Physiologically-Relevant Cellular Models for Drug Discovery - Day 1
Wednesday, February 19
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7:30 am Conference Registration and Morning Coffee
8:15-8:20 Welcoming Remarks from Conference Director
Julia Boguslavsky, Executive Director, Conferences, Cambridge Healthtech Institute
8:20-8:25 Chairperson’s Opening Remarks
D. Lansing Taylor, Ph.D., Director, University of Pittsburgh Drug Discovery Institute & Allegheny Foundation Professor, Computational and Systems Biology, University of Pittsburgh
8:25-8:50 Quantitative Systems Pharmacology in Drug Discovery and Development
D. Lansing Taylor, Ph.D., Director, University of Pittsburgh Drug Discovery Institute & Allegheny Foundation Professor, Computational and Systems Biology, University of Pittsburgh
We are implementing quantitative systems pharmacology (QSP) as a novel approach to drug discovery and development. Phenotypic discovery/development using high-content analysis (HCA) is a central platform in a variety of disease areas and early safety assessment. For example, we are implementing QSP for understanding the heterogeneity of response within tumors and in cell-based assays and have created a heterogeneity index (HI) to guide the decisions during cell profiling and screening. In addition, QSP is being applied to the development and implementation of a 3-D, human biomimetic liver acinus model to be used as an early safety assessment platform to optimize the development of lead compounds.
8:50-9:15 Modeling Invasion: Monitoring Cell/Tissue Interactions with 3-D Cell Co-Cultures
Carsten Wenzel, Scientist, Global Drug Discovery, Bayer Pharma AG
Invasion processes or uncontrolled fibroblast recruitment are not limited to cancer but also to other fibrotic diseases (e.g. lung fibrosis). Most in vivo or in vitro assays to model cell-tissue interactions for these indications are not designed for higher throughput, and are labor intensive and often expensive. We developed a 3-D cell co-culture-based assay which allows monitoring fibroblast invasion and migration processes in a medium throughput capable environment with automated dispensing of cells/compounds and integration in an automated microscopy system for high-content screening.
9:15-10:00 Coffee Break in the Exhibit Hall with Poster Viewing
10:00-10:25 3-D Brain Tissue-Based HCA Screening Platforms for CNS Drug Discovery
Donald C. Lo, Ph.D., Director and Associate Professor, Center for Drug Discovery and Department of Neurobiology, Duke University Medical Center
10:25-10:50 Talk Title to be Announced
Anthony M. Davies, Ph.D., Director, Irish National Center for High-Content Screenin and Analysis (INCHSA)
10:50-11:15 3-D Multicellular Tumor Spheroid Model Systems for Image-Based Drug Discovery Targeting Cancer Stem Cells in Luminal Breast Cancer
Daniel V. LaBarbera, Ph.D., Assistant Professor, Drug Discovery and Medicinal Chemistry, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado
The multicellular tumor spheroid (MCTS) model has been used for decades with proven superiority over monolayer cell culture models, yet its use in high-content screening (HCS) drug discovery has been limited. Here we report a significant advance using a validated luminal breast cancer stem cell (CSC) biomarker, cytokeratin 5 promoter (CK5Pro) green fluorescent protein (GFP) reporter. We developed an algorithm to quantify changes in CK5Pro-GFP expression locally (Z-stack-planes) or globally (maximal-projections) of MCTS. We demonstrate that acquiring data in this manner is statistically robust (Z’=0.85) for use in primary HCS drug discovery.
11:15-12:45 pm Enjoy Lunch on Your Own
12:45-12:50 Chairperson’s Opening Remarks
Fredika M. Robertson, Ph.D., Professor and Executive Director, Clinical Research Service, Center for Clinical and Translational Research, Virginia Commonwealth University
12:50-1:15 Development and Characterization of a Three-Dimensional Lung Tumor Spheroid System for Compound Screening
Jason Ekert, Ph.D., Senior Research Scientist, Biotechnology Center of Excellence, Janssen Research & Development
To reduce drug attrition rates and development expenditures, more predictive drug screening assays must be developed. Our goal was to develop a more physiologically relevant, high-throughput 3-D lung tumor spheroid assay system to measure compound effects utilizing the EGFR and cMET pathways. We also compared differences between 2-D monolayer and 3-D spheroid culture systems through EGFR and cMET receptor density, and phosphorylation status. This study showed that a 3-D spheroid platform provides a valuable tool for target validation and drug discovery.
1:15-1:40 Use of Patient-Derived Tumor Spheroids with Cancer Stem Cell Characteristics for Elucidation of Drug Activity
Fredika M. Robertson, Ph.D., Professor and Executive Director, Clinical Research Service, Center for Clinical and Translational Research, Virginia Commonwealth University
Freshly isolated tumor cells from breast cancer patients who have metastatic disease manifested by development of pleural effusion spontaneously form 3-D tumor aggregates that retain characteristics of tumor initiating cells/cancer stem cells. Using tumor spheroids, we have identified specific gene signatures and genetic abnormalities that are linked to changes in cell signaling pathways that can be targeted using small molecule inhibitors. The combination of technical platforms including high-content, live-cell imaging, confocal microscopy, and flow cytometry allows evaluation of drug responses by individual patient tumor cells in real time. Collectively, these approaches provide powerful tools to define those patients who may benefit for inclusion into clinical trials and to identify specific signaling pathways and molecular drivers of disease progression that may lead to development of new therapeutics targeting metastasis.
1:40-2:05 On-Chip Models for Improved Breast Cancer Therapy and the Design of Cancer Prevention Drugs
Sophie Lelièvre, Ph.D., Associate Professor, Cancer Pharmacology, Purdue University
On-chip tissue culture that recreates structural and functional environments of human tissues will revolutionize drug discovery. Engineered hemichannels covered with phenotypically normal breast epithelium are used to recapitulate tumorigenesis within breast terminal ducts and have revealed that the tissue geometry and the non-neoplastic epithelium both influence cancer cells’ sensitivity to drugs. On-chip models permit simultaneous assessment of a drug’s impact on normal and cancerous epithelia, design of nanotechnology-based theranostic tools and breakthroughs for prevention therapy.
2:05-2:30 Q & A with the Speakers
2:30-3:30 Refreshment Break in the Exhibit Hall with Poster Viewing
3:30-3:55 Characterizing Heterogeneity in Cancer Cell Activation and Inhibition: Establishing a “Heterogeneity Index”
Albert Gough, Ph.D., Associate Professor, Computational and Systems Biology, University of Pittsburgh
Heterogeneity in cellular responses has become an important issue in the development of assays, therapeutics and diagnostics, as well as understanding the complexity of pathway functions. The population average values derived from cell-by-cell distributions may mask important subpopulations of cells that respond differently, impacting the efficacy of a drug or the reliability of a diagnostic. We have employed computational tools for visualizing and characterizing distributions to identify key cancer pathways that exhibit multimodal response profiles, and used those pathways to evaluate the performance of a variety of metrics as a potential heterogeneity index. We will present the analysis of those subpopulations and data demonstrating the performance of several candidate heterogeneity indices.
3:55-4:20 3-D Microfluidic Angiogenesis Models to Analyze the Physicochemical Regulators of Brain Tumor Therapy Response
Scott S. Verbridge, Ph.D., Assistant Professor, School of Biomedical Engineering and Sciences, Virginia Tech - Wake Forest University
While 2-D and spheroid cell models have helped clarify the role of soluble signaling in tumor angiogenesis, physiological 3-D models promise important insights into the interplay between physical hallmarks of tissue and vasculature, and response to anti-angiogenic drugs. We will summarize our work in microengineered 3-D tumors and the role of tumor-ECM interactions, as well as geometrical aspects of vasculature in regulating angiogenesis. We will also discuss our work in targeting the unique physical properties of therapy-resistant brain cancer cells.
4:20-4:45 Microfluidic Approach to Deconstructing Tumor Microenvironment Activity
Elaine T. Alarid, Ph.D., Professor, Oncology, University of Wisconsin-Madison
5:00-6:00 Welcome Reception in the Exhibit Hall with Poster Viewing
6:00-9:00 Dinner Course*
SC3: High-Content Analysis for 3-Dimensional Cellular Models
*Separate Registration Required.
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