HigH-Content AnAlysis

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Cambridge Healthtech Institute’s TENTH Annual January 8-11, 2013 High-Content Analysis Anniversary Studying the Tumor Microenvironment: HCA of 3-D Tumor Spheroids 10:45-11:10 3-D High-Content Screening for the Identification of Compounds that Target Chemo-Resistant Tumor Cells Carsten Wenzel, High-Content Analysis, Bayer Healthcare Limited predictability of cellular assays based on 2-D cell culture for the efficacy of drug candidates in vivo has fostered the search for novel culture techniques for drug discovery in oncology. Based on significant differences in gene expression between cells cultured in 2-D and 3-D, as well as more physiological growth conditions that resemble the situation in tumor tissue, spheroid-based 3-D cell culture is being recognized as a potential test platform to better predict drug efficacies in vivo. Here, we present our current work on evaluating and implementing different methods for the automated generation of 3-D spheroids in microtiterplates, visualization of selected markers, automated microscopy and image analysis. By this approach we identified several compounds that specifically target cells in quiescent tumor spheroid core regions. Additionally we could show that these hits, combined with cytostatics, show a significant increase in cell death in our spheroid model compared to single treatment conditions. 11:10-11:35 Elucidation of Cell Signaling Using High-Content Imaging of Patient-Derived Breast Tumor Spheroids with Cancer Stem Cell Characteristics Fredika M. Robertson, Ph.D., Professor, Experimental Therapeutics, Center for Targeted Therapy, Translational Therapeutics Laboratory, University of Texas MD Anderson Cancer Center Using tumor spheroids, we have identified specific gene signatures and genetic abnormalities that are involved in cancer metastasis which we find to be associated with changes in cell signaling pathways that can be targeted using small molecule inhibitors. This presentation will discuss the use of the combination of high-content live-cell imaging, confocal microscopy, flow cytometry, and histological approaches that allow imaging of these surrogates of metastasis and the evaluation of a patient’s tumor cells for drug responses in real time. 11:35-12:00 pm 4-D MAME Models for Live-Cell Imaging of Interactions between Breast Tumor Cells and Their Microenvironment: Adapting for Compound Screening Bonnie Sloane, Ph.D., Distinguished Professor and Chair, Pharmacology and Karmanos Cancer Institute, Wayne State University To define druggable pathways involved in breast cancer progression, our laboratory has pioneered the development of techniques for functional imaging of protease activity associated with live human breast cells and of 3- and 4-D co-culture models that recapitulate breast tumor architecture as well as the cellular and non-cellular tumor microenvironment, i.e., MAME (mammary architecture and microenvironment engineering) models. Use of these techniques and models in concert with various types of imaging probes has allowed us to image, quantify and follow the dynamics of proteolysis in the tumor microenvironment and to test interventions that impact directly or indirectly on proteolytic pathways. 12:00-12:25 The Multicellular Tumor Spheroid: A Systems Biology Approach for High-Content Imaging and Cancer Drug Discovery Daniel V. LaBarbera, Ph.D., Assistant Professor, Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado In vitro 3-D models, particularly multicellular tumor spheroids (MCTS), offer a systems biology approach to bridge information from in silico, molecular target, and 2- D cell-based screening, with in vivo models to increase the predictability of cancer drug discovery. Here we will discuss our current research targeting the metastatic phenotype in cancer using MCTS models suitable for high-content imaging. 12:25-1:55 Enjoy Lunch on Your Own 8 | High-Content Analysis HighContentAnalysis.com
Cambridge Healthtech Institute’s TENTH Annual January 8-11, 2013 High-Content Analysis Anniversary Phenotypic Drug Discovery (continued) 10:45-11:10 A Chemical Approach to Controlling Cell Fate Sheng Ding, Ph.D., William K. Bowes, Jr. Distinguished Investigator and Professor, Pharmaceutical Chemistry, Gladstone Institute of Cardiovascular Disease, University of California San Francisco Recent advances in stem cell biology may make possible new approaches for the treatment of a number of diseases. A better understanding of molecular mechanisms that control stem cell fate as well as an improved ability to manipulate them are required. Toward these goals, we have developed and implemented high-throughput cell-based phenotypic screenings of arrayed chemical libraries to identify and further characterize small molecules that can control stem cell fate in various systems. This talk will provide the latest examples of discovery efforts in my lab that have advanced our ability and understanding toward controlling stem cell fate, including self-renewal, survival, differentiation and reprogramming of pluripotent stem cells. 11:10-11:35 Screening of Protein Kinase Inhibitors to Identify Target and Liability Kinases in Axon Growth John L. Bixby, Ph.D., Professor, Pharmacology and Neurological Surgery; Vice Provost for Research, University of Miami We screened 995 protein kinase inhibitors (PKIs) in primary neurons to identify critical kinase targets and “hit” PKIs that promote growth of neuronal processes. We analyzed the activity profiles of hit and non-hit PKIs against a kinase panel, narrowing the set of informative kinases. A machine learning model was trained using these kinases and will be used to perform in silico searches for novel hits using experimentally acquired or predicted activity profiles. Our novel approach allows us to search for hits based on biochemical profiles rather than SAR, and addresses the problem of PKI polypharmacology. 11:35-12:00 pm Zebrafish as a Tool for Rapid, in vivo Identification of Complex Behavioral Chemotypes Andrew J. Rennekamp, Ph.D., Postdoctoral Researcher, Cardiovascular Research Center and Division of Cardiology, Massachusetts General Hospital, Harvard Medical School Zebrafish larvae are well suited for in vivo, high-content screens and yet they are neurocompetent organisms exhibiting complex behavioral phenotypes with neurophysiology that is remarkably similar to humans. Using zebrafish, we have identified several reproducible behaviors amenable to high-content screening. By probing these behavioral phenotypes with compounds having known pharmacological targets in humans, we are able to identify neurological pathways relevant to human diseases. Subsequently, we are able use the zebrafish as a tool for the identification of novel drugs which perturb those important pathways via previously unknown mechanisms. 12:00-12:25 Image-Based High-Dimensional Profiling of Cell Response to Perturbation Auguste Genovesio, Ph.D., Group Leader, Image Analysis, Broad Institute of MIT and Harvard From each image in a high-content experiment, hundreds of cells can be detected and analyzed leading to millions of high-dimensional cell profiles for an experiment. These profiles may be a rich source of information about the corresponding RNAi or small molecule treatments, revealing complex and subtle phenotypes and identifying families of treatment conditions. How to maximize the insights gained from these huge datasets is currently a challenging question for the community. In this talk, we discuss the data analysis of high dimensional datasets of this kind and show applications in drug discovery and basic research. HCA of Stem Cells 1:55-2:00 Chairperson’s Opening Remarks 2:00-2:25 Development of Screening Platforms for Modifiers of Cell Fate in Human Pluripotent Stem Cells April Pyle, Ph.D., Assistant Professor, Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles Differentiated cells from human pluripotent stem cells (hPSCs) provide an unlimited source of cells for use in regenerative medicine. However, prior to establishment of patient specific cells for cell therapy it is important to understand the basic regulation of cell fate decisions in hPSCs. One caveat is that hPSCs survive poorly upon dissociation, which limits genetic manipulation because of poor cloning efficiency of individual hPSC, and hampers production of large-scale culture of hPSCs. Improving our understanding of pathways that are important for hPSC growth could improve our ability to culture, differentiate and derive new hPSCs. Our large scale screening work provides a comprehensive evaluation of chemical space for modifiers of cell fate in hPSCs. 2:25-2:50 Patient-Specific Cell-Based Disease Models for Drug Discovery Anne Bang, Ph.D., Director, Cell-Based Disease Modeling and Screening, Sanford-Burnham Medical Research Institute Patient-specific primary cells and induced pluripotent stem cells (iPSCs) complement traditional cell-based drug discovery assays, allowing testing on differentiated features not reflected by immortalized lines. We used patient cells to develop a phenotypic assay for muscular dystrophy that distinguishes between affected and unaffected siblings, faithfully recapitulating key molecular features of the disease. A high-content screen of patient cells was conducted with the goals of identifying early treatment candidates, and probes to gain a greater understanding of underlying cellular defects. We will discuss screening results and development of iPSC-based models for testing of drugs on disease relevant cell types. 2:50-3:15 HCS to Discover Drugs for Heart Failure Mark Mercola, Ph.D., Professor and Director, Muscle Development and Regeneration Program, Sanford-Burnham Medical Research Institute There is an urgent need for therapies that reverse the course of ventricular dysfunction in heart failure, which remains a leading cause of morbidity and mortality in Western countries. Current therapies do not treat the underlying cause—death or damage of heart muscle cells combined with increased scarring. Our research is focused on developing high-content screening assays and instrumentation to discover targets and screen for molecules active in cardiac regeneration and cardiomyocyte contractility. The presentation will discuss modeling regeneration using stem cells in high-throughput analysis of cardiomyocyte physiology, and demonstration of small molecules that promote differentiation and RNA molecules that sustain contractility in the failing heart. 3:15-4:15 Refreshment Break in the Sponsored by Exhibit Hall with Poster Viewing 12:25-1:55 Enjoy Lunch on Your Own HighContentAnalysis.com High-Content Analysis | 9
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