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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 3-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 Second Annual Screening and Functional Analysis of 3D Models meeting will explore the use of 3D models to profile compound action and predict toxicity and efficacy. The meeting will cover assay development using 3D cellular models, high-content analysis and imaging of 3D models, and applications of screening 3D models for compound profiling and target discovery/validation.
Tuesday, November 18
12:00 pm Conference Registration
1:30 Chairperson’s Opening Remarks
Aron Jaffe, Ph.D., Novartis Institutes for BioMedical Research
1:35 Developing and Utilizing 3D Culture Systems for Novel Target Discovery
Aron Jaffe, Ph.D., Senior Investigator, Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research
Target identification and validation have historically relied on immortalized or tumor cell lines grown on plastic. Recent techniques involving growth of cells in three-dimensional matrices have enabled modeling of cellular processes in an environment that more closely resembles the in vivo setting. This presentation will highlight the strategies for designing complex cellular assays for target discovery using medium and high-throughput screening methods in three dimensions.
2:00 3D versus 2D: Insight from Pharmacology and Genomics
Jean-Louis Klein, Ph.D., Target and Pathway Validation, Platform Technology and Science, GlaxoSmithKline
2:30 Technology Showcase (Sponsorship Opportunities Available)
This showcase provides an opportunity for sponsoring companies to showcase their new and emerging 3D cell models and technologies for the next generation of drug and target phenotypic screening.
2:30 High-Throughput Compatible Co-Spheroid Model Analyzing Compound Effects on Both Tumor and Stroma Cells
Jan E. Ehlert, Ph.D., Head, Cellular Drug Discovery, ProQinase GmbH
A spheroid-based co-culture system for the simultaneous analysis of compound effects on the proliferation of tumor as well as of stroma cells was established. The modular HTS-compatible system reveals results reflecting cell-specific drug susceptibility and cell/cell interactions.
2:50 Showcase #2
3:10 Showcase #3
3:30 Refreshment Break in the Exhibit Hall with Poster Viewing
4:25 Chairperson’s Remarks
David Nolte, Ph.D., Professor, Physics, Purdue University; President, Animated Dynamics, Inc.
4:30 Drug Discovery and Development of Novel Anticancer Agents: Applications of Novel 3D Multicellular Tumor Spheroid Models
Daniel V. LaBarbera, Ph.D., Assistant Professor, Drug Discovery and Medicinal Chemistry, The Skaggs School of Pharmacy and Pharmaceutical Sciences, The University of Colorado
Aberrant regulation of epithelial-mesenchymal transition (EMT) is a driving force in the most prominent human diseases. In particular, EMT driven tumor progression promotes the expansion of cancer stem cells, drug resistance, and the mesenchymal phenotype, which is invasive with a high metastatic potential. Therefore, one therapeutic strategy to prevent metastatic dissemination is to develop small molecule drugs that can revert the mesenchymal phenotype to the more benign epithelial state. Using novel 3D multicellular tumor spheroid (MCTS) models of EMT, suitable for high-throughput and high-content screening (HTS/HCS), we have identified lead compounds that block TCF-transcription, which regulates the mesenchymal phenotype in colorectal cancer.
4:55 Novel Stromal Targets that Support Tumor Spheroid Formation
Shane R. Horman, Ph.D., Research Investigator, Advanced Assay Group, Genomics Institute of the Novartis Research Foundation
The stroma of solid organ tumors influences all phases of tumor progression indicating that environment may be dominant to the genetics of cancer cells. To expand these concepts to early stage drug discovery we have scrutinized the interactions between colon stroma and colorectal carcinoma (CRC) cells in a high-content co-culture 3D spheroid screen. Subsequently we were able to identify novel fibroblast genes that, when depleted, abrogate CRC spheroid formation revealing an extended chemotherapeutic space by which to target tumors.
5:20 Developing Biodynamic Screening Assays for 3D Live-Tissue Models
David Nolte, Ph.D., Professor, Physics, Purdue University; President, Animated Dynamics, Inc.
Biodynamic screening performs three-dimensional functional imaging of living tissue by measuring drug-induced changes in intracellular dynamics. It is compatible with many 3D tissue formats, including tumor spheroids grown in bioreactors or in multiwell plates, as well as tissue biopsies and other organotypic models. Dynamics-based phenotypic profiling of tissues provides a new type of high-content screening. This talk presents 3D assays being developed for chemosensitivity and resistance, proliferation and toxicity screening.
5:45 Close of Day
5:45 Short Course Registration
Wednesday, November 19
7:30 am Breakfast Presentation (Sponsorship Opportunity Available) or Morning Coffee
8:00 Chairperson’s Remarks
Mary C. Farach-Carson, Ph.D., Rice University
8:10 Targeted Electric Field Therapy Development in 3D Models of the Heterogeneous Glioma Microenvironment
Scott S. Verbridge, Ph.D., Assistant Professor, School of Biomedical Engineering and Sciences, Virginia Tech – Wake Forest University
3D tissue models that incorporate the physico-chemo-cellular heterogeneities of human tumors are a valuable tool for the development of treatments targeted against the cells that resist traditional therapies. We will discuss our recent work in targeting the physical properties of therapy resistant brain cancer cells, leveraging 3D models to analyze the impact of cell type and mechanical microenvironment on cellular response to high frequency electric fields.
8:35 Targeting Physical and Stromal Determinants of Tumor Heterogeneity in Bioengineered 3D Models
Imran Rizvi, Ph.D., Instructor, Medicine and Dermatology, Harvard Medical School; Associate Bioengineer, Brigham and Women’s Hospital; Assistant, Biomedical Engineering, Wellman Center for Photomedicine, Massachusetts General Hospital
The biological characteristics and treatment response of cancers is influenced by an array of factors including flow-induced shear stress, stromal partners, and matrix composition, which play deterministic roles in the fate of disseminated tumours. Research platforms that integrate these cues are critically needed to identify mechanism-based combinations. Current findings will be presented on the impact of flow and stromal partners, including tumor endothelial cells, on the biological characteristics of 3D co-cultures, and their susceptibility to conventional and emerging therapies.
9:00 3D Hydrogel Co-Culture Systems for Growing Patient-Derived Xenografts: Use in Selective Drug Screening
Mary C. Farach-Carson, Ph.D., Ralph and Dorothy Looney Professor, Biochemistry and Cell Biology; Scientific Director, BioScience Research Collaborative, Rice University
Building on success culturing metastatic prostate cancer (PCa) cell lines using 3D HA-based hydrogels, we now can culture ‘never in 2D’ patient-derived xenograft (PDX) tumors alone or with other cells from the tumor microenvironment. Hydrogel-encapsulated PDX tumoroids retain viability over two weeks, proliferate and express androgen receptor, providing a valuable new platform for drug discovery and screening. We now aim to eliminate the ‘middle mouse’– a leap towards personalized medicine.
9:25 Human Stroma-Derived Extracellular Matrices: 3D ECM Physiological Systems
Edna Cukierman, Ph.D., Associate Professor, Cancer Biology, Fox Chase Cancer Center
The talk will describe desmoplasia (i.e., cancer-associated) and fibrosis in vivo-like 3D ECM models. It will highlight the system’s physiologic and pathologic relevance. The seminar will illustrate target validation, phenotype assessment, functional analysis and drug efficacy uses. Assorted tumor-associated microenvironments will showcase tissue patterning, multi-spectra acquisitions and digital imaging analyses together with classic cell biology and biochemistry approaches. Finally, the use of well-annotated human pathological samples will establish clinical applicability.
9:50 Coffee Break in the Exhibit Hall with Poster Viewing
10:45 Chairperson’s Remarks
Alan H. Wells, M.D., D.M.Sc., University of Pittsburgh
10:50 Microfluidic Models with Microvascular Networks to Study Metastatic Disease
Roger D. Kamm, Ph.D., Cecil and Ida Green Distinguished Professor, Biological and Mechanical Engineering, MIT
Metastatic disease requires multiple steps, each involving a set of signaling events among multiple cell types in a variety of microenvironmental settings. Studies have been performed using microfluidic platforms to simulate each step in the metastatic cascade. Selected results will be presented addressing several of these phenomena, but focusing on extravasation. Results show that this system is capable of discriminating between cells of various levels of invasiveness, and that resident cells such as osteoblasts or myoblasts can differentially influence the rate of extravasation.
11:15 Monitoring Extravascular Migratory Metastasis of Angiotropic Cancer Cells Using a 3D in vitro Co-Culture System
Claire Lugassy, M.D., Research Associate Professor, Pathology and Lab Medicine, UCLA School of Medicine; Member, Jonsson Comprehensive Cancer Center
During extravascular migratory metastasis (EVMM), angiotropic tumor cells migrate along the abluminal vascular surfaces without intravasation (pericytic-mimicry) and may spread to nearby or more distant sites. Our recent publication in Nature confirmed again the importance of this underexplored metastatic pathway. We have developed a fluorescence-based 3D co-culture model to monitor in real time single tumor cell migration/EVMM in a vascular microenvironment. This assay can be adapted for anticancer drug screening.
11:40 An All-Human Microphysiologic Liver System for Carcinoma Metastasis
Alan H. Wells, M.D., D.M.Sc., Vice Chair and Thomas J. Gill III Professor, Pathology, University of Pittsburgh
Metastases kill patients, but disseminated cancers are resistant to therapies. The tumor biological events behind this are unknown due to lack of relevant model systems. Further, humans metabolize agents and present toxicities uniquely, hampering drug development. We have developed an all-human microphysiological system of the liver to study both tumor behavior in the common metastatic site, and drug metabolism/efficacy in the main metabolizing organ.
12:05 Using Block Cell Printing to Develop Single Cell Arrays for Drug Screening
Lidong Qin, Ph.D., Associate Professor, Nanomedicine, Methodist Hospital Research Institute
12:30 pm Close of Screening and Functional Analysis of 3D Models Conference