Core A will focus on biological evaluation of extracts, chromatographic fractions, and pure isolates prepared by all of the Projects within the Program in order to help prioritize subsequent biological and chemical work. This strategy of using bioassay-guided isolation will afford us the opportunity to pursue biological activity within complex mixtures. Extracts found active by Core A will be further purified by Projects 1-3 (OSU, UIC, and UNCG, respectively) and the pure isolates will be sent to us for further analysis. Promising pure compounds will ultimately be further tested in animal models to assess efficacy and toxicity. Mechanism of action studies will be conducted to study the molecular pharmacology of pure compounds with the most favorable therapeutic indices. The Director of Core A has well-established collaborations with all ofthe Project Leaders and Core Directors of this Program Project and has previously employed a variety of assays for natural product drug discovery. Our ongoing working relationships with other Projects and Cores and our ability to develop new biological assays as needed will assure that Core A is fully integrated in the program project and serves all projects therein.
The Specific Aims for Core A are to (1) conduct cell-based assays on extracts and fractions provided by each Program. These assays will score the activity of specific molecular targets including inhibition of histone deacetylase (HDAC) or the 20S proteasome. We will work with Core C to determine the most active fractions and with the Program Leaders to decide which fractions will serve as source material for compound isolation.
Our second aim i s to test pure compounds in cell-free molecular target (HDAC &proteasome) assays to confirm activity and identify the most promising leads for in vivo studies.
Our third aim i s to assess the activity of our most promising active pure compounds in vivo. Before our animal studies are conducted, Core B will develop analytical assays, assess solubility, prepare appropriate formulations as needed and conduct preliminary pharmacokinetic and toxicity experiments. Based on data from these studies, we will work with Core B to establish the optimal formulation and dosing schedule for hollow fiber or tumor xenografts studies in immunodeficient mice. Further pharmacological studies will be performed on those pure compounds that prove to be effective anticancer agents with limited toxicity in mice. The biological assays outlined in this Core, used in concert with Cores B and C, will provide a solid foundation of support for all the Projects within the program and our industrial partner, Eisai, Inc.
The overarching goal of this Program Project is to isolate novel agents from natural sources for the treatment of cancer. The role of Core A is to provide biological testing using a variety of molecular, cellular and animal based systems to identify promising leads for further development. Core A will obtain materials for testing from each of the three Programs, work with Core C on statistical analysis, identify leads that Core B can modify to enhance activity and Eisai, Inc can further develop for translation into the clinic.
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