Merging Marine-Derived Cytotoxic Natural Products With Experimental Therapeutics

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DESCRIPTION (provided by applicant): Our long-term objective is to discover and develop leads for new anticancer agents. This research utilizes a collaboration between the Marine Bioorganic Chemistry group at U. of California Santa Cruz (UCSC) led by Prof. P. Crews and the Developmental Therapeutics Program at the Josephine Ford Cancer Center (JFCC) led by Dr. F. A. Valeriote. The hypothesis is that small molecule natural products (<2000 amu), can be identified and used, to selectively inhibit the growth of solid cancer tumors. The aims outlined below will provide a foundation to discover and explore new biomolecules that will be of broad interest while also addressing general hypotheses guiding this research. Our focus is on tumors with relative insensitivity to most of the standard anticancer drugs. Thus, the overall aim is to obtain new compounds with effective activity against solid tumors, especially pancreatic, colo-rectal, breast, prostrate, brain, ovarian, and lung cancers. The general aims for the next grant period are: 1. To mine our repository of unstudied sponges either to continue or to begin new studies on both known and new bioactive, small biomolecules. 2. To use marine-derived fungi cultured in various media as a source for new active small biomolecules. 3. To use and refine our sponge-inspired hypothesis as the rationale for pursuing culture of Gram-positive and Gram-negative bacteria as a source of new active small biomolecules. 4. To utilize the in vitro cytotoxicity disk diffusion assay network to identify extracts obtained from Aims 1, 2, and 3 with solid tumor selectivity for follow-up fractionation and SAR expansion in Aim 6. 5. To make use of promising analytical methodologies, especially DART MS and DANS NMR, to guide further work on marine extracts, fractions, and library pure compounds obtained from Aims 1, 2, and 3. 6. To efficiently isolate, characterize and/or dereplicate compounds by focusing on the priority hits identified in Aims 4 and 5. 7. To continue capstone studies of solid tumor selective compounds through pharmacology evaluations and therapeutic assessment.