Why not combine the best of both phenotypic and 3D approaches for drug discovery? There is a resurgence in using primary phenotypic screening strategies as a more productive approach over conventional target-directed methods. Three-dimensional cell culture
recapitulates normal and pathological tissue architectures, thus providing physiologically relevant models to study normal development and disease. Challenges remain, though, for high-throughput screeners as researchers must procure large numbers
of identical 3D cell cultures, develop assays and obtain fast, automated readouts from these more complex assays. Join cell biologists, tissue engineers, assay developers, screening managers and drug developers at Cambridge Healthtech Institute’s
Inaugural 3D Cellular Models conference as they discuss strategies to accelerate the identification of novel therapeutic leads.
Thursday, June 11
12:00 pm Registration
2:00 Chairperson’s Opening Remarks
Jeffrey Morgan, Ph.D., Professor, Medical Science and Engineering, Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University
2:05 FEATURED PRESENTATION: 3D SPHEROIDS FOR INVESTIGATING DRUG UPTAKE, ACCUMULATION AND TRANSPORT
Jeffrey Morgan, Ph.D., Professor, Medical Science and Engineering, Department of
Molecular Pharmacology, Physiology and Biotechnology, Brown University
In addition to recapitulating normal and disease phenotypes, the small 3D microtissues formed by multi-cellular spheroids also mimic the physical/ biological barriers to drug penetration that are significant contributors to a drug’s efficacy
as well as toxicity. This talk covers the use of micro-mold technology to form long-lived designer spheroids and their use to quantify drug transport.
2:35 Engineered 3D Microsystems: Recapitulating in vivo Form, Function and Responses
Christopher S. Chen, M.D., Ph.D., Professor, Biomedical Engineering, Boston University and Wyss Institute
for Biologically Inspired Engineering, Harvard University
The 3D organization of cells defines the adhesive, mechanical and soluble microenvironment that ultimately governs cell phenotype. Understanding how forces, form and cellular function are related provides a mechanism for engineering 3D cultures that can
more faithfully reproduce in vivo function. This presentation discusses both the underlying fundamental insights and examples of engineered cultures that have the potential for enhancing discovery, validation and safety studies.
3:05 When Time Is the Third Dimension: Combining Computer Simulation and Primary Tissue Cell Culture to Identify Tissue Stem Cell-Toxic Drug Candidates
James L. Sherley, M.D., Ph.D., Director, Asymmetrex, LLC
Screening out drug candidates that are toxic to tissue stem cells before conventional preclinical testing would accelerate drug development and reduce its high cost. Human tissue stem cell toxicity may also elude animal testing and lead to even more
expensive failures due to intolerable toxicity in clinical trials or after marketing. AlphaSTEM is a new computer simulation technology for predicting tissue stem cell toxicity against any human tissue in a relatively inexpensive cell culture
NanoCulture Plate (NCP): Scaffold Type High-Throughput 3D Cell Culture System
M. Mamunur Rahman, Ph.D., PI &
Lab Director, 3D Cell Culture, SCIVAX USA, Inc.
NCP is engineered with micro-patterned square or honeycomb structure on the plate surface that supports cells to form cell spheroid. NCP is prime for many studies, i.e. signaling, hypoxia, live imaging, anti-cancer drug sensitivity screen, primary
cancer cell culture, EMT assay, toxicology or regenerative medicine researches, co-culture, and stem cells differentiation.
Use of Co-Spheroids Systems for the Analysis of the Impact of Stromal Cells on Anti-Cancer Drug Activity
Jan E. Ehlert, Ph.D., Head, Cellular Drug Discovery,
In cancer treatment, stroma-derived microenvironmental cues are suspected to exert an adversary impact on anti-cancer drug efficacy. For taking such influences into account, we established a spheroid-based co-culture system for the analysis of compound
effects on the proliferation of tumor as well as of stromal cells. This modular HTS-compatible assay system generates information on stroma-attenuated drug activity that may prove valuable in early drug development to focus on compounds that remain
active under microenvironmental conditions.
4:05 Refreshment Break in the Exhibit Hall with Poster Viewing
4:45 Challenges & Opportunities toward Enabling Phenotypic Screening of Complex & 3D Cell Models
Christophe Antczak, Ph.D., Laboratory Head, CPC Integrated Lead Discovery, Novartis Institutes
for Biomedical Research
More and more complex and three-dimensional cell models derived from primary or iPS cells are described that recapitulate aspects of in vivo tissue organization and function. Challenges toward enabling high-throughput phenotypic assays relying
on these emerging models can be overcome by new opportunities in detection technologies. Progress toward enabling live, minimally invasive readouts is key to being able to take full advantage of more physiologically relevant cell models in drug
5:15 Developing More Disease-Predictive Assays for Phenotypic Screening
Fabien Vincent, Ph.D., Associate Research Fellow, Assay Development and Pharmacology, Hit Discovery and Lead
Profiling, Pfizer Global Research & Development
Phenotypic screening promises to positively impact the translation of preclinical discoveries to the clinic. Nonetheless, not all phenotypic screens will offer the same potential in that regard. A critical question then follows: What are the characteristics
of the best phenotypic screens? This presentation covers an analysis of this question conducted by a team of Pfizer scientists as well as proposes three specific criteria to help identify and design the most promising screens.
5:45 3D Skin Equivalents for the Assessment of Skin Health Benefits
Teresa DiColandrea, Ph.D., Senior Scientist, Life Sciences Innovation Core, Procter & Gamble
Three-dimensional skin and hair equivalents offer the potential for preclinical assessment of technologies for skin health but face challenges in specificity, robustness, scale and cost for integration into screening methods. Examples of characterization
and application of 3D models for preclinical studies will be discussed.
6:15 Close of Day
Friday, June 12
7:30 am Interactive Breakout Discussion Groups with Continental Breakfast
Each discussion group in this session is led by a moderator/s who ensures focused conversations around key issues. Attendees join a specific group and the small, informal setting facilitates sharing of ideas and active networking.
TABLE 4: Microtechnology for 3D Cellular Models
Moderator: Jeffrey Borenstein, Ph.D., Laboratory Technical Staff, Biomedical Microsystems, Draper Laboratory
- Tools to recapitulate the in vivo microenvironment
- Microfluidic technologies for automation and interacting 3D cellular models
- Microscale 3D cellular disease models
TABLE 5: Evaluating the Use of Human-Derived Neurons for Preclinical Phenotypic Screens
Moderator: Elizabeth D. Buttermore, Ph.D., Research Fellow, F.M.
Kirby Neurobiology Center, Boston Children's Hospital; Neurobiology Department, Harvard Medical School
- Are human-derived neurons accurately mimicking human neurological disease?
- What can we do to decrease batch variability of human-derived neurons?
- Can we utilize 3D culture systems to improve the success of phenotypic screens utilizing human-derived neurons?
- Can we use human-derived neurons for precision medicine?
TABLE 6: Tumor Heterogeneity in 3D Cancer Models
Moderator: Imran Rizvi, Ph.D., Instructor, Medicine and Dermatology, Medicine, Brigham and Women’s Hospital and Harvard Medical School
- Communication of tumor cells with heterocellular signaling partners
- Physical stress-based modulation of molecular targets and morphological features of 3D tumors
- Influence of the extracellular matrix on 3D tumor growth and treatment response
TABLE 7: Engineering Stem Cell Kinetics Dynamics into 3D Cellular Models
Moderator: James L. Sherley, M.D., Ph.D., Director, Asymmetrex, LLC
- Review of in vivo tissue stem cell kinetics dynamics
- Importance of tissue stem cell kinetics dynamics for tissue cell function
- Advantages from engineering stem cell kinetics dynamics into 3D tissue models
8:30 Chairperson’s Remarks
Christophe Antczak, Ph.D., Laboratory Head, CPC Integrated Lead Discovery, Novartis Institutes for Biomedical Research
8:35 FEATURED PRESENTATION: 3D PRINTING OF IN VITRO CELL/TISSUE MODELS FOR DRUG TESTING
Wei Sun, Ph.D., Albert Soffa Chair Professor, Mechanical Engineering, College of Engineering, Drexel
University; Professor and Director, Biomanufacturing Research Center, Mechanical Engineering, Tsinghua University
Rui Yao, Ph.D., Assistant Professor, Biomanufacturing Research Center, Mechanical Engineering, Tsinghua University
This presentation reports on the application of 3D cell printing techniques to construct functional in vitro cell/tissue models for drug testing. Examples of printing of HeLa cells for 3D cervical tumor models in vitro and the printing
of micro-organ devices will be presented.
9:05 Engineering the Tumor Microenvironment ex vivo for Translation Studies Using Patient-Derived Explants
Amir Aref, Ph.D., Instructor, Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School
Personalized cancer medicine is based on an emerging knowledge of the cancer mutation repertoire and the tailored application of drugs that target altered genes or pathways in individual patients. This work will enhance studies of tumor cell biology
in a physiologic context, open a new avenue for drug screening and biomarker development and accelerate the preclinical evaluation of novel personalized medicine strategies for patients in real time.
Epigenetic Screening: Phenotypic Cancer Cell Line Profiling with Long-Term Cell Culture + Univariate Genetic Analyses in a Single Platform
Don Axworthy, Senior Director, In Vivo
Pharmacology, Eurofins Pharma Discovery Services
Epigenetic target inhibition may exhibit delayed drug responses undetected by short-term cell growth assays. The OncoPanel™ profiling assay of 240 genomically characterized cell lines, optimized for subconfluent exponential growth over 10 day
cultures. Epigenetic selective inhibitors elicit drug responses dependent on assay duration, mutational status, confirmed by univariate genomic analysis.
Physiologically Relevant Tissue Models in High Throughput Organ-on-a-Chip Platform
Jos Joore, Ph.D., Chief Business Officer, MIMETAS
Abstract OrganoPlates™ are a novel microfluidic culture platform enabling long-term, membrane-free 3D co-culture models in a microtiterplate format. We have developed a large variety of tissue- and disease models, applicable for drug testing
and evaluation. The platform is compatible with standard readout equipment, making the technology suitable for high‐throughput automation.
10:20 Coffee Break in the Exhibit Hall with Poster Viewing
11:00 Targeting Biomarker Modulation, Cellular Heterogeneity and EMT in a Microfluidic Model for 3D Tumor Growth
Imran Rizvi, Ph.D., Instructor, Medicine and Dermatology, Medicine, Brigham and Women’s Hospital and Harvard
Understanding the role of hydrodynamic stress as a physical modulator of genetic, molecular and morphologic heterogeneity in tumor metastases may have important implications in treatment resistance and the design of targeted therapies. The impact
of flow on tumor morphology and biomarker modulation was investigated in a microfluidic model for 3D ovarian cancer. Flow-induced shear stress caused an increase in epithelial-mesenchymal transition and increased expression and activation of molecular
markers associated with aggressive disease.
11:30 Modeling Pain and Peripheral Neuropathy Using Fibroblast-Derived Nociceptor Neurons
Elizabeth D. Buttermore, Ph.D., Research Fellow, F.M. Kirby Neurobiology Center, Boston Children’s Hospital; Neurobiology Department, Harvard Medical School
Current model systems for preclinical pain and peripheral neuropathy studies are not providing adequate options in the clinic. To address this issue, we developed a method for deriving nociceptor neurons in vitro from mouse and human fibroblasts.
With these derived neurons, phenotypic screens can be completed to identify novel therapeutic strategies for ailments ranging from chronic pain to chemotherapy-induced neuropathy, with the goal of increased success rates moving into the clinic.
12:00 pm Cancer-on-a-Chip for Target Identification and Drug Screening
Sophie Lelièvre, D.V.M., LLM, Ph.D., Professor, Department of Basic Medical Sciences; Associate
Director, Collaborative Science, NCI-Designated Purdue Center for Cancer Research, Purdue University
Tissue architecture has been long known as an important feature to reproduce in order to identify pathways that control cancer onset and progression. Here I discuss specifically the impact of tissue geometry, notably that of ductal structures,
on the architecture and behavior of breast tumors, and the consequences for the development and assessment of therapeutic approaches.
12:30 Drug Discovery with Patient-Specific 3D Engineered Heart Tissues
Tetsuro Wakatsuki, Ph.D., CSO & Co-Founder, InvivoSciences, Inc.
InvivoSciences developed an in vitro disease model that recapitulates individual patient’s cardiomyopathy in 3D engineered heart tissues (EHTs) using the patient-derived cells. Automated cell culture and cardiomyocyte-differentiation
protocol improved the productivity and reproducibility for generating patient-specific disease models for drug and diagnostics development.
12:45 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:30 Session Break
2:00 Chairperson’s Remarks
Jeffrey Borenstein, Ph.D., Laboratory Technical Staff, Biomedical Microsystems, Draper Laboratory
2:05 FEATURED PRESENTATION: ORGANS-ON-CHIPS: ENGINEERING THE CELLULAR MICROENVIRONMENT TO RECREATE TRUE HUMAN PHYSIOLOGY AND ADVANCE DRUG DISCOVERY
Geraldine A. Hamilton, Ph.D., President and CSO, Emulate;
former Senior Staff Scientist, Wyss Institute for Biologically Inspired Engineering, Harvard University
Organs-on-Chips are smart in vitro surrogates of the human body that may accelerate the identification of novel therapeutics, ensure their safety and efficacy, and reduce significant drug development costs. We review our Organs-on-Chips
platform, which goes beyond conventional 3D cell culture models by recapitulating tissue-tissue interfaces, spatiotemporal chemical gradients, mechanical microenvironments and physiological function in an organ-specific context. Based
on experimental data collected from this platform, it is evident that it stands as a more predictive, human-relevant alternative to traditional drug development methods.
2:35 Lab-on-a-Chip Technologies for Automated High-Throughput Drug Discovery
Jeffrey Borenstein, Ph.D., Laboratory Technical Staff, Biomedical Microsystems, Draper
We have developed a range of technologies capable of automating the screening of compounds in a medium- to high-throughput manner. These technologies have been applied to important problems in cardiovascular diseases, in addition to kidney,
liver and lung models. In this presentation we demonstrate the use of these prototype lab-on-a-chip systems in several applications.
3:05 KEYNOTE PRESENTATION: INTEGRATING MULTIPLE ORGANS-ON-CHIPS: WHAT MIGHT WE LEARN, WHAT DO WE NEED AND HOW MIGHT WE DO IT?
John P. Wikswo, Ph.D., Founding Director, Vanderbilt Institute for Integrative
Biosystems Research and Education and Gordon A. Cain University Professor, Vanderbilt University
Organs-on-chips (OoCs) are beginning to recapitulate human physiology in compact, two- and three-dimensional tissue models that are more accurate than monolayer monocultures on plastic or matrix, and minimize the dilution of paracrine
signals intrinsic to Petri-dish or well-plate culture. Refined OoC microfluidics and analytics are now enabling the study of organ-organ interactions, including physiological regulation and drug toxicity. The next step is to optimize
insertion of coupled OoCs into the drug development pipeline.
3:45 Close of Conference