one of the leading causes of cancer death among women in the United States. As a result, new treatment options that improve overall survival in patients with advanced or recurrent metastatic disease are greatly needed. The safety and effectiveness of eribulin mesylate (HALAVEN™) was demonstrated in a pivotal phase III clinical trial, where an overall survival benefit was shown in women with heavily pretreated metastatic breast cancer compared with treatment of physician’s choice. This agent was subsequently approved by the FDA for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting. Eribulin, a non-taxane inhibitor of microtubule dynamics with a distinct spectrum of biological effects, is a totally synthetic macrocyclic ketone analogue of the structurally complex marine natural product halichondrin B. The challenges associated with the discovery and structure-activity relationship investigation of this new anticancer drug will be discussed.

Yondelis: A Twenty-Year Pathway From Discovery To The Clinic

Arturo Soto-Matos, MD, PharmaMar, Madrid, Spain

Yondelis is derived from the colonial tunicate Ecteinascidia turbinata and its molecular structure was first elucidated in 1990. Initially, the source of the drug substance consisted in farming the tunicate in mariculture and aquaculture plants, method that was considered insufficient for the supply of the whole preclinical and clinical programs. The chemical synthesis with a feasible, large-scale process was completed by the PharmaMar team in 2000. Preclinical studies, started in 1994, demonstrated activity of Yondelis in a broad spectrum of solid tumor cell lines, both in vitro and in vivo. In 1996, the first patient was treated with Yondelis. The initial Phase I clinical trials with Yondelis administered as a single agent, included seven different administration schedules from which two were finally selected for further development: infusions of 3 and 24 hours every 3 weeks. During the Phase II clinical development, which started in 1998, Yondelis showed activity in many different tumors, including sarcomas, ovarian, prostate and breast cancers. Yondelis was approved in the European Union (EU) in 2007 for the treatment of soft tissue sarcomas after doxorubicin and ifosfamide, and for patients unsuited to receive these agents. The basis for the approval was the activity of Yondelis in several Phase II trials, including a large randomized trial. In 2009 a Phase III trial of Yondelis in combination with pegilated liposomal doxorubicin finished, serving for the approval of Yondelis in the EU and many other countries in platinum-sensitive ovarian cancer patients. Up to today, more than 12,000 patients have been treated with Yondelis.

Lessons from Ecteinascidin 743; Symposium Highlights and Future Directions

Yves Pommier, MD, PhD, National Cancer Institute, NIH, Bethesda, MD

Ecteinascidin 743 (Yondelis®) is presently approved in Europe for the treatment of sarcomas and in clinical trials for a broad range of tumors including ovarian cancers. We will summarize the molecular pharmacology studies that led to the identification of transcription-coupled nucleotide excision repair (TCR) as target for ecteinascidin 743 (1-4). We will also review the concept of interfacial inhibitors, which is highly pertinent to the mechanism of action of natural products (5). This will precede our closing remarks for the conference New Frontiers in Marine Drug Discovery.

1. Pommier Y, Kohlhagen G, Bailly C, Waring M, Mazumder A, Kohn KW. DNA sequence- and structure-selective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the carribean tunicate Ecteinascidia Turbinata. Biochemistry 1996; 35: 13303-9.
2. Takebayashi Y, Pourquier P, Zimonjic DB, et al. Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair. Nat Med 2001; 7: 961-6.
3. Aune GJ, Takagi K, Sordet O, et al. Von Hippel-Lindau-coupled and transcription-coupled nucleotide excision repair-dependent degradation of RNA polymerase II in response to trabectedin. Clin Cancer Res 2008; 14: 6449-55.
4. Guirouilh-Barbat J, Redon C, Pommier Y. Transcription-coupled DNA double-strand breaks are mediated via the nucleotide excision repair and the Mre11-Rad50-Nbs1 complex. Mol Biol Cell 2008; 19: 3969-81.
5. Pommier Y, Cherfils J. Interfacial protein inhibition: a nature's paradigm for drug discovery. Trends Pharmacol Sci 2005; 28: 136-45.

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