The goal of this project is to pursue the pre-clinical development of 10 active leads with selective cancer cell cytotoxicity. Extracts (320) of 160 biologically diverse temperate and polar marine macroorganisms, representing regions largely unexplored by other discovery programs, were evaluated in a preliminary study. Actives were determined by random screening against a panel of cancer cell lines that compared growth inhibition of the L1210 murine and CCRF-CEM human leukemias versus severe drug insensitive tumors (murine colon 38, murine mammary 410.4, human colon H-116), and compared inhibition of a normal stem cell (CFU-GM) versus the murine and human solid tumor types. Phase I will purify sufficient material using activity-directed isolation methods from frozen archive raw tissue, no recollection is required. Active leads will then be evaluated in an animal model and their chemical structures will be characterized. Phase II will extend the effort by moving actives forward in the drug-development pipeline. The applicant expects that novel compounds with important anti-cancer activities will be discovered by this project. Lead candidates will be developed by White Point BioMarine and its collaborators through solid-tumor animal models, pharmacokinetics, preclinical toxicology and mechanism of action studies, at which time they will be patented and licensed to others for further development.
