Traditional drug screening relies on monolayer cell culture, which is not always predictive of natural physiological state. This is especially problematic in cancer drug discovery, where simple cell cultures are not predictive of a complex tumor microenvironment that consists of various cell types that interact in 3-dimensional structures. As the cost of drug development rises, there is increasing pressure for more predictive in vitro models for functional analysis and compound characterization. Cambridge Healthtech Institute’s Inaugural Physiologically-Relevant Cellular Tumor Models for Drug Discovery meeting will focus on the latest advances in 3-D cellular tumor models and complex co-culture systems for functional analysis studies and compound screening/characterization.
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Tuesday, October 29
12:00 pm Main Conference Registration
1:30 Chairperson’s Opening Remarks
1:35 Phenotypic-Based Primary Screen for Angiogenesis Inhibitors
Mohanraj Dhanabal, Ph.D., Group Leader, Lead Discovery Technology, EMD Serono
Angiogenesis, the formation of new blood vessels from the pre-existing microvasculature, is among the key events for many physiological and pathological processes. We describe an angiogenesis assay system that allows rapid and reliable quantification of three-dimensional vessel formation in vitro in a miniaturized format using (BD Matrigel™) onto 384 plates. Such platform is used for screening compounds in a 384-well plate format to a high-content screening. Finally, we used this to screen more compounds during the drug discovery and development process, which led us to the identification and prioritization of compounds with potent antiangiogenic activity.
2:00 BioDynamic Imaging of Three-Dimensional Drug Response in Spheroids and Cancer Tissue
David Nolte, Ph.D., Professor, Physics, Purdue University
BioDynamic Imaging is a new form of three-dimensional functional imaging. It detects intracellular motions that act as a suite of biomarkers and provides an endogenous form of image contrast inside living tissue. Heterogeneous three-dimensional drug response affecting diverse intracellular motions is mapped out in real time after application of drugs. Delayed penetration, internal hypoxia, quiescent cell populations, and differential responses are captured. Correlation of the dynamic signatures with conventional high-content analysis provides insight into the mechanistic origins of the dynamic images.
2:25 A Chemical Biology Approach to Identify New Microtubules Dynamics Regulators
Laurence Lafanechère, Ph.D., CNRS Research Director, Department of Cell Differentiation and Transformation, Institut Albert Bonniot
The emergence of tumor resistance to conventional microtubule-targeting drugs restricts their clinical use. Using a cell-based assay that recognizes microtubule polymerization status to screen for chemicals that interact with regulators of microtubule dynamics, we identified Pyr1, a cell permeable inhibitor of LIM Kinase, which is the enzyme that phosphorylates and inactivates the actin depolymerizing factor cofilin. Pyr1 reversibly stabilized microtubules, blocked actin microfilament dynamics, and inhibited cell motility in vitro. Pyr1 inhibition of LIM Kinase caused a microtubule stabilizing effect, which was independent of any direct effects on the actin cytoskeleton. Thus, LIM Kinase functions as a signaling node that controls both actin and microtubule dynamics. In addition, Pyr1 retained its activity in multidrug resistant cancer cells that were resistant to conventional microtubule targeting agents. It is also effective in animals, where it delays tumors formation while showing a good tolerability. Thus, Pyr1 is a “first in class” LIMK inhibitor, showing efficacy on mice tumor models. Our results show that LIMK, which is an emerging target for cancer therapy, is indeed a targetable enzyme for cancer treatment.
2:50 Sponsored Presentations (Opportunities Available. Contact Ilana Quigley at 781-972-5457 or email@example.com.)
3:20 Refreshment Break in the Exhibit Hall with Poster Viewing
4:15 4-D Co-Culture Models of Breast Cancer for Target Identification
Ray Mattingly, Ph.D., Professor, Pharmacology, Wayne State University
We have developed 3-D coculture models that we term MAME (mammary architecture and microenvironment engineering). These MAME models include tumor cells cocultured with a variety of other elevant subtypes, including myoepithelial cells, tumor-associated fibroblasts and macrophages, and endothelial cells of blood and lymphatic origin. Proteolysis can be imaged and quantified using a live-cell assay of the degradation of fluorescently-quenched collagens. Extension of these models into 4-D (3-D plus time) demonstrates processes such as development of positive feedback loops between the cocultured cells, invasion of tumor cells into the angiogenic and lymphangiogenic networks, and allows identification of targets through profiling of cytokine production and responses.
4:40 A Stromal-Based 3-D Co-Culture Model for Chemotherapy Sensitivity Testing
Omar S. Aljitawi, M.D., Assistant Professor, Internal Medicine, University of Kansas Medical Center
The discrepancy in leukemic cell responses to chemotherapy in vivo, compared to in vitro, is partly related to the interactions of leukemic cells with the 3-dimensional (3-D) bone marrow (BM) stromal microenvironment. We describe an in vitro model that we have developed to investigate the effects of chemotherapy on leukemic cell lines co-cultured with human BM stromal cells in 3-D. This novel model provides an opportunity to study leukemic cell responses to chemotherapy in 3-D.
5:05 Micropatterned Surfaces for the Study of Cancer and Endothelial Cell Interactions with Hyaluronic Acid
Sharon Gerecht, Ph.D., Associate Professor, Chemical and Biomolecular Engineering, Johns Hopkins University
Hyaluronic acid (HA) has been implicated in cellular interactions that are associated with cancer progression. Functional HA surfaces were developed to study interactions between cancer cells and HA. A similar surface patterning approach was used to create HA regions next to fibronectin in two- and three- dimensional settings to study the interactions between cancer and endothelial cells. The ability to observe the dynamic interactions of cancer cells and angiogenesis within HA–rich microenvironment will improve fundamental understanding towards therapeutic targets.
6:00-9:00 Dinner Expert ThinkTank* (see page 2 for details)
SC4: How to Meet the Need for Physiologically-Relevant Assays?
Moderator: Lisa Minor, Ph.D., President, In Vitro Strategies, LLC
Anne Bang, Ph.D., Director, Cell Biology, Sanford-Burnham Medical Research Institute
Anthony M. Davies, Ph.D., Director, Irish National Center for High-Content Screening and Analysis (INCHSA)
Marina Fitzek, Associate Principal Scientist, Discovery Sciences, AstraZeneca
Aaron Morris, Ph.D., Lab Head, Cancer Biology, Sanofi Oncology
Michelle Palmer, Ph.D., Director, Discovery and Preclinical Research, Broad Institute
Caroline Shamu, Ph.D., Lecturer, Systems Biology and Director, ICCB-Longwood, Harvard Medical School
D. Lansing Taylor, Ph.D., Director, University of Pittsburgh Drug Discovery Institute and Allegheny Foundation; Professor, Computational and Systems Biology, University of Pittsburgh
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*Separate registration required
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