Cambridge Healthtech Institute’s
January 26-27, 2015 | Hilton San Diego Resort & Spa | San Diego, CA
Sunday, January 25
5:00-6:30 pm Short Course Registration and Main Conference Pre-Registration
6:00-9:00 Dinner Course*: SC1: Introduction to High-Content Phenotypic Screening
Instructor: Anthony M. Davies, Ph.D., Center Director, Translational Cell Imaging Queensland (TCIQ), Institute of Health Biomedical Innovation, Queensland University of Technology
*Separate registration required
Monday, January 26
7:00 am Conference Registration and Morning Coffee
8:00 Welcome Remarks from Conference Director
8:10 Chairperson’s Opening Remarks
Larry A. Sklar, Ph.D., Director, University of New Mexico Center for Molecular Discovery
8:15-8:40 High-Content Imaging Approaches for in vitro Toxicology
Armin Wolf, Ph.D., Professor and Director, Preclinical Safety, Novartis Institutes for BioMedical Research
HCI provides multiplexed detailed information at the level of a single cell, as well as characterization of cellular population distributions. It serves as a superior investigational tool compared to standard spectrophotometric plate readers that measure only average properties of a cell population. Moreover, mechanisms of compound-induced toxicity and the specific cellular pathways involved can be studied in vitro in combination with the use of specific enzyme inhibitors, enzyme inducers or RNA interference.
8:40-9:05 Use of HCI for Preclinical Safety Assessment at Roche
Stefan Kustermann, Ph.D., Head, High Content Imaging, Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel
High-content imaging-based profiling of drug candidates is part of preclinical safety assessment at Roche and applied either early on in the drug development process to prioritize compound series for further development, or to assess mechanisms of toxicity of compounds displaying liabilities later on in development. While selection of the appropriate assay panel is key, we also experienced that choice of the relevant time point for measurement has a strong impact on the outcome of the analysis. Multiparameter- and live-imaging approaches allow optimization of both of these aspects and subsequent establishment of tailored screening cascades to streamline drug safety testing.
9:05-9:30 High-Content Analysis for Predictive Toxicology
Mikael Persson, Ph.D., Primary Exploratory Toxicologist, Exploratory Toxicology, H. Lundbeck A/S
Predictive toxicology has been integrated in the drug discovery process, with the aim to design safer drug candidates and timely deselect drug candidates with potential safety risks. During the last decade, high-content imaging/analysis has emerged as a powerful tool for predictive toxicology as it can be used for identifying and mitigating potential safety risks early in drug discovery. By careful selection of endpoints, some cellular assays can show better predictivity than routine animal toxicity testing for certain adverse events. The perhaps most utilized high-content screening assays for predictive toxicology in the pharmaceutical industry will be presented as well as highlights from the HCA initiative in the MIP-DILI consortium. Multi-parametric imaging of cell health in simple and cost effective model systems can be used to predict human hepatotoxicity and identify potential mechanisms of toxicity, and imaging of bile salt transport inhibition in sandwich-cultured hepatocytes can be used to predict cholestasis inducing compounds. HCA is also useful for genotoxicity studies as imaging of micronuclei formation in simple cell models can be used to detect the genotoxic potential of a compound and elucidate aneugenic or clastogenic mode of actions.
9:30-9:55 Phenotypic Screening of Primary Human Cell Culture Systems to Identify Potential for Compound Toxicity
Keith Houck, Ph.D., Research Scientist, National Center for Computational Toxicology, U.S. Environmental Protection Agency
Assessing phenotypic changes in human primary cells in vitro provides a means to evaluate chemical effects in physiologically-relevant systems that can be useful for compound safety assessment. We evaluated a large library of environmental chemicals, reference pharmaceuticals and failed drugs in complex, primary human cell systems for interactions disrupting critical pathways. Chemical-response signatures derived from 87 endpoints covering functions relevant to toxic and therapeutic pathways were generated. Computational analysis identified abundant chemical clusters showing polypharmacology and potential off-target effects. This abstract does not necessarily reflect EPA policy.
9:55-10:10 Sponsored Presentation (Opportunity Available)
10:10-10:55 Coffee Break in the Exhibit Hall with Poster Viewing
10:55 Chairperson’s Opening Remarks
Neil Carragher, Ph.D., University of Edinburgh
11:00-11:25 A Simple Assay for Complex Biology
Christian N. Parker, Ph.D., Senior Investigator, Developmental and Molecular Pathways, Novartis AG
This presentation describes an assay, monitoring metabolic activity, that serves as an ex vivo model of radiation-induced, intestinal mucositis. The assay utilizes mouse-derived primary intestinal crypts that are grown in a complex 3D matrix. Control treatments promote crypt recovery after irradiation, as they do in vivo. It is hoped that such ex vivo, 3D, physiologically-relevant, organoid systems represent a bridge between relatively simple in vitro assays using 2D immortalized cell lines and complex in vivo models using whole animals.
11:25-11:50 The Phenotypic Screening “Rule of 3”: Developing More Predictive Assays
Fabien Vincent, Ph.D., Associate Research Fellow, Assay Development and Pharmacology, Hit Discovery and Lead Profiling, Pfizer Global Research & Development
Phenotypic screening is enjoying a renaissance since Sweeney and Anthony (Nat. Rev. Drug Discov., 2011) documented its positive impact on the translation of preclinical discoveries to the clinic. Nonetheless, it is to be expected that not all phenotypic screens will offer the same potential in that regard. A critical question then follows: what are the characteristics of the best phenotypic screens? This presentation will cover an analysis of this question conducted by a team of Pfizer scientists as well as propose three specific criteria to help identify and design the most promising screens.
11:50-12:15 pm Development of High-Throughput Phenotypic Screening Assays to Identify Small Molecules that Induce Gamma-Globin in Human Erythroid Progenitor Cells
Wensheng Xie, Ph.D., Investigator, Target and Pathway Validation, GlaxoSmithKline
Sickle cell anemia (SCA), a genetic disorder of the beta-globin gene, results in chronic ischemia with pain and tissue injury. One promising therapeutic strategy is to upregulate gamma-globin expression to replace the malfunctional beta-globin. Towards this goal, several phenotypic assays were developed and optimized for high-throughput screening. In this talk, I will describe the design, optimization and validation of these phenotypic screening methods. In addition, I will summarize the lessons we learned from these assays.
12:15-12:30 Sponsored Presentation (Opportunity Available)
12:30-1:55 Enjoy Lunch on Your Own
1:55 Chairperson’s Opening Remarks
Neil Carragher, Ph.D., University of Edinburgh
2:00-2:25 Integrating High-Content Imaging and Reverse Phase Protein Microarray to Advance Phenotypic Screening in Disease-Relevant Models
Neil Carragher, Ph.D., Principal Investigator, Drug Discovery, Institute of Genetics and Molecular Medicine, University of Edinburgh
Limited understanding of drug mechanism-of-action and the use of preclinical models which do not represent the molecular heterogeneity and pathophysiology of human disease contributes to poor efficacy and attrition at later stages of drug discovery and development. We demonstrate how recent advances in high-content imaging and Reverse Phase Protein Microarray (RPPA) technologies combine to characterize the relevance of phenotypic screening assays and also provide a cost-effective approach to profiling the mechanism-of-action of hit compounds, supporting further preclinical development or target deconvolution.
2:25-2:50 Phenotypic HTS Assays Enabled with Genome Editing
James Inglese, Ph.D., National Center for Advancing Translational Sciences, National Institutes of Health
Using the targeting precision of TALEN-mediated genome editing reporters were embedded within the genetic loci of neurologic target genes of interest to create HTS assays for the interrogation of chemogenomic compound libraries. Our goal was to identify transcriptionally active pharmacological agents acting by a variety of mechanisms, including through chromatin co-regulators accessible by our assay design. Specific case studies will serve to illustrate progress and findings to date.
2:50-3:15 Integrating Chemistry and Novel Technologies in Phenotypic Screening Workflows
Michelle Palmer, Ph.D., Director, Discovery and Preclinical Research, Broad Institute
Molecular characterization of patient-derived samples is providing new insights into the root cause of many diseases. Many of these insights point to targets that have traditionally been challenging for small-molecule therapeutics. Identification of drugs to modulate targets where knowledge of the function in disease is poorly understood and processes such as disruption of these novel targets require innovation in chemistry, phenotypic cell-based assays and target identification studies. At the Broad Institute, we have integrated technology across all aspects of lead identification in an effort to realize the benefit of the genes to drugs approach in multiple disease areas including psychiatric disease. Examples that illustrate the application of novel targets and pathways in a phenotypic screening approach will be presented.
3:15-4:15 Refreshment Break in the Exhibit Hall with Poster Viewing
4:15-4:40 Smart High-Content Screening Methods for Drug Combinations by Combining Single-Cell Phenotyping with Whole Genome Profile of Perturbation Responses
Stephen T.C. Wong, Ph.D., Chair and Professor, Systems Medicine and Bioengineering, Houston Methodist Research Institute, Weill Cornell Medical College
High-content screening (HCS) enhances the top-down workflow for understanding disease progressions and searching of potential therapeutics. However, it is infeasible to exhaustively screen the combinatorial space of possible drug cocktails, and smart screening strategies are desperately needed. We present such a new strategy for drug combination design by incorporating multiple-omics profile for perturbation responses with single-cell phenotype and computationally predicting and validating cellular phenotypes resulting from HCS studies.
4:40-5:05 Use of Cell-Based Assays to Guide Personalized Medicine in Cystic Fibrosis
Fredrick Van Goor, Ph.D., Senior Research Fellow, Vertex Pharmaceuticals
Cystic fibrosis (CF) is caused by the loss of epithelial chloride transport due to mutations in the CF transmembrane conductance regulator (CFTR) gene that encodes the CFTR chloride ion channel. There are over 1900 CFTR mutations, many of which result in the loss in chloride transport and presentation of the disease phenotype, with individual mutations varying in their severity. A potential therapeutic strategy to treat CF is to enhance chloride transport by increasing the amount and/or function of CFTR at the cell surface using CFTR correctors and potentiators. Recombinant cells expressing different mutant CFTR forms and cultured human airway epithelial cells derived from people with CF may be used to help stratify patients with CF who have different CFTR genotypes for studies investigating the potential clinical benefit of CFTR correctors and potentiators.
5:05-6:05 Welcome Reception in the Exhibit Hall with Poster Viewing
6:00 Short Course Registration
6:30-9:00 Dinner Course*: SC2: Introduction to High-Content Data Analysis
Instructor: Peter Horvath, Ph.D., Group Leader, Synthetic and Systems Biology Unit, Hungarian Academia of Sciences; Finnish Distinguished Professor (FiDiPro) Fellow, Institute for Molecular Medicine Finland
*Separate registration required
Tuesday, January 27
7:30-8:15 am Breakfast Technology Showcase
7:30-7:45 Intelligent Acquisition; Image Analysis Steps Dictate Acquisition Path for Performing Automated HCA Experiments. Case Study: Evaluating Phenotypic Stem Cell Screening
Ned Jastromb, Senior Application Product Manager, Product and Marketing, Nikon Instruments, Inc.
Improving the efficacy of stem cell derivation methods results in faster production of pure populations. Combining Nikon’s confocal HCA platform and software with live cell detection reagents, we evaluated the stem cell differentiation process, in real-time, devising new strategies for extracting meaningful measurements which should lead to optimized phenotypic screens.
7:45-8:15 Sponsored Presentation
Speaker to be Announced
8:25 Chairperson’s Opening Remarks
Litao Zhang, Ph.D., Executive Director, Applied Biotechnology, Bristol-Myers Squibb Company
8:30-8:55 Screening for Autism-Linked Phenotypes in Human Stem Cell-Derived Neurons
Sannah Zoffmann, Ph.D., Phenotypic Drug Development and Target Identification, F. Hoffmann-La Roche
Neurons of human origin with genetic defects related to neuropsychiatric disorders like autism have become accessible to in vitro imaging techniques with the recent advances in stem-cell technologies. The development of image-based assays targeting disease-related phenotypes and their potential for systematic profiling of drug candidates of novel and known mechanism-of-action will be presented. The presentation will emphasize strengths and technical challenges inherent to the identification of morphological structures such as neuronal synapses.
8:55-9:20 Modeling Neurological Diseases Using Patient Neuronal Cells Differentiated from Induced Pluripotent Stem Cells
Wei Zheng, Ph.D., Group Leader, Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health
Many human neurological diseases are not properly modeled by both animal models and classical cell lines due to the species difference or unavailability of human neuronal cells. The lack of appropriate disease model systems has partly contributed to clinical attrition and prevented successful development of new drugs. Recent advancement in stem cell technology has enabled us to generate various human nature cells from patient induced pluripotent stem (iPSC) cells. Many of these differentiated patient cells such as neurons, cardiomyocytes and hepatocytes exhibit specific disease phenotypes that can be used as new disease models. We have generated several phenotypic disease models of lysosomal storage diseases using differentiated neuronal cells derived from patient iPS cells. Results from drug efficacy tests and compound library screens using the phenotypic assays with these differentiated disease cells will be presented.
9:20-9:45 Applying Technology Platforms for Phenotypic Screening in Physiologically-Relevant Cellular Systems
Liang Schweizer, Ph.D., Director, Lead Discovery & Optimization, Bristol-Myers Squibb Company
9:45-10:45 Coffee Break in the Exhibit Hall with Poster Viewing
10:45-11:10 Opportunities and Challenges of High-Content Phenotypic Screening in Patient Cells
Regis Doyonnas, Ph.D., Senior Principal Scientist, High-Content Screening and HTS-Flow Cytometry, Hit Discovery and Lead Profiling, Worldwide Research & Development, Pfizer
High disease relevance in cell-based assays is one of the most important goals in phenotypic assay development. Opportunities and challenges to combine patient-derived, disease-specific cells with high-content screening technologies with the aim of finding new drugs will be discussed during this presentation.
11:10-11:35 Phenotypic Drug Discovery for Alzheimer’s Disease in Physiologically-Relevant Brain Cells
Tae-Wan Kim, Ph.D., Associate Professor, Pathology and Cell Biology, Columbia University Medical Center
The development of effective and safe therapeutics for complex neurodegenerative diseases, such as Alzheimer’s disease (AD) is hampered in part by lack of physiological cell models. We will discuss our progress on phenotypic, high-throughput screening platforms targeting key AD-relevant cellular pathways (i.e. tau, amyloid and apoE) in primary and stem cell-derived neurons and glial cells. Our approach will facilitate preclinical discovery of promising therapeutic lead molecules for AD drug discovery.
11:35-12:00 pm Decoding Developmental Pathways Using 4D High-Content Imaging of C. elegans Embryos
Rebecca Green, Ph.D., Research Scientist, Ludwig Institute for Cancer Research
To functionally classify ~1800 conserved developmental genes, we have developed a 4D-high-content screening-based approach for the model metazoan, C. elegans. ~400 genes have been piloted, performing RNA-interference in two specially engineered reporter strains that read out morphogenetic developmental defects. This pilot data-set is being used to develop custom data management and analysis protocols, including methods for manual and automated scoring of complex phenotypic features. When complete, this will provide the first systems-level view of embryonic development in a complex multicellular organism.
12:00-1:30 Enjoy Lunch on Your Own
1:30 Chairperson’s Opening Remarks
Aron Jaffe, Ph.D., Investigator, Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research
1:35-2:00 Developing and Utilizing 3D Culture Systems for Novel Target Discovery
Aron Jaffe, Ph.D., Investigator, Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research
Target identification and validation have historically relied on immortalized or tumor cell lines grown on plastic. Recent techniques involving growth of cells in three-dimensional matrices have enabled modeling of cellular processes in an environment that more closely resembles the in vivo setting. This presentation will highlight the strategies for designing complex cellular assays for target discovery using medium- and high-throughput screening methods in three dimensions.
2:00-2:25 Leveraging the Use of 3D Spheroid Models in Oncology Drug Discovery
Lesley Mathews Griner, Ph.D., Investigator & Lab Head, Molecular Pharmacology/Oncology, Novartis Institutes for BioMedical Research
2:25-2:50 Novel Methods for 3-Dimensional High-Content Analysis
Daniel V. LaBarbera, Ph.D., Assistant Professor, Pharmaceutical Sciences, 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 at recapitulating in vivo tumor growth. Yet its use in high-throughput drug discovery has been limited, particularly with image-based screening, due to practical and technical hurdles. This presentation will describe recent advances that we have developed for volumetric high-content analysis using MCTS suitable for high-content screening drug discovery.
2:50-3:10 Networking Refreshment Break
3:10-3:35 Comparative Analysis of Pharmacological Responses in 3D Tumor Models
Marc Ferrer, Ph.D., Team Leader, Preclinical Innovation, NCATS, NIH
The use of physiologically-relevant three dimensional (3D) cellular systems is being explored as more predictive in vitro tumor models for drug discovery. We sought to further understand and delineate the differences in cytotoxic responses by chemotherapeutics agents in different cellular models of cancer by screening a library of 1912 small molecule chemotherapeutics, both as single agents and in combination. The biological annotation of the compounds screened enabled the identification of key cellular pathways driving chemotherapeutic responses in each of the 3D tumor models tested.
3:35-4:00 Phenotypic Profiling of Intracellular Dynamics in 3D Tissues for Therapeutic Screening
David Nolte, Ph.D., Professor, Physics, Purdue University; President, Animated Dynamics, Inc.
Doppler spectroscopy of intracellular dynamics can extract drug responses from as deep as 1 mm inside living tissue using biodynamic imaging. There are a growing number of different types of 3D tissue models, but not all 3D models are created equal. Multicellular tumor spheroids, co-cultures, organoids, tissue biopsies and engineered tissue matrices all have different structural and cellular morphological differences that can lead to different responses to therapeutic compounds. The leading question is: Which of these responds most like an in vivo response?
4:00 Close of Conference