Selection of appropriate animal models based on similarity to human biology carries considerable potential to ensure a higher predictability of preclinical trials.

Cambridge Healthtech Institute’s Novel 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. Highly characterized patient-derived tumor tissue xenograft models that allow us to more effectively evaluate novel targeted therapeutics as well as to identify predictive biomarkers in early stages of drug development will be discussed along with other novel models of cancer. Case studies and solutions for increasing the predictability of preclinical cancer studies will be presented.

Final Agenda

7:00 am Registration and Morning Coffee

Modeling for Cancer Genomic Medicine

7:55 Chairperson’s Opening Remarks

Peter Olson, Ph.D., Senior Principal Scientist, Pfizer Pharmaceuticals

8:30 Session Break

8:35 Preclinical Models Uncover a Novel Notch Mutant Oncogenic Driver Class in Triple Negative Breast Cancer Sensitive to a Gamma Secretase Inhibitor

Peter Olson, Ph.D., Senior Principal Scientist, Pfizer Pharmaceuticals

While the Notch pathway is reportedly activated in breast cancer, the molecular mechanisms leading to hyperactivation are poorly understood. To identify predictive biomarkers for the gamma secretase inhibitor PF-03084014, we sequenced sensitive PDX models and mined The Cancer Genome Atlas. We uncovered a disparate array of alterations in the extracellular and PEST domains in multiple Notch receptors that activated the pathway and were sensitive to drug. These data define a new oncogenic driver class that may respond to Notch targeted therapies.

9:05 Patient Derived Xenograft Clinical Trial Program

Neal Goodwin, Ph.D., Director, Corporate Research Development, Champions Oncology

A PDX clinical program to guide patient treatment has engrafted >750 patient specimens with a 70% patient tumor take rate and a >80% correlative treatment accuracy in completed clinical tests. This program has been expanded to support predictive clinical trials for breast, sarcoma, and lung cancers in partnership with clinical trial centers and cooperative trial groups. Ultimately, this program will include matched patient translational studies across numerous patient models for Phase II trial patient stratification.

9:35 Next-Generation Genetically Engineered Cancer Models

Professor Dieter Saur, M.D., Consultant and Senior Group Leader, Technische Universität München (TUM), School of Medicine

We generated an inducible dual-recombinase based PDAC model that permits spatial and temporal control of gene expression. This tool provides unparalleled access to the native biology of cancer cells and their hosting stroma, and rigorous genetic validation of candidate therapeutic targets. We performed tumor cell-autonomous and non-autonomous targeting, uncovered hallmarks of human multistep carcinogenesis, validated genetic tumor therapy, and showed that mast cells in the tumor microenvironment, which had been thought to be key oncogenic players, are in fact dispensable for tumor formation.

10:05 Coffee Break in the Exhibit Hall with Poster Viewing

ANALYSING AND LEVERAGING RESULTS

10:45 Chairperson's Remarks

Neal Goodwin, Ph.D., Director, Corporate Research Development, Champions Oncology

10:50 Statistical Analysis of PDX Studies and Preclinical Phase-II-Like Trials (PP2T) at EMD Serono

Anderson Clark, Ph.D., Director, In vivo Pharmacology, Oncology, EMD Serono Research & Development Institute

At EMD Serono, we use PDX models in Preclinical Phase 2-Like Trials (PP2T) to support Phase 2 clinical decisions for which the use of statistics has become paramount. Working closely with clinical biostatisticians, we have developed statistical approaches to different aspects of the trials which will be discussed, such as trial design, relationships between preclinical responses and RECIST criteria, responses and how to measure them, and determining treatment differences.

11:20 The Art of the Cocktail: Optimizing Multidrug Combinations in Preclinical Studies

Arijit Chakravarty, Ph.D., Director, Modeling & Simulation (DMPK), Takeda Pharmaceutical International Co.

The design of optimal combinations relies on maximizing combination efficacy for a given toxicity budget. This presentation will describe the development of novel mathematical modeling methods (based on tricks used by bartenders to develop recreational cocktails), to visualize and design efficient studies for two-drug (and higher-order) combinations, and their application in a practical drug development context, showing their impact on actual study design, and validation with in vivo datasets.

11:50 Evaluating Efficacy Coupled with Toxicity in a Preclinical Model of Head and Neck Cancer

Benjamin G. Cuiffo, Ph.D., Scientist, Biomodels, LLC

Chemoradiation used for the treatment of HNC results in regimen- related mucosal toxicity (mucositis) which impedes optimum cancer therapy and causes significant physiologic and resource adversities. We present a new, highly translational animal model which simultaneously assesses both the targeted efficacy of new anti-tumor agents and their impact on mucositis.

12:05 pm Can Animal Study Software Technology That Emulates Clinical Trial Methods Improve the Predictability of Clinical Outcome?

Eric Ibsen, Vice President, Studylog Systems, Inc.

The 95% failure rate of anticancer therapeutic approvals after positive Phase III trials suggests that existing pre-clinical approaches and tools are suboptimal predictors of clinical outcome. Recent software innovations enable animal researchers to mirror multi-arm, multi-site, clinical trials with rolling enrollment and run “piggy-backed” studies under a common protocol.

12:20 LUNCHEON PRESENTATION: 2nd Generation PDX Models Can Help the Progression of Precision Medicine

Jean-François Mirjolet, Ph.D., Technology Director, Oncodesign

Panels of PDX models reflecting the genetic diversity of human cancers can increase the predictivity of patients’ tumor response to treatments. But there is still a critical need for better predictive models for novel agents targeting the tumor microenvironment. In addition to the well characterized syngeneic models used for immuno-oncology drug testing, Oncodesign developed highly refined PDX models in microenvironment-humanized mice, demonstrating usefulness in PDX tumor dissemination and immuno-oncology research.

1:00 Refreshment Break in the Exhibit Hall with Poster Viewing

IMAGING ADVANCES AND END POINTS IN CANCER RESEARCH

1:30 Chairperson’s Remarks

Susanta Sarkar, Ph.D., Adjunct Associate Professor, Radiology, University of Pennsylvania; President, CadenzaMed LLC

1:35 Translational Imaging in Oncology

Daniel P. Bradley, Ph.D., Head, Biomedical Imaging, Takeda Boston, Takeda Pharmaceuticals International Co.

Daniel will present on a number of programs that he has directly worked on, or working on, that have been developed in translational imaging in oncology. Importantly, this talk will highlight important lessons learned about collaboration, timing, perspectives and science with a hope that other groups in the imaging community can leverage this information for future developments. The Biomedical Imaging Group balances its portfolio between the use of conventional imaging biomarkers used in a novel biological and/or pharmacological context to advanced imaging techniques.

2:05 Non-Invasive and Simultaneous Measurement of Pharmacokinetics and Pharmacodynamics in Preclinical Cancer Models

Werner Scheuer, Research Leader, Pharma Research and Early Development, Discovery Oncology, Roche Diagnostics GmbH

Non-invasive imaging modalities (optical and micro-computed tomography) in combination with ex vivo analysis (3D-multispectral fluorescence microscopy, FACS) are an undispensable tool to assess the anti-tumoral efficacy of new compounds. Proliferation of tumor cells, metastasis, angiogenesis, and induction of apoptosis as well as phosphorylation of kinases can be monitored in mice carrying tumor cells s.c. or orthotopically. The quantification of these pharmacodynamics (Pd) read-outs are combined with optical pharmacokinetics (Pk). The simultaneous measurement of Pd and Pk reduces the number of animals significantly and provides a comprehensive evaluation of new drugs.

2:35 Normalizing Tumor Microvasculature and Microenvironment

Dai Fukumura, M.D., Ph.D., Deputy Director, Edwin L. Steele Laboratory; Biologist, Department of Radiation Oncology, Massachusetts General Hospital; Associate Professor, Harvard Medical School

Intravital microscopy techniques and sophisticated animal models have been providing unprecedented molecular, cellular, anatomical and functional insights in tumor biology. Tumor microvasculature is structurally and functionally abnormal hindering drug delivery and inducing a hostile microenvironment that causes ineffectiveness of anti-tumor treatments. Imbalance of pro- and anti-angiogenic factors is causing these pathophysiological features in the tumor. Hence, restoring the balance of these factors in tumors may “normalize” tumor vasculature, improve its function and microenvironment, and enhance the efficacy of cytotoxic therapies.

3:05 Imaging-Based Companion Diagnostics: a New Paradigm in Drug Development

Susanta Sarkar, Ph.D., Adjunct Associate Professor, Radiology, University of Pennsylvania; President, CadenzaMed LLC

Development of companion diagnostics will improve the benefit to risk ratio of a given therapy and thus will help reduce drug development costs significantly. A molecular imaging approach allows noninvasive assessment of target expression and its interaction with drugs in situ. This presentation will elaborate on these approaches for the successful development of imaging based companion diagnostics.

3:35 Light In and Sound Out: High Resolution Deep Tissue Imaging Via Multispectral Optoacoustic Tomography Imaging

Neal C. Burton, Ph.D., Senior Application Specialist, iThera Medical

Multispectral optoacoustic tomography (MSOT) imaging opens up a wide field of research for development of novel tumor markers and therapeutic agents, dynamic contrast enhancement, and toxicological assessment of novel pharmaceuticals in small animal models. Initial results of MSOT clinical imaging studies are also showing high potential for clinical translation.

4:05 Refreshment Break in the Exhibit Hall with Poster Viewing

5:00 PLENARY KEYNOTE PANEL - click here for detailed agenda

6:00 Welcome Reception in the Exhibit Hall with Poster Viewing

7:00 Close of Day

Thursday, June 11

MODELING CANCER HETEROGENEITY

8:35 Chairperson’s Remarks

Jeffrey E. Green, M.D., Chief, Transgenic Oncogenesis and Genomics Section, Laboratory of Cancer Biology and Genetics, National Cancer Institute

8:45 Modeling Tumor Cell Dormancy in the Mouse

Jeffrey E. Green, M.D., Chief, Transgenic Oncogenesis and Genomics Section, Laboratory of Cancer Biology and Genetics, National Cancer Institute

Although dissemination of tumor cells often occurs at early stages of cancer, clinical recurrence as metastatic disease may not become manifest until many years later following a period of tumor cell dormancy. Modeling the process of tumor dormancy is critical for understanding mechanisms governing late tumor recurrence and translating this knowledge into potential therapeutic or preventive strategies. Recent advances in studying tumor dormancy and potential translational approaches to improve survival will be presented.

9:15 Applications of CRISPR-Cas9 for in vivo Genome Editing

Randall Platt, Biological Engineering, MIT, Laboratory of Feng Zhang

CRISPR-Cas9 is a versatile genome editing technology for studying the function of genetic elements. To broadly enable the application of Cas9 in vivo, we established a Cre-dependent Cas9 knockin mouse and demonstrated genome editing using adeno-associated virus (AAV)-, lentivirus-, or particle-mediated delivery of guide RNA in neurons, immune cells and endothelial cells. These genome editing strategies empower a wide range of biological and disease modeling applications.

9:45 Selected Poster Presentations: 3D Cell Cultures as Tumor Models

10:15 Mechanisms of Resistance to HER2 Targeted Therapy in HER2+ Breast Cancer

Rachel Schiff, Ph.D., Associate Professor, Molecular and Cellular Biology, Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston

In spite of the proven efficacy of anti-HER2 combined therapies, resistance still remain key challenge, as observed in patients and in preclinical models. Resistance is due to either reactivation of the HER pathway via compensatory, redundant, or mutated elements of the pathway, or switch to alternative survival pathways that can bypass HER network inhibition. These escape pathways may be derived from epi/genetic aberrations or compensatory signals and may preexist predominately in the primary tumor, or enriched under treatment selection.

10:45 Coffee Break in the Exhibit Hall with Poster Viewing

11:30 Preclinical Models for Precision Medicine in Metastatic Colorectal Cancer: Challenges and Opportunities

Livio Trusolino, M.D., Ph.D. Associate Professor, Department of Oncological Sciences, University of Torino School of Medicine, Laboratory of Molecular Pharmacology, IRCC, Institute for Cancer Research and Treatment

Our objective is to unravel the signaling pathways and genomic makeups that mediate responsiveness to anticancer therapies, with an emphasis on colorectal cancer. To this aim, we use different technological platforms (phosphoproteomics, next-gen DNA/RNA sequencing) and experimental settings (patient-derived tumorgrafts and patient-derived cancer cell lines). Our pipeline involves the integration of large-scale data for discovery, followed by cell-based mechanistic insight and validation in animal models. This knowledge will form a predictive basis for the rational identification of novel tumor targets.

12:00 pm PANEL DISCUSSION: Modeling and Researching Cancer Metastasis

Moderator: Bruce R. Zetter, Ph.D. Charles Nowiszewski Professor of Cancer Biology, Department of Surgery, Harvard Medical School

Panelists:

Arijit Chakravarty, Ph.D., Director, Modeling & Simulation (DMPK), Takeda Pharmaceutical International Co.

Jeffrey E. Green, M.D., Chief, Transgenic Oncogenesis and Genomics Section, Laboratory of Cancer Biology and Genetics, National Cancer Institute
Jean-François Mirjolet, Ph.D., Technology Director, Oncodesign

12:30 Close of Conference