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Screening and Functional Analysis of 3-D Models

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 3rd 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.

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Tuesday, November 10

12:30 pm Conference Registration

Integrated Approach to in vitro Drug Discovery: Tissue Engineering Meets Systems Biology

1:55 Chairperson’s Opening Remarks

2:00 Integration of Microdevices, Systems Biology and Tissue Engineering for Drug Development

Linda G. Griffith, Ph.D., Professor, Biological Engineering, MIT

2:25 3D Cell Models and Screening: The Yin and Yang

Jean-Louis Klein, Ph.D., Target and Pathway Validation, Platform Technology and Science, GlaxoSmithKline

The pharmaceutical industry needs to develop more effective novel drugs and reduce the drug attrition rate. The very high percentage of failure during clinical trials suggests that our current preclinical models are not good enough at predicting the activity of novel molecules in humans. The design of the initial screen is critical since the whole drug development process is based on its output. The need for better preclinical assays fuels a debate about utilizing phenotypic or target-based approaches in early phases of drug discovery. However, both approaches require the inclusion of predictive human disease-relevant models earlier in the drug development process. Too often, screening assays have been oversimplified to increase the throughput and Z' values, and decrease cost; this has resulted in the identification of chemical series that have minimal chances of becoming successful drugs. The cellular assay predictive capacity should be the main driver in the choice of assays for screening, implying that cell assays with closer physiological approximation, such as 3D cell models, should be used. The capacity of a model to be human relevant needs to be determined; it should not be based on assumptions but on scientific data, and it should be validated. The use of human relevant assays at every step of drug discovery, including the initial screen, will improve the quality of candidate molecules and reduce the overall cost of drug discovery.

2:50 Exploring Pancreatic Neogenesis with LWM Compounds

Jesse Lugus, Ph.D., Research Investigator, Developmental & Molecular Pathways, Novartis Institutes for BioMedical Research

To determine whether the ductular epithelial cells of the adult pancreas possess the capacity to differentiate into beta cells, we developed a 3D culture of “miniducts” and screened them with a LWM compound library to look for expression of insulin.

PerkinElmer NEW 20093:15 Imaging Bile Canaliculi in 3D Liver Microtissues using the Opera Phenix High Content Screening System

Ty Voss, Ph.D., Senior Applications Scientist, Cellular Imaging and Analysis Team, PerkinElmer

BioBots3:30 What Will You Build?

Ricky Solorzano, CTO, Bioengineering, BioBots

The BioBot 1 was truly the birth arising from the ideas of a collective community of visionary biological engineers from around the world. We attentively listened to their feedback and rigorously navigated the literature to understand what experience is needed to design the next generation of biological constructs. The BioBot 1 is a desktop 3D bioprinter that builds 3D living tissues out of human cells. It is a beautifully designed, precision manufactured robot that prints cells and bioinks, bringing a new dimension to biology.

3:45 Refreshment Break in the Exhibit Hall with Poster Viewing

Microengineered 3D Models for Drug
Safety Testing

4:30 Microengineered Cell and Tissue Systems: Evolution of in vitro Liver Technologies

O. Berk Usta, Ph.D., Instructor, Surgery, Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School

The liver performs many key functions such as serving as the metabolic hub of the body. For this reason, the liver is the focal point of many investigations aimed at understanding an organism’s toxicological response to endogenous and exogenous challenges. We will present a survey and critical comparison of in vitro liver technologies along a broad spectrum, but focus on the current renewed push to develop “organs-on-a-chip” in our laboratory and elsewhere.

4:55 A 3D Human Kidney Microphysiological System for Drug Safety Testing

Edward J. Kelly, Ph.D., Associate Professor, Pharmaceutics, University of Washington, Seattle

The kidney proximal tubule is a primary target of drug-induced nephrotoxicity. In this talk, I will describe the development and functional characterization of a 3-dimensional human kidney proximal tubule microphysiological system or MPS. The MPS anatomically replicates the polarity of the proximal tubule, expresses appropriate marker proteins, and exhibits biochemical and synthetic activities, as well as secretory and reabsorptive processes associated with in vivo proximal tubule function. Current studies with the MPS are focused on response mechanisms to prototypical nephrotoxins as well as new chemical entities.

5:20 Development of a Rat Primary Hepatocyte Spheroid Model for Toxicity Screening

Lorin Jakubek, Ph.D., Postdoctoral Researcher, Predictive and Investigative Toxicology, Sanofi

Current in vitro predictive hepatotoxicity screens rely on monolayers of primary hepatocytes to predict in vivo drug-induced liver injury. Hepatocytes cultured in monolayers lose their phenotype and metabolic function within days of seeding. This creates a defined and brief experimental window that limits the type, nature and predictive capacity of the assays which can be conducted. It has previously been shown that three-dimensional spheroids of primary hepatocytes possess structural polarity, functional bile canaliculi and remain viable for more than fourteen days in vitro. Common methods used to produce spheroids are often limited in their application to toxicity screening due to cell loss, cell number or feasibility of the culturing method to existing assays. The objective of this work is to develop spheroids of primary hepatocytes in a format amenable to assays currently in use in the pharmaceutical industry. Here we show a characterization of the model for viability, morphology and functionality of primary hepatic spheroids. Examples of preliminary toxicity data will be presented as part of the ongoing model validation. While still in the validation phase, this model shows promise for predictive toxicity screens.

5:45 Short Course Registration

6:00-9:00 Dinner Expert ThinkTank*: (SC3) How to Meet the Need for Physiologically Relevant Assays

*Separate registration required.

Day 1 | Day 2 | Short Courses | Download Brochure

Wednesday, November 11

7:00 am Conference Registration and Morning Coffee

Phenotypic and High-Content Screening of
3D Models

8:30 Chairperson’s Opening Remarks

David Nolte, Ph.D., Professor, Physics, Purdue University; President, Animated Dynamics, Inc.

8:35 Next-Generation Assays for Next-Generation Oncology Targets

Serena Silver, Ph.D., Senior Investigator & Group Leader, Molecular Pharmacology, Novartis

Growth of cancer cells in 2D format has been a workhorse of the cancer research world, enabling high-throughput biology endeavors to identify new targets and new drugs. However, it is clear that we are sampling only a subset of cancer complexity in these models, for example by comparison of genomic characterization between primary tumors, xenografts, and cell lines grown in 2D. I will discuss our efforts to use methods such as co-culture and high-content imaging of cells grown in 3D systems to assess if these can indeed “fill the gap” and advance oncology drug discovery.

9:00 A Perspective on the Current State of 3-Dimensional and Complex Phenotypic Screening in Contemporary Drug Discovery

Shane Horman, Ph.D., Research Investigator, Genomics Institute of the Novartis Research Foundation

The initiation of a drug discovery project which involves a complex or 3-dimensional phenotypic screening platform requires grappling with logistical challenges that influence every step of the process. Primarily, can the disease or tissue be accurately mimicked in an in vitro microtiter plate environment? But beyond that, careful consideration must be given to the cell type(s), growth matrix, assay and readout methods as well as the downstream data analyses. Collectively, these factors can make or break a drug discovery effort. Herein I discuss the benefits and potential pitfalls of complex and multi-culture 3D cell models currently used in the pharmaceutical industry.

9:25 Heterogeneity on a Plate: A Soft Agar-Based Assay System for Studying Tumor Evolution

Arijit Chakravarty, Ph.D., Director, Modeling and Simulation, Takeda Pharmaceuticals

Tumor evolution is well accepted as a feature of clinical cancer etiology and response to treatment. Evidence for evolutionary processes can also be found in the preclinical in vitro and in vivo settings. Tumor evolution has clear implications for drug discovery and development, but in order to understand those implications, we have to be able to study the process first. In my talk, I will present an in vitro tumor evolution assay, developed from a soft agar culture using automated microscopy and high-content analysis. I will then discuss the analysis of this data, using methods derived from population biology and evolutionary theory.

9:55 Coffee Break in the Exhibit Hall with Poster Viewing

10:40 The Challenges of Identifying Cellular Phenotypes in 3D in vitro Cellular Assay Systems

Anthony M. Davies, Ph.D., Center Director, Translational Cell Imaging Queensland (TCIQ), Institute of Health Biomedical Innovation, Queensland University of Technology

Currently, one the biggest drivers in the field of translational research is the need to improve the relevance of cell-based assays. To achieve this goal many investigators are turning their attention to high-content analysis used in conjunction with primary cells and/or 3D cell assay models. Despite the potential benefits that these new experimental approaches may offer, their use has not been without both technical and practical difficulties. In this presentation we will discuss the challenges we have encountered here at TCIQ and the solutions that we have arrived at to meet our research objectives.

11:05 Biodynamic Imaging of 3D Tissue Models and ex vivo Biopsies

David Nolte, Ph.D., Professor, Physics, Purdue University; President, Animated Dynamics, Inc.

The challenge to extract high-content information from inside three-dimensional tissue is met by biodynamic imaging that probes a wide range of intracellular dynamics up to 1 mm deep inside living tissue. Biodynamic imaging is compatible with virtually all three-dimensional tissue culture, such as multicellular tumor spheroids grown either in bioreactors, by the hanging drop method, or in multi-well spheroid plates, as well as ex vivo biopsies of living tissue.

11:30 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

Cancer-on-a-Chip: Engineering 3D Models of Tumor Microenvironment

1:00 pm Chairperson’s Opening Remarks

Treena Arinzeh, Ph.D., Professor, Biomedical Engineering, New Jersey Institute of Technology

1:05 Hydrogels as Artificial Extracellular Micro-Environments to Study Angiogenesis

Sharon Gerecht, Ph.D., Associate Professor, Chemical & Biomolecular Engineering, Johns Hopkins University

Hydrogel biomaterials provide a highly controlled three-dimensional (3D) environment that is structurally and biomechanically similar to the native extracellular matrix (ECM). These can provide a rich biochemical landscape as well as biophysical cues to influence cell behavior. In this talk I will present our recent efforts to develop hydrogel matrices that activate signaling pathways during 3D vascular assembly.

1:30 Targeted Combinations to Overcome Physical and Stromal Determinants of Treatment Resistance in 3D Tumor Models

Imran Rizvi, Ph.D., Instructor, Medicine and Dermatology, Brigham and Women’s Hospital, Harvard Medical School

The susceptibility of cancers to therapeutic intervention is determined by epithelial mesenchymal transition status as well as a complex milieu of physical and cellular cues in the tumor microenvironment. These cues originate from many sources including the surrounding matrix, diffusible growth factors and cytokines, the architectural and organizational features of the tumor, and heterotypic communications between tumor cells and stromal partners. Among the various microenvironmental factors that warrant investigation, hydrodynamic stress and tumor endothelial cells are emerging as important modulators of biology in many cancers including ovarian cancer. Understanding the therapeutic implications of heterogeneity that result from physical and stromal cues is critical to designing more effective regimens for challenging cancers, including metastatic OvCa.

1:55 Implantable Microenvironments to Capture Stem/Cancer Cells

Biju Parekkadan, Ph.D., Assistant Professor, Surgery (Bioengineering), Harvard Medical School, Massachusetts General Hospital

Bone marrow is an important, yet inaccessible, site to understand stem/cancer cell biology. In this presentation, we will introduce a 3D implant to model human bone marrow in mice and discuss several in vivo case studies that have captured human stem/cancer cells at this localized implant site. We also describe a bone marrow microchip as a bridge platform to capture and implant circulating stem/cancer cells for end-to-end longitudinal research.

2:20 Engineered Culture Systems for Cancer Stem Cells

Esmaiel Jabbari, Ph.D., Professor of Chemical and Biomedical Engineering, Chemical Engineering, University of South Carolina

The 3D in vitro cell culture system has emerged as an attractive approach to bridge the gap between 2D cell culture and in vivo systems. With naturally derived matrices, it is difficult to isolate and study cell response to individual factors in the microenvironment on cancer cells. Therefore, there is a need to develop engineered matrices for selection and enrichment of the most malignant stem cell subpopulation in the cancer cell population to study the role of individual factors in the tumor microenvironment on tumorigenesis.

2:45 Networking Refreshment Break

3:15 TRACER: A 3D Engineered Tumor for Quantifying Spatial Metabolic Reprogramming in Hypoxic Gradients

Alison McGuigan, Ph.D., Associate Professor, Chemical Engineering and Applied Chemistry, University of Toronto

Currently it is challenging to characterize specific properties of cells and the corresponding microenvironment from where they originated. We have developed a modular approach to assemble 3D engineered tumors by rolling thin (30 micron thick) tumor cell-impregnated scaffolds on an oxygen impermeable core. In our Tumor Roll for Analysis of Cell Response (TRACER), cells at different depths within the roll experience different oxygen and nutrient levels mimicking the variation seen in tumors at progressively further distances from a blood vessel. Our system can be rapidly (<1s) disassembled for analysis by unrolling. The geometry of the system allows the spatial location of the cells along the length of the strip in the disassembled construct to be easily mapped to their location in the 3D construct to facilitate separation of populations of cells from different microenvironments. Furthermore, this cell isolation can be achieved rapidly, enabling acquisition of snap-shot data such as metabolic profiles. Here we will describe use of TRACER to perform a 3D spatial metabolomics analysis of tumor cells in hypoxic gradients.

3:40 Investigating Breast Cancer Dormancy Using Tissue Engineering Models

Treena Arinzeh, Ph.D., Professor, Biomedical Engineering, New Jersey Institute of Technology

Despite early detection through the use of mammograms and aggressive intervention, breast cancer remains a clinical dilemma. Breast cancer (BC) can resurge after >10 years of remission. Studies indicate that BC cells (BCCs) with self-renewal and chemoresistance could be involved in dormancy. The majority of studies use in vitro, two-dimensional (2D) monolayer cultures, which do not recapitulate the in vivo microenvironment. Thus, to determine the effect of the three-dimensional (3D) microenvironment on BCCs, we use tissue engineering scaffolds that more closely mimic the extracellular matrix of the tumor and sites of metastasis. We will present findings demonstrating BC dormancy can be supported by specific features of the tissue engineering scaffolds.

4:05 Hydrogel-Facilitated 3D Tumor Microenvironment Models of Cancer Dormancy, Relapse and Micrometastasis: Fundamentals and Synergistic Drug Treatments

Kaushal Rege, Ph.D., Associate Professor, Chemical Engineering, Arizona State University

We describe novel 3D tumor microenvironment models of cancer dormancy, relapse from dormancy and formation of micrometastatic nodules, all on a novel hydrogel platform. This technology facilitates the formation of dormant cancer cell and/or cancer cell-stromal cell co-cultures. These dormant 3D dormant microenvironments are resistant to anti-proliferative drugs including docetaxel and mitoxantrone. New synergistic approaches that include targeting the protein production machinery were effective in complete ablation of dormant cells. Chemo-mechanical modulation of the hydrogel results in escape of cells from dormancy, which can be greatly reduced using docetaxel.

4:30 Close of Conference

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For questions about the meeting, please contact:
Julia Boguslavsky
Executive Director, Conferences
Cambridge Healthtech Institute (CHI)
Email: juliab@healthtech.com

For sponsorship and exhibit sales information, please contact:
Katelin Fitzgerald
Senior Business Development Manager
Cambridge Healthtech Institute (CHI)
Phone: (+1) 781-972-5458
Email: kfitzgerald@healthtech.com 

For media and association partnerships, please contact:
James Prudhomme
Senior Marketing Manager
Cambridge Healthtech Institute (CHI)
Phone (+1) 781-972-5486
Email: jprudhomme@healthtech.com