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Monday, November 8
7:30-8:30 am Conference Registration
8:30-8:40 Welcoming Remarks from Conference Director
Julia Boguslavsky, Executive Director, Conferences, Cambridge Healthtech Institute
Stem Cells as Models for Drug Screening and Safety Assessment
Chairperson's Opening Remarks
Joshua E. Babiarz, Ph.D., Principal Scientist, Non-Clinical Safety, F. Hoffmann-La Roche, Ltd.
8:40-9:10 Human iPS-Derived Cardiomyocytes for Early Safety Screening
Cardiac liabilities are a significant cause of compound attrition, however non-clinical models are often insufficient, relying on animals or cell cultures lacking the full features of cardiomyocytes. Here we report a human iPS-derived cardiomyocyte model that is senescent, beats, and expresses key markers of in vivo cardiomyocytes, including the clinically relevant ion channels. Nearly 40 compounds, both cardiotoxic and non-cardiotoxic, were assessed in a number of assays including cytotoxicity and electrophysiology. We will discuss the utility of this model, as well as high-throughput potential.
9:10-9:40 Human Pluripotent Stem Cell Based Models for Hepatotoxicity and Cardiotoxicity Assessment
Peter Sartipy, Ph.D., Senior Principal Scientist, Project Manager, Cellartis AB
Pluripotent human stem cells have the ability to proliferate indefinitely and to differentiate into virtually any cell type. These features can be harnessed to generate large quantities of partially differentiated progenitors or terminally differentiated specialized cells. Recent technical advancements have now made it possible to culture undifferentiated cells under standardized feeder free conditions which allows for cost efficient large scale cell production, paving the way for future developments of in vitro and in vivo applications based on these cells. Such applications can include in vitro toxicity testing, compound screening, or cell therapy. This presentation will illustrate new achievements using human pluripotent stem cells for assessment of toxicological profiles of drug molecules. Specifically, differentiation of the cells towards hepatocytes and cardiomyocytes will be highlighted, together with examples of current and future opportunities to use these cells for the assessment of adverse side effects of drugs. It is anticipated that the implementation of human stem cell based assays in the drug discovery process will lead to lower attrition rates and the development of safer new drugs.
9:40-10:10 High-Throughput Screening to Identify Small Molecules Modulating Neural Stem Cell Proliferation and Differentiation
Yaping Liu, Ph.D., Senior Research Biologist, Automated Biotechnology, Merck Research Labs
Adult mouse subventricular zone (SVZ) neural stem/progenitor cells retain the capacity of generating the major cell types of central nervous system in vitro and in vivo. The relative ease of expanding SVZ cells in culture as neurospheres makes them an ideal model for carrying out large scale screening. We performed a high-throughput screen with a 1.4 million compound library using mouse SVZ cells to identify small molecules that regulate neural stem cell proliferation and differentiation. Assay development, statistical criteria for hit selection, follow-up screens and hit funneling strategy will be discussed.
10:10-11:00 Networking Coffee Break with Poster and Exhibit Viewing
11:00-11:30 Developing Screens in Human Pluripotent Stem Cells
Xianmin Zeng, Ph.D., Associate Professor and Director, Laboratory for Stem Cells and Aging, Buck Institute
We have developed a scalable process that uses defined conditions to generate neural stem cells (NSCs) and subsequently differentiate them into authentic A9 dopaminergic neurons from human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs). Our system provides a ready source of large numbers of neurons for potential drug screening applications. To test the validity of the scalable process for screening we have utilized our hESC/NSC to dopaminergic neuron protocol to develop an in vitro hESC/iPSC-based MPTP model for automatic screening of compounds of neurotoxic and/or neuroprotective effects, and to identify drugs that can be used in a manufacturing protocol to deplete unwanted contaminating precursor cells from dopaminergic neurons.
11:30-11:45 New Approaches to Using Stem Cells as Drug Discovery Targets and Tools
Dan Shoemaker, Ph.D., CTO, Fate TherapeuticsSponsored by
The ability to use stem cells in drug screening and to develop new therapeutics to target stem cells necessitates quantification of cell state. While induced pluripotent stem cells (iPSCs) hold the possibility of recreating adult stem cell biology for drug screening and disease modeling, iPSCs need to be characterized and quantified to confirm successful recapitulation in vitro of in vivo biology. This talk will explore using gene expression technology with novel selection and visualization tools to confirm and monitor cell state to establish new stem cell screening paradigms.
Sponsored by11:45-12:00 pm Human Pluripotent Stem Cell-Derived Neural Stem Cells: A Cell-Based System for Pharmaceutical Screening Applications
Simone Haupt, Dipl.Biol., Head of Bioengineering, Cellomics Platform, LIFE&BRAINHuman pluripotent stem cells (hPSC) provide fascinating possibilities for disease modeling, compound screening, drug discovery and regenerative therapies. A particular focus of LIFE&BRAIN is the controlled differentiation of hPSC into a stable neural stem cell population. Proprietary technology enables the generation of highly purified neuronal and glial cell types, which serve as cell-based assay systems. By implementing induced pluripotent stem cell (iPSC) technology, we generate a variety of patient-specific disease-relevant cell types, including midbrain dopamine neurons, motoneurons, GABAergic neurons and oligodendrocytes.
12:00-12:30 Live Image-Based Chemical Screens on Glioma Stem Cells
Davide Danovi, M.D., Ph.D., Neural Stem Cells Group, UCL Cancer Institute, University College London
Glioblastoma is the most common and aggressive primary brain tumor in adults with one year average survival. Cell models for this disease are to date largely inadequate. We report here the development of live image-based chemical screens on novel adherent neural stem cells derived from brain tumors, mirroring the elusive tumor initiating cells to which therapy and drug screens should be directed.
12:30-2:00 Lunch on Your Own
High-Content Screening of Stem Cells
Hakim Djaballah, Ph.D., Director, HTS Core Facility, Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center
2:00-2:30 High-Content Assay Strategies for the Identification of Modulators of hES & iPS Cells
We have successfully implemented a strategy to screen hESCs in 384-well plates against compound libraries and identified several modulators exhibiting differential effects on the fate of these hESCs. I will describe in some depth the adapted flow and discuss the pros and cons of our strategy and its scale up limitations. More recently, we switched our attention to iPS cells where we have developed a novel screening strategy involving an unusual readout for HTS. I will present some data on this novel way to screen iPS cells and discuss its merits for HTS.
2:30-2:45 Sponsored Presentation (Opportunity Available)
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2:45-3:15 Using High-Content Screening to Discover Small Molecules that Control Human Embryonic Stem Cell Fate
Paul D. Andrews, Ph.D., Senior Scientist, Stem Cell Programme, Drug Discovery Unit, College of Life Sciences, University of Dundee
The use of small molecules to target cellular pathways is a powerful method for driving stem cell differentiation in vitro and assist in somatic cell reprogramming. Working closely with Cellartis AB we have developed extensive capabilities for routine screening using human embryonic stem cells (hESCs). Feeder-free culture gives us > 1 billion fully-pluripotent hESCs per week for primary and secondary screening. Using high-content imaging and analysis we have screened a range of libraries: commercially available “bioactive” libraries and bespoke libraries of lead-like molecules. I will present our data from a 22,500 compound cell survival screen where we identified and characterized novel pro-survival small molecules. In another screen we discovered new kinase inhibitors that target the BMP signaling pathway.
3:15-4:00 Networking Refreshment Break with Poster and Exhibit Viewing
Stem Cells as Drug Targets
4:00-4:30 Strategies for Targeting Colon Cancer Stem Cells
Peter Chu, Ph.D., Scientist, Discovery Cancer Therapeutics Group, Biogen Idec, Inc.
Colon cancer is an ideal model for the development of cancer stem cell (CSC) drugs, as the normal biology of the colon supports the hypothesis that CSCs play a key role in colon cancer. Recent data emerging from both academia and industry continue to strengthen the rationale for targeting CSCs in colon cancer. Many challenges exist, however, and this presentation will provide an overview as well as some specific strategies for CSC drug development. Topics to be covered include a review of potential CSC targets, identification and validation of novel CSC targets, novel drug modalities, pre-clinical evaluation of potential lead candidates and additional critical issues to consider.
4:30-5:00 Development of New Therapeutic Agents that Reduce Tumor Initiating Cell Frequency
Sanjeev Satyal, Ph.D., Director, Cancer Biology, OncoMed
Cancer stem cells (CSCs), or tumor initiating cells, have been shown to mediate tumor progression, metastasis, and recurrence after therapy. We have characterized CSCs from a variety of major tumor types and have found that these cells are preferentially resistant to many current therapies. We have developed new therapeutic agents that block key CSC pathways including Notch and Wnt. These treatments inhibit tumor growth through multiple mechanisms, promote tumor cell differentiation and reduce CSC frequency.
5:00-5:30 BMS Smoothened Inhibitor (BMS 833923): Inhibition of the HH Pathway and Its Effect on Cancer Stem Cells
Jan M. Van Tornout, M.D., M.Sc., Group Director & Lead EDT #2, Discovery Medicine Oncology/Immunology, Bristol-Myers Squibb Co.
5:30-6:30 Opening Reception with Poster and Exhibit Viewing
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