The objectives of this program are to utilize the Cyanamid Oncology Drug Screen (CODS) to identify and develop structurally novel marine and microbial natural products that have novel mechanisms of action against solid tumors and utility in the treatment of human cancer. This goal is accomplished through the following specific aims: 1. To screen approximately 1,200 marine invertebrate, fungi, and microorganism samples per year, provided by Drs. Ireland, Clardy, Maiese and Andersen. The CODS assay exploits the phenotypic diversity of 26 different human tumor cell lines in order to generate unique activity. 2. To provide biologic support for the bioassay guided purification of active metabolites. This will be achieved either by transferring appropriate cell lines and biochemical assays to the program leaders or can be conducted by this core biological program. 3. To conduct biochemical, gene reporter and flow cytometry studies to characterize the mechanism of action of screening leads. Compounds that act vs. non-validated oncology targets (e.g., signal transduction) or novel targets can be identified. Detailed biochemical studies on known oncologic targets (e.g., topoisomerase, tubulin, DNA) also enable us to identify compounds that act by novel mechanisms against these therapeutically relevant targets. 4. To conduct in vivo studies against a battery of human and murine tumor models to establish the in vivo efficacy of screening leads. 5. To screen for the immune response activity of samples not demonstrating antiproliferative or cytotoxic activity. In collaboration with Immunex, samples are evaluated for activity as immune response regulators that either stimulate the immune response and thereby suppress tumor growth, or that ablate chemotherapy induced myelosuppression. 6. To design and implement preclinical and clinical strategies for development of lead compounds.
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