Core 1: Biological Correlation and Analysis Core

Ohio State University, Columbus OH

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Abstract

PROJECT SUMMARY – BIOLOGICAL CORRELATION AND ANALYSIS CORE (CORE 1) The Biological Correlation and Analysis Core (Core 1) will focus on the biological evaluation of anticancer natural products that are identified from complex extracts, and after subsequent isolation, confirmed to be the active constituent. This strategy, called bioassay-guided isolation, facilitates the identification of biological activity within complex mixtures from plants, fungi, and cyanobacteria. The overarching goal of Core 1 is to determine if novel natural products are cytotoxic in cancer cells, decipher the pathways that they impact in the cancer cell, identify their molecular target, and test their potency in vivo. The biological core of the Program Project Grant (PPG) collaborates directly with all three projects and the Medicinal Chemistry and Pharmacokinetics Core (Core 2) to test the antitumor properties of extracts, fractions, and compounds and then prioritizes leads for the design and execution of specific strategies to move compounds into preclinical testing. Core 1 has successfully used these strategies on numerous compounds including phyllanthusmins, verticillins, rocaglamides, cardiac glycosides, eupenifeldin, aulosirazole, and wheldone. Because natural products are often isolated in small quantities and these compounds have diverse biological activities, the Core does not use a one-size-fits-all approach, and instead employs tailored plans. Projects collaborate in these approaches because the structures and abundance often dictate access to semi- or total synthesis as well as help inform biological mechanisms. Core 2 synthesizes compounds and analogs focused on enhancing potency or providing the material for target identification by biotinylation or photoaffinity probe development. RNA sequencing and proteomics integrated with the bioinformatics core provides context for the molecular pathways modified after treatment with the natural products, which helps decipher if compounds would be useful in chemoresistant models or as a combination therapy. Core 2 directly feeds into Core 1 as they confirm dosing and formulations that increase the chance of identifying in vivo activity. Xenografts and syngeneic models are used to test the role of anticancer compounds against human tumors and in the presence of an intact immune system. Overall, Core 1 tests all compounds from the Projects as well as those made in Core 2 for in vitro and in vivo activity. Data are then integrated fully with Core A for biostatistical analysis.