BIOSYNTHETIC OPTIMIZATION OF BRYOSTATINS IN AQUACULTURE

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The commercial goal of this project is to develop technology for increasing the yield of the promising anticancer drug, bryostatin 1, from aquaculture of the marine bryozoan, Bugula neritina. Bryostatin 1, which is in Phase II clinical trials for treatment of several cancers, cannot be synthesized economically and must be obtained from the animal. Presently bryostatin 1 yields from the system are sub-optimal (7-8 mu g/g vs. 15-16 mu g/g dw from nature) due, in part, to sub-optimal amounts of biochemical precursors in the diet of laboratory-settled colonies. Proprietary aquaculture diets will be supplemented with specific essential lipids and known precursors of bryostatin 1 synthesis to determine which combinations induce the greatest yields of biomass and drug. Bryostatin 1 yields are expected to increase two-fold or more. Determining which bryostatin is the precursor to bryostatin 1 will help in designing the optimal diet. The metabolic relationships of the various bryostatins will be investigated using radiolabeled bryostatins in whole animal and cell-free experiments. The improved technology will allow CalBioMarine's aquaculture system to compete economically with natural collections of Bugulu neritina populations which could not sustain large-scale harvests on a year-to-year basis. PROPOSED COMMERCIAL APPLICATION: Provide for significant increases in overall yield of the anticancer compound bryostatin l in the biomass output from a commercial sea-based BuguLa neritina AquaPharm by improving diet through applying knowledge of the biosynthetic mechanisms, and addition of precursor substances to the diet formulation. Bryostatin yield-improvements in the range 2-3 times present yields are thought to be attainable, thus greatly reducing production costs, and allowing the system to be competitive.