Targeting Cancer Stem Cells
Promising New Therapeutics for Oncology
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The science of cancer stem cells continues to evolve, and holds significant promise for the next phase of oncology therapeutics. The second annual Targeting Cancer Stem Cells will highlight achievements in basic science enhancing our understanding of cancer stem cells, and advances in the discovery and development of novel therapeutics making their way to the clinic. Presentations will focus on the unique challenges of working with CSCs, from characterizing cell populations to the development of screening assays, identification of druggable targets and pathways, validation in pre-clinical models, and translation to the clinic.
Monday, February 11
7:30 am Registration and Morning Coffee
8:25 Chairperson's Opening Remarks
8:30 Towards a Unifying Theory of Stem Cells and Human Diseases: Cancer as a Model System
Carlos Cordon-Cardo, M.D., Ph.D., Professor and Chairman, Department of Pathology; Professor, Department of Genetics and Genomic Sciences, The Mount Sinai School of Medicine
The discovery of the human cancer stem cell has important clinical implications in diagnostic and predictive laboratory assays, as well as for development of novel therapeutic strategies. These findings and translational clinical applications will be discussed during the presentation.
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9:00 A Restricted Cell Population Propagates Glioblastoma Growth Following ChemotherapyLuis F. Parada, Ph.D., Diana K. and Richard C. Strauss Distinguished Chair in Developmental Biology, Southwestern Ball Distinguished Chair in Nerve Regeneration Research, University of Texas Southwestern Medical CenterIt is only in the last decade that the existence of self-renewing cells in the brain has become fully appreciated. As a consequence, classic models of tumor development in the nervous system have invoked dedifferentiation as a requisite for tumor initiation. New concepts have arisen, however, with the continuing study of “adult” neural stem cells in vivo and in vitro. For example, preparation of neurosphere cultures from primary glioma tissue from human tumors and mouse genetic models permits detailed analysis and the hope for a full molecular understanding of these cells and how they compare to normal stem cells. A central question remains the identification of the cell of tumor origin. Our own work using tumor suppressor models of gliomagenesis leads us to propose that the cell of origin in these tumors is an early progenitor cell or possibly the primary stem cell. Recent data suggests that these “cancer stem cells” are responsible for sustaining tumor growth and infiltration, and for tumor recurrence following chemotherapy. I will discuss the nature of these mouse models, recent advances, how we hope to resolve our current working hypothesis, and implications for sporadic human cancer. If indeed stem or progenitor cells give rise to glioma, it becomes critical to fully understand their properties and physiological roles. Importantly, the ability to isolate these stem/progenitor cells and expand them in culture gives us a powerful resource for high-throughput screens that could yield potentially novel therapies for cancer treatment.
9:30 Radiation-Induced Reprogramming of Breast Cancer Cells
Frank Pajonk, M.D., Ph.D., Associate Professor, Radiation Oncology, David Geffen School of Medicine, University of California Los Angeles
10:00 Coffee Break with Exhibit and Poster Viewing
10:30 The Tumor Microenvironment as a Target for Breast Cancer Stem Cells
Max S. Wicha, M.D., Distinguished Professor of Oncology and Director, University of Michigan Comprehensive Cancer Center
The tumor microenvironment plays an important role in the regulation of breast cancer stem cells. Cytokine loops modulate cancer stem cell microRNAs which effect stem cell self-renewal and EMT/MET transitions. Targeting these pathways provides a novel therapeutic strategy.
11:00 Defining Novel Drugs and Pathways that Selective Target Human Cancer Stem Cells
Mick Bhatia, Ph.D., Director and Senior Scientist, McMaster Stem Cell and Cancer Research Institute, McMaster University
Pathways that regulate self-renewal processes are shared among normal stem cells, as well as rare cancer cells with stem cell properties. In the human, approaches to isolate, interrogate, and define drugs selectively targeting "cancer stem cells" will be discussed.
11:30 High-Throughput Capabilities to Identify Cancer Stem Cell Targeting Agents
Lilian van Vlerken, Ph.D., Scientist, Oncology Research, MedImmune
As drug discovery research to target cancer stem cells is rapidly evolving, so are the assays used to monitor effects on this sub-population of cancer cells. While flow cytometry and limiting-dilution assays are often the gold standard in cancer stem cell research, these techniques can be time-consuming and labor intensive. In this seminar we will discuss novel approaches using high content screening to monitor effects on cancer stem cells, allowing for cancer stem cell research to move closer into the high-throughput realm.
12:00 pm Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own
1:25 Chairperson's Remarks
1:30 Identification of Specific Cancer Stem Cell Inhibitors by Chemical Genetic Screens
Michael Detmar, M.D., Professor of Pharmacogenomics, Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich
We have carried out chemical library screens in melanoma stem cells derived from human melanoma vs. normal neural crest stem cells and non-stem cell-like melanoma cells.We identified several specific cancer stem cell inhibitors, and potential novel targets for the selective inhibition of cancer stem cells.
2:00 Cancer Stem-Like Cells from Colon and Lung Tumors Provide Tools for Drug Discovery and Development
Jennie Mather, Senior Vice President, Stem Cell Technologies, Macrogenics, Inc.
There is increasing evidence that many solid tumors, as well as hematopoetic malignancies, are hierarchically organized with the bulk of the tumor cells having limited replication potential but deriving from a stem-like cell (CSC) that perpetuates the tumor. We have used direct in vitro selection of CSC from tumors using defined serum-free conditions specific for each tumor type. We will discuss a series of colon and lung cancer derived CSC-like lines that self renew, reconstitute patient-like tumors from a few, or a single cloned cell, and metastasize from xenografts. These lines can be differentiated in vitro in 3D matrigel culture to cells expressing appropriate, lung or colon, multi-lineage markers and having limited replication potential. These CSLC lines and defined culture systems are useful in studying the maintenance of the stem-like state vs differentiation. They also provide tools for the discovery, and improved in vitro and in vivo screening, of novel cell surface targets for anti-cancer antibody therapeutics.
2:30 Targeted Therapy of the Tumor-Initiating Lgr5 Cell in Colorectal Cancer
Melissa R. Junttila, Ph.D., Scientist, Molecular Biology, Genentech, Inc.
With the availability of both a pharmacologic and genetic means for selective Lgr5 targeting, we aim to explore the feasibility of targeting the tumor-initiating Lgr5 cell in colorectal cancer and furthermore identify potential resistance mechanisms that occur as a result of Lgr5 targeted therapy.
3:00 Refreshment Break with Exhibit and Poster Viewing
3:30 Novel Strategies for the Detection and Therapeutic Eradication of Leukemia Stem Cells
Leslie Crews Robertson, Ph.D., Jamieson Laboratory, Sanford Consortium for Regenerative Medicine & Moores UC San Diego Cancer Center
Leukemia progression and relapse is fueled by leukemia stem cells (LSC) harboring aberrant self-renewal, differentiation and survival capacity. Activation of stem cell pathways promotes LSC generation in chronic myeloid leukemia, and these pathways represent novel therapeutic targets currently under investigation.
4:00 Targeting Quiescent and Proliferating AML Stem Cells
Robert J. Tressler, Ph.D., Vice President, Research & Development, Cellerant Therapeutics, Inc.
Targeting CSCs is required for more effective cancer treatment. We identified antigens expressed on AML stem cells and are developing antibodies against these targets that bind AML patient samples, have antitumor activity in vitro and in vivo and kill proliferating and quiescent AML cells, making these mAbs promising therapeutic candidates for AML.
4:30 ET-101: A Novel Therapeutic Antibody Targeting Colorectal Cancer Stem Cells
Peter Chu, Vice President, US Operations and Cancer Biology, Bionomics
Using our validated CSC Rx Discovery platform, we have discovered a novel therapeutic monoclonal antibody that targets a key CSC receptor overexpressed in colorectal (CRC) and other solid cancers. This antibody, ET-101, binds with high affinity to a functional receptor that is highly specific to cancer stem cells. In pre-clinical studies, ET-101 blocks the growth of cancer stem cells derived from primary colorectal cancer patient tumors both in vitro and in vivo. These data support our therapeutic hypothesis that ET-101 targeting of CSCs can lead to durable cures in the clinic by eliminating stem cells at the root of cancer.
5:00 Breakout Discussions
6:00 Close of Day
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