2016 Archived Content

Phenotypic Screening

CHI’s Second Annual Phenotypic Screening meeting will address the advantages of phenotypic screening vs. target-based screening, and focus on assay development, selection of physiologically relevant models and subsequent target identification, as well as case studies of phenotypic screens from leading pharma.

Final Agenda

Day 1 | Day 2 | Download Brochure

Wednesday, February 10

5:00-6:00 pm Short Course Registration and Main Conference Pre-Registration

6:00-9:00 pm (SC1) DINNER SHORT COURSE: High-Content Phenotypic Screening

The ever-increasing demand for improved productivity in research through the generation of robust analysis outputs has driven both the development and deployment of automated high-content analysis (HCA) and phenotypic cell-based approaches to drug discovery. In contrast to the more traditional cellular analysis and target-based approaches, here the researcher is able to evaluate the efficacy of potential therapeutics by monitoring the physiological state of cells through the simultaneous analysis of multiple cellular parameters in the context of an intact biological system. This course will cover the key features of HCS/A technologies and the best approaches to using these technologies for phenotypic cell-based 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.

Thursday, February 11

7:30 am Conference Registration and Morning Coffee

Phenotypic and High-Content Screening in 3D Cellular Models

8:00 Chairperson’s Opening Remarks

Anthony M. Davies, Ph.D., Center Director, Translational Cell Imaging Queensland (TCIQ), Institute of Health Biomedical Innovation, Queensland University of Technology

8:15 The Trials and Tribulations of Complex Phenotypic Screening

Shane Horman, Ph.D., Research Investigator, Advanced Assays, Genomics Institute of the Novartis Research Foundation

With the emergence of new biomimetic phenotypic screening platforms comes the inevitable complexities and technical challenges associated with such initiatives. Side-stepping assay-related landmines on the road to drug discovery is an iterative process, characterized by repeated trial and error. Herein I present benefits and potential pitfalls of complex and multi-culture 3D cell models currently used for drug discovery in the pharmaceutical industry.

8:45 The Challenges of Identifying Cellular Phenotypes in 3D in vitro Cellular Assay Systems

Anthony M. Davies, Ph.D., Center Director, Translational Cell Imaging Queensland (TCIQ), Institute of Health Biomedical Innovation, Queensland University of Technology

Currently, one the biggest drivers in the field of translational research is the need to improve the relevance of cell-based assays. To achieve this goal many investigators are turning their attention to high-content analysis used in conjunction with primary cells and/or 3D cell assay models. Despite the potential benefits that these new experimental approaches may offer, their use has not been without both technical and practical difficulties. In this presentation we will discuss the challenges we have encountered here at TCIQ and the solutions that we have arrived at to meet our research objectives.

Beckman Coulter Life Sciences9:15 Automated 3D Culture and Sample Preparation for Imaging and Flow Cytometry Analysis

Jennifer MacFarland, Field Marketing Manager, Automation and Genomics, Beckman Coulter Life Science

Spheroid cultures can be challenging to manipulate and are amplified as sample throughput increases. We will demonstrate how the Biomek FXP was used to automated steps include the plating of cells, media exchange, and compound and staining reagent addition within the hanging drops.

Persommics9:30 High Content Discovery with Persomics Technology: Reduction of Scale and Cost with Turnkey Printed Libraries.

Neil Emans, Ph.D., CEO, Persomics

RNAi is routinely used in High-content and Phenotypic screening. However, set-up and operational costs exceed the scope of individual labs. Persomics technology miniaturizes, accelerates and de-industrializes screening. Preprinted libraries integrate with High-content imaging platforms, removing barriers to entry and lowering costs. This presentation will introduce Persomics technology and future applications.

9:45 Coffee Break in the Exhibit Hall with Poster Viewing

3D Cellular Models (Cont.)

10:30 Label-Free Nonlinear Optical Microscopy for Non-Invasive Viability Screening in 3D Engineered Tissues

Mary-Ann Mycek, Ph.D., Professor and Associate Chair for Translational Research, Biomedical Engineering, College of Engineering & Medical School, University of Michigan

Label-free nonlinear optical microscopy with quantitative image analysis reliably and non-invasively screened viability in 3D living engineered tissues manufactured from primary human cells. Optically-derived metrics for tissue morphology and function could serve as release criteria for cell-based tissue-engineered devices prior to implantation in patients, a critical regulatory requirement in regenerative medicine. Prospects for rapid, automated tissue assessment will be discussed.

11:00 Bioengineering Approaches and High-Content Analysis Routines to Characterize Heterogeneity and Treatment Response in 3D Tumor Models

Imran Rizvi, Ph.D., Instructor, Medicine and Dermatology, Brigham and Women’s Hospital, Massachusetts General Hospital, Harvard Medical School

Among the challenges associated with scaling complex cell-based screening platforms is balancing biological relevance with requirements for high-content analysis. Development of a quantitative analysis framework for a microfluidic 3D tumor model and one that restores heterotypic cell signaling will be presented.

11:30 Development of Physiologically Relevant Screening Platforms to Probe Various Disease Pathologies

Madhu Lal-Nag, Ph.D., Acting Team Lead, RNAi Screening Facility, National Center for Advancing Translational Sciences, National Institutes of Health

Historically, screening for oncology directed compounds has been performed in 2-dimensional monolayer cultures which fail to replicate the complex architecture and the microenvironment of tumors in vivo. In vitro model platforms that are designed to be biologically relevant fill a critical gap between the cellular and animal model domains and offer the opportunity to study, screen and select compounds that are therapeutically attractive in real-time.

12:00 pm Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

Implementing Phenotypic Screening

1:25 Chairperson’s Remarks

D. Lansing Taylor, Ph.D., University of Pittsburgh

1:30 The Role of Phenotypic Screening in Quantitative Systems Pharmacology (QSP)

D. Lansing Taylor, Ph.D., Director, University of Pittsburgh Drug Discovery Institute and Allegheny Foundation Professor, Computational and Systems Biology, University of Pittsburgh

We have implemented a quantitative systems pharmacology platform for drug discovery and the advancement of personalized medicine. Our first three programs are in metastatic breast cancer, hepatocarcinoma and Huntington’s disease. Phenotypic screening plays a central role in this iterative and integrated approach.

2:00 Linking Industry with Academia at the UK’s National Phenotypic Screening Centre: Bringing Technology to the Biology

Paul Andrews, Ph.D., Director, National Phenotypic Screening Centre, University of Dundee, UK

Understanding the molecular mechanisms underlying disease still remains a major challenge for academia and industry. Only through an in-depth understanding of diseases starting at the patient level and working down through to organ, tissue and cell behavior, can the myriad intracellular biochemical networks, pathways and targets that orchestrate cell function be put into their true context. Drug development costs are unsustainably high with the low clinical efficacy and late stage failures partly due to the prevailing emphasis on molecular targets (assayed outside of their physiological or pathophysiological context). Phenotypic drug discovery (PDD) encompasses a range of approaches that allow the quantitative measurement of the observable manifestations of the complex systems operating at the subcellular and cellular level.

2:30 Phenotypic Screening from Target ID to Profiling Cellular Function in Early Stage Drug Discovery

Susanne Heynen-Genel, Ph.D., Director, High Content Screening Systems, Sanford Burnham Prebys Medical Discovery Institute

Phenotypic screening has been experiencing a resurgence in the last few years. SBP Medical Discovery Institute started to incorporate high-throughput imaging assays to quantify cellular phenotypes into early stage drug discovery 10 years ago. Examples of image-based phenotypic screens will outline how phenotypic imaging assays have been employed to enable drug discovery from target identification to high-throughput screening of large libraries and profiling of cellular function of small molecules.

3:15 Refreshment Break in the Exhibit Hall with Poster Viewing

Organoids and 3D Organotypic Cell Culture

4:00 Phenotypic Screening to Accelerate Lead Discovery and Drug Repositioning

Zhuyin Li, Ph.D., Translational Biomarker Team Lead, Lead Discovery & Optimization, Bristol-Myers Squibb

Potential leads from high-throughput screening (HTS)-based drug discovery approaches often result in a high lead attrition rate, due in part to lack of disease relevant in vitro cellular models and predictive assay technologies. Recent developments in phenotypic screening using disease-relevant cellular models and advanced assay technologies have reduced attrition rate and improved in vitro to in vivo connectivity. In this presentation, three examples will be highlighted: 1) identification of potent inhibitors of tumor growth and metastasis for an anaplastic thyroid cancer in vivo model using in vitro phenotypic screening; 2) phenotypic screening for potential drug repositioning to promote functional remyelination in vivo; 3) phenotypic screening using 3D organotypic cellular models that mimic omental tissue for the identification of ovarian cancer metastasis inhibitors with demonstrated efficacy in vivo.

4:30 A 3D Phenotypic Screening Platform to Mimic Tumor Microenvironment and Tissue Architecture

Malin Akerfelt, Ph.D., Senior Research Scientist, High-Content Screening Laboratory, Institute of Biomedicine, University of Turku

5:00 High-Throughput Imaging: Focusing in on Cancer Drug Discovery in 3D

Daniel V. LaBarbera, Ph.D., Associate Professor, Drug Discovery and Medicinal Chemistry, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado

High-throughput imaging drug discovery using 3D tissue culture and organoids has been limited due to practical and technical hurdles. This presentation will describe recent advances that we have developed for volumetric high-content analysis using multicellular tumor spheroids suitable for high-content screening drug discovery.

AxioGenesis5:30-6:30 Welcome Reception in the Exhibit Hall with Poster Viewing

5:30 Short Course Registration

6:30-9:00 (SC2) Dinner Expert ThinkTank: How to Meet the Need for Physiologically Relevant Assays

It used to be adequate to build target-specific and robust assays to drive lead optimization. These assays were relatively inexpensive and reliable and could be counted on to provide chemists with usable results. However, with time, it has become apparent that it is not enough to be robust and target specific. To build therapies for patients, we need to have assays that are more predictive of patient outcome. The current buzz words are “physiologically relevant assays.” This session will explore the need for physiologically relevant assays and explore the ways that we can achieve this endpoint.

Moderator: Lisa Minor, Ph.D., President, In Vitro Strategies, LLC

Separate registration required.

Day 1 | Day 2 | Download Brochure

Friday, February 12

7:45 am Breakfast Presentation (Opportunity Available) or Morning Coffee

Phenotypic Drug Discovery: Lessons Learned

8:25 Chairperson’s Remarks

Ulrich Schopfer, Ph.D., Novartis Institutes for BioMedical Research

8:30 Lessons from Phenotypic Lead Discovery

Ulrich Schopfer, Ph.D., Executive Director and Head, Integrated Lead Discovery, Novartis Institutes for BioMedical Research

Phenotypic screening in in vivo or ex vivo models has been the historic origin of drug discovery. When advances in molecular biology enabled target-based screening, these origins lost popularity in favor of more reductionist approaches. Over the last several years, there has been a renaissance of phenotypic discovery approaches in academia and the pharmaceutical industry. It is time to take stock and assess the successes and the difficulties that were encountered. We will discuss the experience with phenotypic lead discovery at Novartis and look out to the integration of phenotypic and target-based approaches that we predict to be the strategy of the future.

9:00 High-Content Cell-Based Assays for Receptor Internalization and Intracellular Trafficking

Regis Doyonnas, Ph.D., Senior Principal Scientist, High-Content Screening and HTS-Flow Cytometry, Primary Pharmacology Group, Pfizer

9:30 Know Your Target, Know Your Molecule

Erik Hett, Ph.D., Team Leader, Senior Scientist, Chemical & Molecular Therapeutics, Biogen

I will pose some key questions about the characteristics of protein targets and small-molecule drugs that may be important to consider in drug discovery projects and could improve prospects for future clinical success. This includes questions such as what is your target, where does it localize, does it have multiple isoforms, as well as, how does your molecule bind, where does it distribute, what are the consequences of it binding your target, and how much occupancy is required to drive your phenotype?

10:00 Coffee Break in the Exhibit Hall with Poster Viewing

Phenotypic Screening in iPSC and Primary Cell Models

10:55 Chairperson’s Remarks

Beatrice Knudsen, M.D., Ph.D., Director, Translational Pathology, Cedars Sinai Medical Center

11:00 Cardiac Regeneration: Influencing Proliferation and Fate Decision of Patient and iPS-Derived Cardiac Progenitors with Small Molecules

Lauren Drowley, Ph.D., Associate Principal Scientist, AstraZeneca

Despite the presence of cardiac progenitor cells, functional repair of the heart after injury is inadequate. Identification of signaling pathways involved in the proliferation and differentiation of cardiac progenitor cells (CPCs) will broaden insight into the fundamental mechanisms playing a role in homeostasis and disease and may provide strategies for in vivo regenerative therapies. We have developed 384-well phenotypic assays using iPS and primary human CPCs and identified novel compounds which are currently being followed up.

11:30 Using iPSC-Derived Cardiomyocytes for Biomarker and Drug Development

Ulrich Broeckel, M.D., Professor, Pediatrics, Medical College of Wisconsin

Left ventricular hypertrophy (LVH) is one of the most potent risk factors for cardiovascular disease. On cellular and molecular levels, studying cardiomyocytes (CMs) as a main target cell can yield important insights into LVH pathophysiology. In this presentation we will discuss results from our disease modeling studies using patient-specific iPSC-derived cardiomyocytes to understand the inter-individual variation of disease risk. Furthermore, we will discuss the potential of patient-specific cell lines for biomarker development as well as the potential of iPSCs for drug development and testing. Our results should demonstrate the spectrum and power of iPSC-derived cells for disease modeling in complex cardiovascular diseases.

12:00 pm A Phenotypic Screen for Apolipoprotein E-Promoting Compounds in Human Primary Astrocytes

Tae-Wan Kim, Ph.D., Associate Professor, Department of Pathology & Cell Biology, Columbia University Medical Center

Apolipoprotein E (apoE) is produced by astrocytes in the brain and is critically involved in the pathophysiology of Alzheimer’s disease (AD). Our phenotypic, high-throughput screening for small molecules of apoE enhancers in human primary astrocytes identified a number of apoE-enhancing hit compounds via previous unknown mechanisms, including regulators of cholesterol metabolism, GPCRs, neurotransmitter receptors and kinases. Our approach may yield useful tool compounds for mechanism studies or therapeutic leads for AD.

12:30 High-Content Image Analysis of Tissue Sections on Slides

Beatrice Knudsen, M.D., Ph.D., Director, Translational Pathology, Cedars Sinai Medical Center

1:00 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

Assay Development for Phenotypic Screening

1:55 Chairperson’s Remarks

Wei Zheng, Ph.D., Group Leader, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health

2:00 Analysis of Cellular Heterogeneity in Phenotypic Assays: Application of Metrics for Assay Quality Control and Biological Interpretation

Mark Schurdak, Ph.D., Research Associate Professor, Computational and Systems Biology, University of Pittsburgh; Director, Drug Discovery Institute

Heterogeneity is an intrinsic feature of cell systems, and is often the result of deterministic regulatory molecular mechanisms. To take full advantage of information obtained from cytometric phenotypic assays and gain a deeper understanding of biological systems and their response to perturbagens, it is necessary to analyze the distribution of cellular phenotypes. We have established metrics to quantify the distribution of cellular responses. The metrics and methods developed are presented here as a workflow for analysis of heterogeneity in large-scale biology projects.

2:30 Cell Line Profiling and Target Identification of Nannocystin A

Nathan Ross, Ph.D., Senior Investigator, High Throughput Biology Group Leader, Novartis Institutes for BioMedical Research

3:00 Tools for MoA Determination and Pathway Interrogation

Fred King, Ph.D., Research Investigator, Novartis Institute for BioMedical Research

3:30 Phenotypic Screening to Identify Combination Drug Therapy for Infections Caused by Drug-Resistant Bacteria and Ebola Virus

Wei Zheng, Ph.D., Group Leader, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health

Hospital drug-resistant bacteria and recent Ebola infection are urgent medical incidences that lack effective therapeutics. We have used the phenotypic screening approach in a drug repurposing screen and identified several three-drug combinations that can effectively inhibit drug-resistant bacteria and Ebola virus.

4:00 Close of Conference

Day 1 | Day 2 | Download Brochure