The key study design elements such as schedule, escalation strategy, targeted patient population, etc. rely heavily on preclinical data. This situation brings utmost scrutiny to the predictability of preclinical tumor models and to the methods of analyzing
and translating the results of preclinical studies. Animal models of cancer develop into more sophisticated and complex representations of disease genotype and phenotype. The next generation cell lines and organoids employ latest advances in genomics
and gene editing that turns them into invaluable tools for combination therapy design. The translational challenges and the efforts to streamline the path of new compounds and combinations to clinic stress the need of staying current in the area of
tumor models and modeling for preclinical design and assessment. Cambridge Healthtech Institute’s Part 1: Preclinical Models in Oncology conference aims to bring together cancer researchers and clinicians in order to initiate
knowledge and opinion exchange around preclinical models and their optimization.
Wednesday, June 15
7:00 am Registration and Morning Coffee
8:25 Chairperson’s Opening Remarks
Quang-Dé Nguyen, Ph.D., Director of the Lurie Family Imaging Center, Senior Scientist, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute
8:35 KEYNOTE PRESENTATION: THE DISCOVERY RESEARCH/CLINICAL DEVELOPMENT INTERFACE IN ONCOLOGY: OPTIMIZING THE BI-DIRECTIONAL FLOW OF INFORMATION
Dominic G. Spinella, Ph.D., Executive Director, Medical Sciences, Head of Clinical Biomarker
Discovery & Development, Amgen
While “translational medicine” approaches to moving projects from bench to bedside are almost cliché in the BioPharma industry, there are still many gaps remaining in the effective interaction between basic and clinical researchers
and the efficient transfer of programs from discovery to clinical development. What do clinicians really require from preclinical and development colleagues, and how can clinical data rapidly inform discovery programs? Using case studies and examples,
this talk will focus on these gaps and what can be done to fill them.
9:05 Translational Cancer Imaging for Drug Development and Precision Medicine: Bidirectional Interactions between the Mouse Hospital and the Cancer Center
Annick D. Van Den Abbeele, M.D., Associate Professor, Radiology, Harvard
Medical School; Chief, Department of Imaging, Dana-Farber Cancer Institute; Founding Director, Center for Biomedical Imaging in Oncology (CBIO), Imaging, Dana-Farber Cancer Institute
Quang-Dé Nguyen, Ph.D., Director of the Lurie Family Imaging Center, Senior Scientist,
Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute
Our mission is to optimize the care of cancer patients by using imaging as a biomarker to accelerate drug development and promote successful and timely translation of cancer discovery into clinical practice. In this context, we have established the Center
for Biomedical Imaging in Oncology with bidirectional exchanges between the mouse hospital at the Lurie Family Imaging Center, and the Clinical Imaging Research laboratory at the Cancer Center.
9:35 PDX Clinical Trial Program
Neal Goodwin, Ph.D., Vice President, Corporate Research Development, Champions Oncology
Responses in PDX clinical programs (patients’ solid tumors engrafted to form tumor models for personalized treatment testing) are being used to prospectively guide patient treatment. To date, >1000 specimens have been engrafted for translational
medicine studies; a pipeline of over 150 patients is maintained. The PDX program has shown >80% correlative accuracy in >125 completed clinical tests and is being employed for conducting translational medicine trials across many patient tumor
types, including AML. Co-clinical and patient matched PDX-directed trials are being implemented through several industry partnerships.
10:05 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing
10:50 Modulation of the Tumor Microenvironment by Large and Small Molecules
Daniela Cipolletta, Ph.D., Investigator II, Exploratory Immuno Oncology, Novartis Institutes
for BioMedical Research (NIBR)
Tumors are composite of many different cellular and non-cellular components including malignant cancer cells, leukocytes, fibroblasts, endothelial cells and other stromal elements. It is widely recognized that tumor microenvironment plays a significant
role in disease progression, metastatic process, drug resistance, etc. This presentation will describe how modulation of tumor microenvironment by large and small molecules can help us to develop effective cancer therapies.
11:20 Patient-Derived Xenograft Models in Drug Discovery and to Study Metastasis and Circulating Tumor Cells
Holger Karsunky, Ph.D., Director, Cancer Biology, Stemcentrx, Inc.
To preserve the gene expression and histology of tumor samples for drug discovery and efficacy testing, Stemcentrx has developed a large number of patient-derived xenograft models from primary tumors of various types. Data will be presented demonstrating
that these PDX models not only better predict treatment responses but also recapitulate the tumor histopathology in regard to circulating tumor cells in the blood and the metastatic properties of the original tumor.
11:50 Current Preclinical Models of Oncology: Focus on Bioluminescent PDX and Gnotobiotics
Benjamin Cuiffo, Ph.D., Scientist, Biomodels LLC
The clinical success of a potential cancer therapy depends upon complimentary inputs of numerous intersecting factors, including tumor and host genetics, microenvironment, immunogenicity, and heterogeneity/evolution. Consequently, the application
of predictive, translational models in pre-clinical development must reliably reflect overall tumor response in the context of multiple, but well-defined variables. Current preclinical oncology models are now more than ever capable of addressing
these influences and assaying therapies aimed at the novel targets they present. We’ll highlight Biomodels’ clinically recapitulative bioluminescent PDX models and immunomodulatory microbiome/gnotobiotic capabilities as tools to advance
a new generation of oncology therapeutics.
12:05 pm A New and Affordable 3D Scanning Device for Subcutaneous Tumors
Cem Girit, Ph.D., Biopticon Corporation
TumorImager-2, like its predecessor is a hand held 3D scanning device similar to a barcode scanner to obtain accurate volumes of subcutaneous tumors. The scans take place in less than a second producing 3D life-like color images displaying segmented
tumor regions. The accurate volume results are tabulated and plotted in tumor growth curves instantly by the accompanying TumorManager software. It can be used as a desktop or hand held device.
12:20 Luncheon Presentation: From Syngeneic to Humanized Mouse Models: Addressing the Needs for Novel Immunotherapies
Philippe Slos, Director, Scientific Operations, Oncodesign
Treatments targeting immune cells such as immune checkpoint modulators, bispecific antibodies or adoptive T cell transfer have now demonstrated clinical efficacy and some of them are already approved.
However, preclinical development of these therapies required models adapted for each target, each class of therapeutic. To address these needs, case studies using syngeneic mouse models as well as tumor bearing humanized mouse models will be presented.
12:50 Session Break
1:40 Chairperson’s Remarks
Kenna Anderes, Ph.D., Founder & President, Translational Medicine Partners, Inc.
1:50 Translating an Unbiased Cell-Based Compound Screen into Novel Drug Combination Strategies
Stuart Shumway, Ph.D., Principal Scientist, Oncology Early Discovery, Merck Research Labs
We conducted a screen of 1,406 compound pairings in 39 tumor cell lines for an unbiased identification of promising cancer drug combinations. Here, we describe two combinations to illustrate challenges that arise in translating hits into combination
strategies. This screening approach identified drug pairings that might have been missed based solely on a current understanding of cancer cell biology.
2:20 In vivo Genetic Screen in Metastatic Mouse Models
Sidi Chen, Ph.D., Assistant Professor, Department of Genetics & Systems Biology Institute, Yale
Cancer Center & Stem Cell Center
We describe a genome-scale CRISPR-Cas9-mediated loss-of-function screen in tumor growth and metastasis. We mutagenized a non-metastatic mouse cancer cell line using a library with 67,405 single guide RNAs (sgRNAs). We discovered that individual
sgRNAs and a small pool of 624 sgRNAs targeting the top scoring genes from the primary screen dramatically accelerate metastasis. In all of these experiments, the effect of mutations on primary tumor growth positively correlates with the
development of metastases.
2:50 Refreshment Break in the Exhibit Hall with Poster Viewing
3:35 From Mouse to Man: Using Cross-Species Analysis of Genome-Wide Regulatory Networks for Drug Discovery in Prostate Cancer
Abate-Shen, Ph.D., Michael and Stella Chernow Professor of Urological Oncology, Associate Director, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center
Although genetically engineered mouse (GEM) models are often used to evaluate cancer therapies, extrapolation of experimental data from GEM models to human cancer can often be challenging because of inherent species differences. In our analyses
of prostate cancer, we have established computational methods for effective integration of experimental data from GEM models to human cancer, which has enabled the elucidation of mechanisms of cancer malignancy, as well as optimization
of drugs and drug combinations for human cancer.
4:05 Genetically Engineered Miniswine Models of Cancer
John Swart, Ph.D., President, Exemplar Genetics
Current preclinical models of cancer fail to accurately recapitulate human disease and do not effectively translated to the clinic. Recently, Exemplar Genetics has developed a genetically engineered miniature swine model that contains
a conditional KRAS mutation on the background of TP53-targeted pigs, the ExeGen® TP53+/R167H& KRAS+/G12D miniswine model. This model should allow for the inducement of human-like tumors in a tissue specific manner.
4:35 In Vivo Phenotypic Screening in PDX Models to Identify Novel Therapeutic Targets in Cancer
Tyler Miller, M.D./Ph.D. Candidate, Case Western Reserve School of Medicine, Stem
Cell Biology and Regenerative Medicine, Jeremy Rich Lab, Cleveland Clinic
We developed a novel high-throughput in vivo screening strategy to identify direct therapeutic targets within solid tumors. Using intracranial PDX models of glioblastoma, we discovered screening within a functional microenvironment
reveals a host of epigenetic targets not detected by parallel in vitro screening. These in vivo-specific targets were more clinically relevant and validated in preclinical models of glioblastoma, demonstrating the power and utility
of functional in vivo screening to identify therapeutically relevant targets in cancer.
4:50 A Tissue-Engineered Vascularized Tumor Microenvironment for Preclinical Testing of Anticancer Therapeutics
Henning Mann, Ph.D., Senior Research Scientist, Research & Development, Nortis,
Nortis provides microfluidic chips for tissue engineering 3D vascularized tissue microenvironments. Endothelial vessels induced to sprout in response to growth factors create a vascular network that invades tumor tissue. The model
will be used to test anticancer therapeutics.
5:05 PANEL DISCUSSION: Preclinical Strategies and Tactics to Improve Clinical Trials
Moderator: Kenna Anderes, Ph.D., Founder & President, Translational Medicine Partners, Inc.
Topics to be Discussed:
- Approaches to PDX generation and molecular characterization
- Beyond PDX genotype--monotherapy drug response correlations
- Models of heterogeneity and clonal evolution: Tools to thwart resistance
5:35 Welcome Reception in the Exhibit Hall with Poster Viewing
6:45 Close of Day
Thursday, June 16
7:00 am Registration.
7:30 Interactive Breakout Discussion Groups with Continental Breakfast
This session features various discussion groups that are led by a moderator/s who ensures focused conversations around the key issues listed. Attendees choose to join a specific group and the small, informal setting facilitates
sharing of ideas and active networking. Continental breakfast is available for all participants.
Gene Editing in Tumor Models
Moderator: Sidi Chen, Ph.D., Assistant Professor, Department of Genetics & Systems Biology Institute, Yale Cancer Center & Stem Cell Center
- Applying genetic engineering to mouse models
- Developing models with major somatic mutations using CRISPR/Cas9
- In vivo screening in animal models of cancer
Novel Cell-Based Compound Screening in Oncology
Moderator: Stuart Shumway, Ph.D., Principal Scientist, Oncology Early Discovery, Merck Research Labs
- In vitro modeling of complex cellular phenotypes for screening.
- Deconvolution of phenotypic screening.
- Quality control of cell-based high throughput compound screening.
Using PDX Models to Inform Cancer Clinical Trials
Moderator: Jianguo Ma, Ph.D., Associate Director, Translational In Vivo Pharmacology, EMD Serono R&D
- Assuring the predictive value of these animal models
- Implementing data analysis and visualization tools for large scale preclinical trials
- Designing drug combination preclinically
8:35 Chairperson’s Remarks
Jianguo Ma, Ph.D., Associate Director, Translational In Vivo Pharmacology, EMD Serono R&D
8:45 The Use of Patient-Derived Xenograft (PDX) Models at EMD Serono: Employing Clinically Relevant Study Design and Analysis
Jianguo Ma, Ph.D., Associate Director, Translational In Vivo Pharmacology, EMD Serono R&D
At EMD Serono, data from PDX (patient-derived xenograft) models of cancer are used to make clinical decisions for Phase II. In increasing the predictive value of these animal models, we have addressed questions about what constitutes a preclinical response in relationship to clinical RECIST criteria and what the proper statistical analyses of these models would be, and these outcomes will be presented.
9:15 Engineered Swine Models of Cancer
David Largaespada, Ph.D., CSO, Surrogen, Inc.
Swine models of cancer have great potential for preclinical safety studies, including efficacy & toxicity testing of pharmaceuticals in genetically prone individuals. We are applying precision genetics to provide swine
cancer models. We will describe our use of TALENs & CRISPR targeted nucleases to develop novel porcine models of cancer with broad preclinical applications. Experience in modeling several human cancers, including:
models of Li-Fraumeni syndrome (TP53), Neurofibromatosis Type 1 syndrome (NF1), Familial Adenomatous Polyposis Coli (APC), and others will be presented.
NEXT GENERATION CELL LINES AND ORGANOIDS
9:45 Recapitulating the BETH Adjuvant Breast Cancer Clinical Trial Using Pre-Clinical Models
Annette Byrne, Ph.D., Senior Lecturer Physiology & Medical Physics,
Royal College of Surgeons in Ireland
We have recapitulated the BETH adjuvant breast cancer trial implementing clinically relevant surgical resection breast cancers models. Our models have accurately replicated the negative clinical response observed in a Phase
III setting, where the addition of bevacizumab combined with chemotherapy plus trastuzimab did not prolong disease free survival in the adjuvant Her2+ Breast cancer setting.
10:15 Coffee Break in the Exhibit Hall with Poster Viewing
11:00 New and Old in vitro Models to Guide Cancer Therapeutic Use and Discovery
Cyril H. Benes, Ph.D., Principal Investigator and Director, Center for Molecular
Therapeutics, Massachusetts General Hospital Cancer Center
Tumor derived cell lines are important models for the study of cancer biology and the discovery of therapeutic strategies for the treatment of cancers. While large collection of currently available cell lines can capture
a substantial fraction of the variations in cancer genomes, recent advances allow to establish cell lines from a variety of tumor material. In recent years we have used tumor biopsy derived cells to study acquired
resistance to targeted therapies. Following up on this work, we use cellular reprogramming methodologies towards the establishment of functional diagnostics. In vitro drug response measurement has the potential
to complement molecular profiling of tumors to improve therapeutic decisions. Old and new in vitro cancer models will be discussed.
11:30 Engineering Cancer Stem Cell Microenvironment for Drug Screening
Esmaiel Jabbari, Ph.D., Professor, Chemical Engineering,
University of South Carolina
Increasing evidence suggests that the tumor heterogeneity is rooted in the existence of a very small sub-population of stem-like cells (CSCs) within the population of tumor cells. Since cancer takes many years to grow,
it is important to develop in vitro models to study tumor initiation and progression. In an effort to regulate the cancer cell microenvironment, my laboratory has merged material synthesis, microscale technologies,
and cancer biology to develop an engineered 3D matrix to delineate the role of individual factors in the tumor microenvironment on CSC maintenance, self-renewal, and differentiation. I will demonstrate in my seminar
that engineered matrices can enrich the CSC subpopulation of cancer cells which is potentially useful in cancer drug screening and personalized cancer treatment.
12:00 pm Bridging Luncheon Presentation: Combination Immune Checkpoint Inhibitors for the Treatment of Colon Carcinoma in Humanized NSG Mouse Models
Martin Graf, Ph.D., Director, Charles River Labs
With the increasing success and interest in cancer Immunotherapy, there is a growing need for relevant preclinical models. Our studies with syngeneic tumors, using immune checkpoint inhibitors targeting CTLA-4 and PD-1,
showed differential responses across tumor types. Recently, we evaluated the efficacy of these inhibitors in a human colon carcinoma model in CD34-NSG and PBMC-NSG humanized mice. Results from these studies shows
significant tumor growth inhibition in response to checkpoint inhibitors associated with T cell activation.
12:30 Session Break
1:00 Coffee and Dessert in the Exhibit Hall with Poster Viewing
1:45 PLENARY KEYNOTE SESSION
3:30 Refreshment Break in the Exhibit Hall with Poster Viewing
4:15 Close of Conference