2013 Archived Content
While more informative than cell-free biochemical assays, monolayer or suspension cell culture HTS assays still fail to accurately reflect the human cellular microenvironment. There is a need for physiologically-relevant cellular models for drug screening and functional analysis that provide high predictive value for clinical efficacy and safety of compounds. The three-dimensional cell culture models mimic the human tissue microenvironment and provide more accurate information for compound and target selection, thereby reducing late-stage attrition. Cambridge Healthtech Institute’s Inaugural Screening and Functional Analysis of 3-D Models meeting will explore the use of 3-D models to profile compound action and predict toxicity and efficacy. The meeting will cover assay development using 3-D cellular models, high-content analysis and imaging of 3-D models, and applications of screening 3-D models for compound profiling and target discovery/validation.
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Wednesday, October 30
7:30 am Breakfast Presentation (Sponsorship Opportunity Available) or Morning Coffee
8:25 Chairperson’s Opening Remarks
8:30 Functional Analysis of Therapeutic Antibodies Using ex vivo Tumor Spheroids
Mitchell Ho, Ph.D., Chief, Antibody Therapy Section, Laboratory of Molecular Biology, National Cancer Institute, NIH
Tumor microenvironments present significant barriers to antibody therapy. We established ex vivo tumor spheroids to study molecular mechanisms of antibody drug resistance. The tumor spheroids may prove invaluable for identifying potential targets in addition to providing an innovative platform for analyzing therapeutic antibodies. We compared the global gene expression profiles of spheroids and monolayers and identified genes specific to the 3-D biological structure of mesothelioma. An update on generation of human single-domain antibodies for cancer therapy will also be discussed.
8:55 Third Dimension: The Future of RNAi-Driven Target Identification in Cancer
Geoffrey A. Bartholomeusz, Ph.D., Assistant Professor and Director, siRNA Core Facility, Department of Experimental Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center
3-D spheroid cell cultures, unlike 2-D monolayer cell cultures, demonstrate properties that are highly co-related to tumors. The ease at which spheroid models can be applied in high-throughput screens has resulted in the realization of their importance to address relevant questions in tumor biology. We are developing 3-D spheroid cell culture models to be used in high-throughput screening, and the design of one such model for target identification utilizing high-throughput RNAi screens will be discussed.
9:20 Presentation to be Announced
9:45 A 3-D Culture-Based siRNA Screening Tool for Secretory Epithelium Cancer Targets
Nathalie Picollet-D’Hahan, Ph.D., Senior Researcher, CEA/DSV/iRTSV/BGE/Biomics
Genetic screening is certainly one of the most powerful approaches to gain insights into gene function and complex biological processes. However, it is becoming evident that functional genomics screens need to be performed in a more physiologically-relevant environment provided by a 3-D context. We propose to combine two technological innovations; both in microfluidic-generated 3-D cultures and parallelized lens-less imaging to perform 3-D RNAi-based HTS and to characterize new biomarkers in prostate cancer. We employed silencing RNAs (siRNA), targeting kinase-related genes to identify 3-D-specific effectors of prostate acini morphogenesis and polarity.
10:10 Perfecta3D® Hanging Drop Plate: A Highly Flexible and Straightforward 3D Screening Tool
Nicky Slawny, Ph.D., Applications Specialist, 3D Biomatrix
Biologically-relevant 3D tissue culture models for drug discovery are simple to create using Perfecta3D Hanging Drop Plates. Single cell type or co-culture spheroids and organoids are created in high-throughput friendly 96-well or 384-well plates and analyzed with existing manual or automated laboratory equipment to generate more physiologically relevant data.
10:25 Coffee Break in the Exhibit Hall with Poster Viewing
11:15 Engineering 3-D in vitro Tumor Models of Antineoplastic Drug Resistance: Use of Malignant Spheroids and Non-Malignant Accessory Cells from the Metastatic Microenvironment
Eugen Dhimolea, Ph.D., Research Fellow, Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School
To model the composition and architecture of metastatic lesions and to address the role of the local metastatic microenvironment in the drug resistance exhibited by disseminated cancers, we assembled heterotypic in vitro 3-D tissue cultures comprised of malignant cells growing in dispersed format vs. growing as spheroids, and in the presence vs. absence of non-malignant accessory cells from organs frequently targeted by metastatic disease. We assessed the pathophysiological relevance of these models by testing the activity of more than 100 FDA-approved antineoplastic drugs. The spheroid morphology significantly decreased the efficacy for several classes of conventional DNA-damaging (e.g. anthracyclins) agents as well as recently established targeted therapies (e.g. kinase inhibitors), while being associated with increased cell-killing activity of others. Our 3-D co-culture system provides a practical and clinically-relevant experimental system to study the mechanisms of metastatic microenvironment-related drug resistance and to screen for biologically active compounds that circumvent it.
11:40 Tumor-Microenvironment-on-Chip (TMOC)
Bumsoo Han, Ph.D., Associate Professor, Mechanical and Biomedical Engineering, Purdue University
Targeted delivery of therapeutic and imaging agents to tumors without non-specific accumulation at normal tissues can significantly improve the treatment and diagnosis of cancers. Nanotechnology recently enabled various functional nanoparticles as vehicles for targeted delivery. However, it is extremely challenging to optimize their design and configuration using traditional cell culture and animal models. In order to address this challenge, a new in vitro model was developed to simulate the complex 3-D tumor microenvironments relevant to the transport of nanoparticles.
12:05 pm Three-Dimensional Melanoma Models: From Screening to Skin Reconstructs
Adina Vultur, Ph.D., Staff Scientist, Wistar Institute
The melanoma field has seen unprecedented clinical successes in the last few years; however, tumor heterogeneity and plasticity indicate the requirement for an arsenal of therapeutic strategies to overcome advanced disease. We focus our efforts on investigating genetically-distinct melanoma subgroups using high-throughput 3-D screening assays (with and without a support matrix) and increasingly complex preclinical models from normal human skin reconstructs to patient-derived xenografts. Our melanoma model pipeline has already allowed us to identify compounds and targets with limited activity in the 2-D setting, but with potential in vivo.
12:30 Close of Screening and Functional Analysis of 3-D Models Meeting
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