The overall objective of the proposed research project is to discover bioactive marine natural products that lead to novel chemotherapeutics for the treatment of pancreatic cancer. Although eleventh in occurrence, pancreatic cancer is the fourth cause of cancer death in the US, with over 33,000 deaths predicted for 2007. Aggressive new combination chemotherapeutic regimes coupled with surgery have resulted in an overall increase in mean survival rate, but even so, fewer than 5% of patients diagnosed with pancreatic cancer will survive five years post diagnosis. Clearly, novel therapeutics are required to treat pancreatic cancer. During the first performance period of the project we made advancements towards the development of new treatments for pancreatic cancer, including findings such as: the discovery of leideormatolide, a potent antimitotic agent, with selective activity for tumor cells, that does not work via tubulin; neopeltolide, a polyketide that induces G1 cell cycle arrest in cancer cells; and the finding that manzamine A can restore anchorage dependent growth in pancreatic cancer cells, block tumor cell migration and re-sensitize the ASPC- 1 pancreatic adenocarcinoma cancer cell line to TRAIL induced apoptosis. In this renewal application we seek to continue to use a forward chemical genetics approach to build upon these successes.
The Specific Aims of the proposed research are: 1. To assay materials from the HBOI marine specimen frozen repository for their ability to 1.1. modify levels of key proteins that have been identified as aberrantly activated in pancreatic cancers and which lead to cancer cell survival, resistance to apoptosis and resistance to currently available chemotherapeutic agents; and block the proliferation of a panel of pancreatic cancer cell lines 2. To utilize state-of-the-art MS and NMR techniques for rapid and accurate dereplication and structure elucidation of candidate compounds. 3. To elucidate the mode of action of materials discovered during the project and to take those compounds which give the best biological profiles forward into experimental models of pancreatic cancer. HBOI maintains a repository of over 20,000 frozen marine specimens which represent a unique collection of natural products for drug discovery. We will use the cytoblot assay to identify small molecules that target pathways that are aberrantly activated in pancreatic cancers and which lead to poor survival rates in patients. Our initial targets will be: the serine/threonine glycogen synthase kinase-3? (GSK-3?) which has been shown to activate nuclear factor-?B (NF-?B) transcription in pancreatic cancer cells leading to cell survival and proliferation; and the MAP kinase members P-MEK and P-ERK which are constitutively activated leading to cell survival, invasion and resistance to apoptosis. We will also continue to screen materials against a panel of pancreatic cancer cell lines.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56CA093455-05
Application #
7656970
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fu, Yali
Project Start
2001-12-01
Project End
2010-06-30
Budget Start
2008-08-22
Budget End
2010-06-30
Support Year
5
Fiscal Year
2008
Total Cost
$339,179
Indirect Cost
Name
Florida Atlantic University
Department
Type
DUNS #
004147534
City
Boca Raton
State
FL
Country
United States
Zip Code
33431
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Paterson, Ian; Dalby, Stephen M; Roberts, Jill C et al. (2011) Leiodermatolide, a potent antimitotic macrolide from the marine sponge Leiodermatium sp. Angew Chem Int Ed Engl 50:3219-23
Paterson, Ian; Naylor, Guy J; Fujita, Takeshi et al. (2010) Total synthesis of a library of designed hybrids of the microtubule-stabilising anticancer agents taxol, discodermolide and dictyostatin. Chem Commun (Camb) 46:261-3
Paterson, Ian; Gardner, Nicola M; Guzman, Esther et al. (2009) Total synthesis and biological evaluation of novel C2-C6 region analogues of dictyostatin. Bioorg Med Chem 17:2282-9
Wright, Amy E; Roth, Gregory P; Hoffman, Jennifer K et al. (2009) Isolation, synthesis, and biological activity of aphrocallistin, an adenine-substituted bromotyramine metabolite from the Hexactinellida sponge Aphrocallistes beatrix. J Nat Prod 72:1178-83
Isbrucker, Richard A; Guzmán, Esther A; Pitts, Tara P et al. (2009) Early effects of lasonolide a on pancreatic cancer cells. J Pharmacol Exp Ther 331:733-9