Phenotypic Screening must evolve to ensure successful Drug Development
Reporter: Aviva Lev-Ari, PhD, RN
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To be useful, phenotypic screening strategies must accurately convey drug effects in 3D physiologies, not just 2D simulations. 3D Cell Models Are Taking Screening into the Third Dimension, helping those methods evolve so they contribute to more fruitful drug development and more successful patient therapies. Experts from industry, academia and government address the possibilities in the above-named session, through talks such as: FEATURED PRESENTATION: DESIGNING 3D TISSUE MODELS OF HUMAN SKIN DISEASE: FROM IPSC TO CRISPR Jonathan Garlick, D.D.S, Ph.D., Professor, School of Dental Medicine, Tufts University; Director, Division of Cancer Biology and Tissue Engineering, Tufts School of Medicine, School of Engineering and Sackler School of Graduate Biomedical Sciences Using in vitro Models of Human-Induced Pluripotent Stem Cells for Drug Screening Mahmud Bani, Ph.D., Team Leader, Senior Research Officer, Translational Bioscience, National Research Council Canada Recent advances in cell reprogramming have enabled the generation of induced pluripotent stem cells (iPSC) as renewable sources of cells for a wide range of applications in drug discovery and cell-based therapies. Our laboratory has established several iPSC lines from human amniotic fluid cells, and differentiated them into various phenotypes. We show that 2D and 3D iPSC models can serve as complementary tools to evaluate drug candidates in preclinical stages. 3D Cellular Models for Therapeutic Target Discovery Aron Jaffe, Ph.D., Senior Investigator, Regenerative Medicine Hub Leader, Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research High-throughput screening of immortalized or tumor cell lines grown on plastic is widely used to identify potential therapeutic targets. However, these methods fail to recapitulate many features of multicellular tissue architecture found in vivo, which have profound effects on a variety of cell behaviors. This presentation highlights the strategies for designing complex (3D) cellular assays for target discovery using medium and high-throughput screening methods. Quantitative High-Throughput Screening Using a Primary Human 3-Dimensional Organotypic Culture Predicts in vivo Efficacy Madhu Lal-Nag, Ph.D., Group Leader, Trans-NIH RNAi Facility, National Center for Advancing Translational Sciences, National Institutes of Health Two-dimensional cell cultures cannot recapitulate the issues of drug gradients, drug perfusion and the effects of hypoxia. Increasing evidence attests to the fact that gene expression signatures and the regulation of various signaling pathways are dependent on various cues from the tumor microenvironment. 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. Development of Biologically Relevant Three-Dimensional Solid Tumor Models for Target Validation and Compound Screening Jason Ekert, Ph.D., Senior Research Scientist, Biologics Research, Janssen BioTherapeutics Development of biologically relevant in vitro models to better mimic the tumor microenvironment for solid tumors need to be established so drug targets can be better characterized. We have established multiple high-content imaging-based 3D tumor models for evaluating biologics and other novel therapeutic platforms. The tumor models should allow for a more informed characterization of drug candidates. SPONSORSHIP & EXHIBIT OPPORTUNITIES NOTE: Due to high demand and limited space, we are now only selling booths as part of sponsorship packages. For more information on our various levels of sponsorship, please contact: Joseph Vacca Associate Director, Business Development Cambridge Healthtech Institute T: (+1) 781-972-5431 |
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From: Mary Ann Brown <pete@healthtech.com>
Date: Thursday, March 10, 2016 at 11:32 AM
To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>
Subject: Phenotypic screening must evolve to ensure successful drug development
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This is very insightful. There is no doubt that there is the bias you refer to. 42 years ago, when I was postdocing in biochemistry/enzymology before completing my residency in pathology, I knew that there were very influential mambers of the faculty, who also had large programs, and attracted exceptional students. My mentor, it was said (although he was a great writer), could draft a project on toilet paper and call the NIH. It can’t be true, but it was a time in our history preceding a great explosion. It is bizarre for me to read now about eNOS and iNOS, and about CaMKII-á, â, ã, ä – isoenzymes. They were overlooked during the search for the genome, so intermediary metabolism took a back seat. But the work on protein conformation, and on the mechanism of action of enzymes and ligand and coenzyme was just out there, and became more important with the research on signaling pathways. The work on the mechanism of pyridine nucleotide isoenzymes preceded the work by Burton Sobel on the MB isoenzyme in heart. The Vietnam War cut into the funding, and it has actually declined linearly since.
A few years later, I was an Associate Professor at a new Medical School and I submitted a proposal that was reviewed by the Chairman of Pharmacology, who was a former Director of NSF. He thought it was good enough. I was a pathologist and it went to a Biochemistry Review Committee. It was approved, but not funded. The verdict was that I would not be able to carry out the studies needed, and they would have approached it differently. A thousand young investigators are out there now with similar letters. I was told that the Department Chairmen have to build up their faculty. It’s harder now than then. So I filed for and received 3 patents based on my work at the suggestion of my brother-in-law. When I took it to Boehringer-Mannheim, they were actually clueless.