About the project - Structure

In total, this program project is comprised of four projects and three core facilities. A diagram illustrating the overall structure and interrelationships is presented in Figure 1. A brief description of each component is presented below.

Figure 1 - Organization Chart

External Advisory Board - The External Advisory Board is comprised of the following individuals: Dr. Robert M. Moriarty, University of Illinois at Chicago; Dr. Koji Nakanishi, Columbia University; Dr. Michael B. Sporn, Dartmouth Medical School; Dr. Lee W. Wattenberg, University of Minnesota. The External Advisory Board has been retained due to their personal knowledge of our program, the experimental approach, and our contributions and progress. Annual External Advisory Board Meetings have been organized to present progress attained over the course of each year. These meetings are attended by all personnel working on the program project and the External Advisory Board. In addition, the meetings are attended by Dr. Richard C. Moon and the National Cancer Institute Program Director. They are designed to present progress attained over the course of the year. The External Advisory Board provides comments or suggestions during the course of the meeting and during the round-table discussion at the end of the presentations. They provide ideas for long-range plans, assessing progress, and implementing any significant changes in direction. The External Advisory Board provides a comprehensive report after each meeting. The dates of previous meetings were: August 11, 1999, October 20, 2000, January 9, 2002, and January 28, 2003. The Administrative Core will handle all arrangements, and maintain and circulate a record of the proceedings.

Project 1 (Chemopreventive Agents: Marine Natural Products) - Dr. William Fenical, Project Leader. As part of this project, deep ocean sediment-derived microorganisms will be collected and characterized. Extracts will be prepared, and tested by Projects 3, 4 and Core C. Active leads will be subjected to bioassay-directed isolation procedures and isolates will be structurally defined. These isolates will be considered as drug candidates, and subject to the work conducted in Projects 2, 3, or 4, or Core C. As appropriate, work will be undertaken for strain improvement, mutation and culture modification to produce related metabolites when structural novelty and bioactivity profiles warrant such work, and mass scale cultivation may be employed to supply gram quantities of target molecules for more advanced testing and analysis.

Project 2 (Chemopreventive Agents: Synthesis and Modification) - Dr. Mark S. Cushman, Project Leader. Initial lead chemopreventive agents will emerge from Project 1 or Core C. Structures will have been elucidated and some indication of biologic potential will be available. This project will provide both natural product synthesis as well as the design, synthesis, and development of novel analogs of the chemopreventive agent isolates. In cases where only small amounts of isolates are available, larger quantities may be provided through syntheses. Moreover, on a case-by-case basis, agents will be chemically modified to improve factors such as potency, efficacy, stability, and solubility. This work may include the study of structure-activity relationships, as well as rational design based on the target structure, using computer graphics molecular modeling approaches. Analogs will be evaluated in close collaboration with Projects 3, 4, and Core B.

Project 3 (Chemopreventive Agents: Structural Biology) - Dr. Andrew D. Mesecar, Project Leader. A primary activity of this project will be determination of three-dimensional structures of active compounds identified or produced in Project 1, 2, or Core C in complex with protein targets. This work will elucidate structural aspects that will be instrumental in guiding the synthetic efforts of Project 2. Beyond these key initiatives, purified protein targets will be produced and provided to Project 4 and Core C, and small molecule structures of natural or synthetic compounds provided by Project 1, 2, or Core C will be determined.

Project 4 (Chemopreventive Agents: LC-MS-MS-based Evaluation) - Dr. Richard B. van Breemen, Project Leader. There are a variety of approaches through which the power of LC-MS and LC-MS-MS can be employed to enhance the discovery and development of cancer chemopreventive agents. For example, we have developed a pulsed ultrafiltration mass spectrometry method that has proven useful for the rapid discovery of compounds that bind to important target molecules (e.g., COX-2, ER, RxR). Working in close collaboration with Project 1 and Core C, the method will be used to obtain compounds from extracts. The isolates will be further assessed in Core B, and may be candidates for further analysis in Project 3. In addition, LC-MS-MS methods have been devised to study metabolism of chemopreventive lead compounds, as well as intestinal permeability. This information will be critical for work to be performed in Project 2. Finally, LC-MS-MS will be used to confirm molecular weights, elemental composition, fragmentation patterns, and purity of compounds, and these data are relevant to all projects and cores, especially Projects 1, 2, and Core C.

Core A (Administrative Core) - Dr. John M. Pezzuto, Core Leader. The core is designed to perform organizational and managerial tasks that will benefit each of the five projects as well as Core B. The core will help coordinate the efforts of the entire program project, distribute necessary materials and information to all principal investigators, coordinate group meetings and sharing information, handle communication with the NCI and others interested in the work, etc. In addition, the core will serve as the primary contact point for the External Advisory Board, and make arrangements for all meetings. Finally, Dr. Bruce A. Craig, Co-Investigator, will help with all biostatistical aspects of the program projects, and he is a member of Core A.

Core B (Chemopreventive Agents: Biological Evaluation) - Dr. John M. Pezzuto, Core Leader. This core will interact with all of the projects and Core C. As examples, extracts will be provided by Project 1 and Core C, and assays will be performed to identify active leads, and subsequent bioassay-directed fractionation. There will also be close interaction with Project 2 in facilitating the optimization of new isolates. In addition, protein targets produced in Project 3 will be supplied to this core, and follow-up work based on studies conducted in Project 4 will be performed in this core. Of great importance, based on the collective efforts of all projects and Core C, compounds will be selected for full-term cancer chemoprevention studies in animal models. These investigations will be conducted in Core B. Dr. Richard C. Moon, Co-Investigator, will be responsible for evaluating progress and results, and making recommendations regarding the best course of action with regard to in vivo studies. He will assist in coordinating scientific activity and will be involved with experimental design and study interpretation in the use of animal models. He will also be involved in reviewing protocols and reports for all animal studies, and will provide histopathologic consultation for such animal studies.

Core C (Chemopreventive Agents: Plant Natural Products) - Dr. Ching-jer Chang, Core Leader. As in the past, the primary objective of this project is the discovery of novel chemopreventive agents from terrestrial plants. Plants will be collected, extracts will be provided to Core B and Project 4 for evaluation, and structures of active constituents will be determined. These isolates will then be considered for further development employing any of the resources and talent of Projects 2, 3, or 4. The ultimate objective will be to have isolates or derivatives of isolates tested in animal models by Core B. Dr. Harry H. S. Fong, Co-Investigator will be responsible for the procurement of candidate plant materials, including field collection, cultivation, and commercial purchase, as well as supervision of the drying, milling, and the preparation of the initial extracts of these materials. He will also be responsible for the large scale re-isolation of active secondary metabolites.