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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA

An MMRF Roundtable

January 27­ 28, 2008

www.the mmrf.org

CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Table of Contents

Welcome Agenda

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Participant List Biographies

Keynote Speakers Co-Chairs Faculty MMRF Abstracts Session Chairs Participants

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Session I ­ Stem Cell Interaction With the Microenvironment G. David Roodman, MD, PhD David T. Scadden, MD Linda M. Pilarski, MD Joshua Epstein, DSc Marta Chesi, PhD Carla Kim, PhD

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Session II ­ Animal Models and Stem Cells

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Session III ­ Targeting the Cancer Stem Cell William Matsui, MD Craig T. Jordan, PhD

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Madhav Dhodapkar, MD

Session IV ­ Clinical Trials Based on Cancer Stem Cells Andrzej J. Jakubowiak, MD, PhD Franziska Michor, PhD Ivan Borrello, MD Notes .

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Supported by grants from

CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Dear Colleague: Welcome to New York City and the Cancer Stem Cell Research Strategies: Applications to Multiple Myeloma roundtable sponsored by the Multiple Myeloma Research Foundation (MMRF). We are pleased and privileged to bring together leading experts from academia, industry, and the National Cancer Institute who are involved in this evolving and exciting field of cancer research. At this roundtable, we will discuss scientific achievements in both myeloma and stem cell biology as well as outline the challenges of translating laboratory findings regarding cancer stem cells (CSC) to the clinic. Through a mutual exchange of ideas, we hope to begin to formulate strategies for targeting multiple myeloma (MM) CSC. Moreover, the MMRF will use the information from this roundtable to issue a Request for Applications (RFA) to the broader research community on critical topics relating to CSC applications to MM. We look forward to an open and stimulating discussion that will challenge our current thinking, increase our collective knowledge, and identify the key questions regarding myeloma stem cells. This roundtable is made possible by the MMRF through educational grants from Celgene Corporation, Geron Corporation, Infinity Pharmaceuticals, Inc., Keryx Biopharmaceuticals, Inc., Millennium Pharmaceuticals, Inc., Semafore Pharmaceuticals Inc., and the generous contributions from donors including Christopher Walker. We would like to take this opportunity to thank them for their continuing support. Once again, thank you for joining us. We look forward to working together today and in future endeavors. Sincerely,

William Matsui, MD Assistant Professor of Oncology Division of Hematologic Malignancies The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, MD

Andrzej J. Jakubowiak, MD, PhD Associate Professor Director, Myeloma Program University of Michigan Comprehensive Cancer Center Ann Arbor, MI

Joan B. Levy, PhD Associate Director of Research Multiple Myeloma Research Foundation Norwalk, CT

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

CO-CHAIRS

William Matsui, MD Assistant Professor of Oncology Division of Hematologic Malignancies The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, MD Andrzej J. Jakubowiak, MD, PhD Associate Professor Director, Myeloma Program University of Michigan Comprehensive Cancer Center Ann Arbor, MI

AGENDA

Sunday, January 27 6:30 PM Reception and Dinner (Keynote Speakers) Max S. Wicha, MD University of Michigan Comprehensive Cancer Center Bart Barlogie, MD, PhD University of Arkansas for Medical Sciences

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

AGENDA

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Monday, January 28 7:15 AM ­ 7:50 AM 7:50 AM ­ 8:00 AM Breakfast and Registration Introduction and Meeting Objectives Review William Matsui, MD, Co-Chair The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Session I ­ Stem Cell Interaction With the Microenvironment G. David Roodman, MD, PhD, Session Chairperson University of Pittsburgh Medical Center David T. Scadden, MD Massachusetts General Hospital, Harvard Stem Cell Institute Linda M. Pilarski, MD University of Alberta and Cross Cancer Institute 9:20 AM ­ 9:35 AM 9:35 AM ­ 10:55 AM Break Session II ­ Animal Models and Stem Cells Joshua Epstein, DSc, Session Chairperson University of Arkansas for Medical Sciences Marta Chesi, PhD Mayo Clinic ­ Scottsdale Carla Kim, PhD Children's Hospital Boston 10:55 AM ­ 11:10 AM Break

8:00 AM ­ 9:20 AM

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

AGENDA

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Monday, January 28

11:10 AM ­ 12:30 PM

Session III ­ Targeting the Cancer Stem Cell William Matsui, MD, Session Chairperson The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Craig T. Jordan, PhD James P. Wilmot Cancer Center University of Rochester Medical Center Madhav Dhodapkar, MD The Rockefeller University

12:30 PM ­ 1:15 PM 1:15 PM ­ 2:35 PM

Working Lunch Session IV ­ Clinical Trials Based on Cancer Stem Cells Andrzej J. Jakubowiak, MD, PhD, Session Chairperson University of Michigan Comprehensive Cancer Center Franziska Michor, PhD Memorial Sloan-Kettering Cancer Center Ivan Borrello, MD The Johns Hopkins University

2:35 PM ­ 3:45 PM

Wrap-Up Session ­ Major Issues to Address for Stem Cell Application to Multiple Myeloma: Defining a Potential Request for Applications (RFA) William Matsui, MD The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Andrzej J. Jakubowiak, MD, PhD University of Michigan Comprehensive Cancer Center

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Participant List Keynote Speakers

Bart Barlogie, MD, PhD University of Arkansas for Medical Sciences 4301 West Markham Street, #816 Little Rock, AR 72205 Phone: 501-526-2873 Fax: 501-526-2273 Email: [email protected] Max S. Wicha, MD University of Michigan Comprehensive Cancer Center 1500 East Medical Center Drive, 6302 CC Ann Arbor, MI 48109-5942 Phone: 734-936-1831 Fax: 734-615-3947 Email: [email protected]

Co-Chairs

William Matsui, MD The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 1650 Orleans Street, CRB 245 Baltimore, MD 21231 Phone: 410-955-2808 Fax: 410-614-7279 Email: [email protected] Andrzej J. Jakubowiak, MD, PhD University of Michigan Comprehensive Cancer Center 1500 East Medical Center Drive Room 4-216 CC, SPC 5936 Ann Arbor, MI 48109-5936 Phone: 734-615-1482 Fax: 734-647-9654 Email: [email protected]

Session Chairs

Joshua Epstein, DSc University of Arkansas for Medical Sciences 4301 West Markham Street, #776 Little Rock, AR 72205 Phone: 501-686-8250 Fax: 501-686-6442 Email: [email protected] G. David Roodman, MD, PhD University of Pittsburgh Medical Center 151-U, University Drive C, Room 2E113 Pittsburgh, PA 15240 Phone: 412-688-6571 Fax: 412-688-6960 Email: [email protected]

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Participant List Faculty

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Ivan Borrello, MD The Johns Hopkins University Cancer Research Building ­ 1 Rm 453 1650 Orleans Street Baltimore, MD 21231 Phone: 410-955-4967 Fax: 443-287-4653 Email: [email protected] Marta Chesi, PhD Mayo Clinic ­ Scottsdale 13400 East Shea Boulevard MCCRB 3-024 Scottsdale, AZ 85259 Phone: 480-301-4703 Fax: 480-301-8387 Email: [email protected] Madhav Dhodapkar, MD The Rockefeller University 1230 York Avenue, Box 196 New York, NY 10065 Phone: 212-327-7118 Fax: 212-327-7119 Email: [email protected] Craig T. Jordan, PhD James P. Wilmot Cancer Center University of Rochester Medical Center 601 Elmwood Avenue, Box 703 MRBX, Room 1-11128 Rochester, NY 14642 Phone: 585-275-6339 Fax: 708-575-3785 Email: [email protected]

Carla Kim, PhD Children's Hospital Boston 300 Longwood Avenue, Karp 8-216 Boston, MA 02115 Phone: 617-919-4644, ext. 44644 Fax: 617-730-0222 Email: [email protected] Franziska Michor, PhD Memorial Sloan-Kettering Cancer Center 417 East 68th Street 1127 New York, NY 10021 Phone: 646-888-2802 Fax: 646-422-0717 Email: [email protected] Linda M. Pilarski, PhD University of Alberta and Cross Cancer Institute 11560 University Avenue Edmonton, AB T6G 1Z2 Canada Phone: 780-432-8925 Fax: 780-432-8425 Email: [email protected] David T. Scadden, MD Massachusetts General Hospital, Harvard Stem Cell Institute 185 Cambridge Street CPZN-4265A Boston, MA 02114 Phone: 617-726-5615 Fax: 617-724-2662 Email: [email protected]

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Participant List Participants

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P. Leif Bergsagel, MD, FRCP(C) Mayo Clinic 13400 East Shea Boulevard MCCRB 3-007 Scottsdale, AZ 85259 Phone: 480-301-4704 Fax: 480-301-8387 Email: [email protected] Laurence Elias, MD Geron Corporation 230 Constitution Drive Menlo Park, CA 94025 Phone: 650-473-7779 Fax: 650-566-7210 Email: [email protected] Joseph R. Garlich, PhD Semafore Pharmaceuticals Inc. 8496 Georgetown Road Indianapolis, IN 46268 Phone: 317-876-3075 Fax: 317-876-3272 Email: [email protected] David S. Grayzel, MD Infinity Pharmaceuticals, Inc. 780 Memorial Drive Cambridge, MA 02139 Phone: 617-453-1146 Fax: 617-453-1001 Email: [email protected]

Lori Hazlehurst, PhD H. Lee Moffitt Cancer Center & Research Institute 12902 Magnolia Drive Tampa, FL 33612 Phone: 813-745-6807 Fax: 813-745-7265 Email: [email protected] Michael Kuehl, MD National Cancer Institute Genetics Branch, Building 8, Room 5101 National Naval Medical Center Bethesda, MD 20889-5105 Phone: 301-496-0901 Fax: 301-496-0047 Email: [email protected] Noopur Raje, MD Massachusetts General Hospital Professional Office Building 55 Fruit Street Boston, MA 02114 Phone: 617-724-3853 Fax: 617-724-3166 Email: [email protected] John D. Shaughnessy, Jr, PhD University of Arkansas for Medical Sciences 4301 West Markham Street, #776 Little Rock, AR 72205 Phone: 501-686-8250, option 1 Fax: 501-686-6442 Email: [email protected]

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Participant List Participants

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Peter Sportelli Keryx Biopharmaceuticals, Inc. 750 Lexington Avenue, 20th Floor New York, NY 10022 Phone: 201-213-9999 Fax: 212-531-5961 Email: [email protected] Attaya Suvannasankha, MD Indiana University School of Medicine 1044 West Walnut Street Indianapolis, IN 46202 Phone: 317-278-9306 Fax: 317-278-2262 Email: [email protected]

Brian G. Van Ness, PhD University of Minnesota 321 Church Street 6-175 Jackson Hall Minneapolis, MN 55455 Phone: 612-624-9944 Fax: 612-626-6140 Email: [email protected]

Multiple Myeloma Research Foundation

Carole Asher, MPA Multiple Myeloma Research Foundation 383 Main Avenue, 5th Floor Norwalk, CT 06851 Phone: 203-652-0221 Fax: 203-972-1259 Email: [email protected] Joan B. Levy, PhD Multiple Myeloma Research Foundation 383 Main Avenue, 5th Floor Norwalk, CT 06851 Phone: 203-652-0233 Fax: 203-972-1259 Email: [email protected]

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Louise M. Perkins, PhD Multiple Myeloma Research Foundation 383 Main Avenue, 5th Floor Norwalk, CT 06851 Phone: 203-652-0208 Fax: 203-972-1259 Email: [email protected]

CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Biographies Keynote Speakers

Bart Barlogie, MD, PhD University of Arkansas for Medical Sciences Dr. Barlogie earned his MD from Heidelberg University, Staatsexamen, and completed his PhD at the Max Planck Institute for Medical Research. He completed training in internal medicine at the University of Munich, a residency in internal medicine at the University of Muenster Medical School, and a clinical fellowship in oncology at MD Anderson Cancer Center in Houston, TX. Dr. Barlogie is currently a Professor of Medicine and Pathology at the University of Arkansas for Medical Sciences and the Director of the Myeloma Institute for Research and Therapy. He is a member of the International Myeloma Foundation Board of Directors and a Scientific Advisory Board Member for the Multiple Myeloma Research Foundation (MMRF). His numerous awards include the 2002 Celgene Career Achievement Award in Hematology Research, the 2003 Francesca M. Thompson Outstanding Service Award from the International Myeloma Foundation, the 2004 Robert A. Kyle Lifetime Achievement Award, and the 2006 Castle Connolly Medical Ltd. National Physician of the Year Award. Dr. Barlogie has coauthored more than 400 publications in peer-reviewed journals and has been an invited speaker at numerous national and international meetings. He is also on the editorial board for numerous peer-reviewed publications including Annals of Hematology, Blood, Clinical Lymphoma and Myeloma, and International Journal of Oncology. His research focuses on tumor growth control in multiple myeloma.

Max S. Wicha, MD University of Michigan Comprehensive Cancer Center Dr. Wicha received his MD from Stanford University School of Medicine and completed his residency in internal medicine at the University of Chicago. He completed a fellowship in oncology at the National Institutes of Health. Dr. Wicha was the Founding Director of the University of Michigan Comprehensive Cancer Center, where he is also a Distinguished Professor of Oncology. Dr. Wicha has received several awards. He was honored by the American Cancer Society in 1999, and has been a fellow of the American Association for the Advancement of Science since 2000. Dr. Wicha has coauthored more than 100 publications in peer-reviewed journals and has spoken at many national and international meetings. His research is focused on breast cancer and he has done a substantial amount of work studying breast cancer stem cells.

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Biographies Co-Chairs

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William Matsui, MD The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Dr. Matsui received his MD from the University of California School of Medicine in San Francisco. He completed his residency in internal medicine at the University of Washington School of Medicine in Seattle, and completed a clinical fellowship in oncology at The John Hopkins University School of Medicine. Dr. Matsui is currently an Assistant Professor of Oncology at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. His research is currently funded by the National Cancer Institute, the National Institutes of Health, the International Myeloma Foundation, The Sidney Kimmel Cancer Center Foundation, and the US Department of Defense. Dr. Matsui is the recipient of multiple awards including a 2004 Career Development Award from the American Society of Clinical Oncology, the 2001 George Santos Research Award from The Leukemia & Lymphoma Society, and a 2001 Young Investigator Award from the American Society of Clinical Oncology. Dr. Matsui has coauthored several publications in peer-reviewed journals and serves as a reviewer for many scientific journals. His research interests include understanding B-cell malignancies, multiple myeloma, leukemia, lymphoma, and bone marrow transplantation.

Andrzej J. Jakubowiak, MD, PhD University of Michigan Comprehensive Cancer Center Dr. Jakubowiak completed his MD and PhD at the Medical Academy of Poznan, Poland. He completed an internship and a residency in internal medicine at the University of Texas Medical School in Houston, TX. Dr. Jakubowiak completed a fellowship in hematology and oncology at the Memorial Sloan-Kettering Cancer Center in New York, NY. He is currently Director of the Multiple Myeloma Program and an Associate Professor in the Department of Internal Medicine at the University of Michigan Comprehensive Cancer Center in Ann Arbor, MI. Dr. Jakubowiak is a member of the American Society of Hematology, the American Society of Clinical Oncology, the Protocol Review Committee at the Multiple Myeloma Research Consortium, and the Myeloma Committee at the Southwest Oncology Group. He has published several peer-reviewed publications and been an invited speaker at multiple national and international cancer meetings. His research is focused on multiple myeloma.

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Biographies

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Session Chairs

Joshua Epstein, DSc University of Arkansas for Medical Sciences Dr. Epstein received his DSc from the Technion in Israel. He completed a research fellowship in pediatrics at Harvard University School of Medicine. Dr. Epstein is currently a Professor in the Department of Medicine at the University of Arkansas for Medical Sciences (UAMS) and the Director of Laboratory Affairs for the Myeloma Institute for Research and Therapy at UAMS. His research is currently funded by a P01 grant from the National Cancer Institute and an R01 grant from the National Institutes of Health. He is a member of many scientific organizations including the New York Academy of Science, the American Association for the Advancement of Science, the American Association for Cancer Research, and the American Society of Hematology. Dr. Epstein has coauthored more than 80 articles in peer-reviewed journals. His research focuses on understanding the relationship between changes in the bone marrow microenvironment and the development of myeloma.

G. David Roodman, MD, PhD University of Pittsburgh Medical Center Dr. Roodman is Director of the Bone Biology Center at the University of Pittsburgh Medical Center Health System in Pittsburgh, PA, in addition to Director of the Myeloma Program at the University of Pittsburgh Cancer Institute and Professor of Medicine and Vice Chair for Research in the Department of Medicine at the University of Pittsburgh School of Medicine. After receiving his medical degree from the University of Kentucky College of Medicine and his PhD from University of Kentucky, Department of Biochemistry, Dr. Roodman completed an internship in medicine at the University of Kentucky and a residency in medicine and a fellowship in hematology at the University of Minnesota. Dr. Roodman is a member of several professional societies, including the American Society of Hematology, the International Bone and Mineral Society, and The Endocrine Society. He is also on the Advocacy Committee for the American Society for Bone and Mineral Research, a member of the Scientific Advisory Board of the International Myeloma Foundation, and a member of the National Institutes of Health SRA Study Section. Additionally, he is an Associate Editor for the Journal of Bone and Mineral Research and on the editorial boards of many journals, such as Endocrinology and the Journal of Clinical Investigation. He has published more than 180 journal articles, 85 book chapters and reviews, and 210 abstracts based on his research. Currently, Dr. Roodman holds two US patents, and is funded by a Department of Veterans Affairs Merit Review Grant, two investigator initiated National Institutes of Health (NIH) grants, and heads a Program Project Grant on the "Pathobiology of Paget's Disease." This program project attempts to answer several important questions about the role measles virus plays in the pathophysiology of Paget's disease and the important role the genetic component plays in the pathologic process.

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Biographies Faculty

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Ivan Borrello, MD The Johns Hopkins University Dr. Borrello completed his MD at the Medical College of Virginia. He then completed his internship and residency in internal medicine at the University of Chicago. Dr. Borrello completed a fellowship in medical oncology at The Johns Hopkins Oncology Center. He is currently an Assistant Professor of Oncology at The Johns Hopkins University School of Medicine. Dr. Borrello's research is currently funded through grants from Infinity Pharmaceuticals, Inc., the National Institutes of Health, The Leukemia & Lymphoma Society, and Celgene Corporation. He has received many awards for his research including the 2004 Kimmel Scholar Award, the 2005 Director's Teaching Award in Clinical Science, and the 2007 Clinical Translational Scholar Award from The Leukemia & Lymphoma Society. He is currently an Associate Editor for Cancer Research and the Journal of Clinical Oncology. Dr. Borrello has authored numerous peer-reviewed articles and has also been an invited speaker at multiple national and international meetings including the European Conference on Gene Therapy of Cancer, the International Workshop on Multiple Myeloma, and the American Society of Clinical Oncology. His research interests include immunotherapy in multiple myeloma with a specific interest in the role of the bone marrow in immune function.

Marta Chesi, PhD Mayo Clinic ­ Scottsdale Dr. Chesi received her PhD from the University of Milan. She completed postgraduate training at the Department of Biological and Technological Research (DIBIT) at San Raffaele Hospital in Milan, Italy, and at the National Cancer Institute in Bethesda, MD. After working 6 years at Cornell Medical College, Dr. Chesi moved to the Mayo Clinic as an Assistant Professor of Biochemistry and Molecular Biology. Her research is currently funded by a Specialized Program of Research Excellence (SPORE) in Multiple Myeloma grant from the National Cancer Institute, an R01 from the National Institutes of Health, and a grant from the Multiple Myeloma Research Foundation (MMRF). She has received awards for her research including a 2002 and a 2005 Senior Investigator Award from the MMRF. Dr. Chesi has coauthored many publications in peer-reviewed journals and has spoken at several national and international meetings. Her research focuses on understanding the molecular pathogenesis of multiple myeloma, and, through a fruitful collaboration with Dr. Bergsagel and Dr. Kuehl, has first identified and cloned most of the recurrent chromosome translocation breakpoints in myeloma, leading to the identification of new therapeutic targets. More recently, she has characterized frequent activating mutations of the NF B pathway and has developed a faithful transgenic mouse model of myeloma that has lead to the reevaluation of the role of MYC in myeloma pathogenesis.

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Biographies Faculty

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Madhav Dhodapkar, MD The Rockefeller University Dr. Dhodapkar received his MD from the All India Institute of Medical Sciences in New Delhi, and completed his residency in internal medicine at the St. Louis University Hospital in Missouri. He completed a fellowship in hematology and medical oncology at the Mayo Clinic in Rochester, MN. Dr. Dhodapkar is currently the Leon Hess Associate Professor at The Rockefeller University in New York City. Dr. Dhodapkar has received numerous awards for his research accomplishments including the 2002 Irma T. Hirschl Career Scientist Award and the 2002 Damon Runyon/Eli Lilly Translational Research Award. He also received the 1999 Cancer Research Institute Investigator Award and the Irene Diamond Professorship in Immunology in 2002. Dr. Dhodapkar has coauthored several publications in peer-reviewed journals. His research focuses on the interactions between tumor cells and the immune system in multiple myeloma patients, particularly the differences between immune responses in patients with myeloma and in patients with monoclonal gammopathy of undetermined significance (MGUS).

Craig T. Jordan, PhD James P. Wilmot Cancer Center University of Rochester Medical Center Dr. Jordan completed his PhD at Princeton University. He completed postdoctoral training at the Whitehead Institute at Massachusetts Institute of Technology and in the Department of Molecular Genetics at Genentech, Inc. Dr. Jordan is currently an Associate Professor of Medicine at the University of Rochester Medical Center and Director of the Hematologic Malignancies Translational Research Program at the James P. Wilmot Cancer Center. Dr. Jordan has been the recipient of several awards including a scholar award from The Leukemia & Lymphoma Society. He is a member of many professional organizations including the American Society of Hematology, the International Society of Experimental Hematology, the American Association for the Advancement of Science, and the American Association for Cancer Research. Dr. Jordan has published several articles in peer-reviewed journals and has served as a reviewer for several journals including Leukemia. His research is focused on understanding the molecular mechanisms that control the growth and development of stem cells.

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Biographies Faculty

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Carla Kim, PhD Children's Hospital Boston Dr. Kim received her PhD in genetics from the University of Wisconsin-Madison and completed postdoctoral training at the Massachusetts Institute of Technology. She currently serves as an Assistant Professor in the Stem Cell Program at Children's Hospital in Boston and the Genetics Department at Harvard Medical School. She is a member of the Harvard Stem Cell Institute and the Dana-Farber Harvard Cancer Center. Dr. Kim is a member of the International Society for Stem Cell Research and the American Society for Cell Biology. Her research is currently funded through grants from the National Institutes of Health, the American Cancer Society, and the V Foundation for Cancer Research. Dr. Kim has coauthored several publications in peer-reviewed journals. Her research focuses on the characterization of non-small cell lung cancer stem cells and normal lung stem cells.

Linda M. Pilarski, PhD University of Alberta and Cross Cancer Institute Dr. Pilarski completed her PhD in biochemistry and her postdoctoral training at the Australian National University in Canberra. She is currently a Professor in the Department of Oncology and Tier I Canada Research Chair in Biomedical Nanotechnology. She is a Senior Scientist of the Alberta Cancer Board and leads a team developing novel technology for genetic analysis of cancer, an initiative that links four institutions and two provinces in Western Canada. She also leads the Alberta Cancer Diagnostics Consortium, an initiative to develop microfluidics prototypes for analysis of cancer. Dr. Pilarski served as an Associate Editor of the Journal of Immunology from 1995 to 2000, and as Vice-President and then President of the Canadian Society of Immunology from 1993 to 1997. She is also a member of the scientific advisory board of the International Myeloma Foundation. Dr. Pilarski has received numerous awards including the 1998 YWCA Woman of Distinction for Science and Technology, the McCalla and Killam Professorships at the University of Alberta, and the 2002 Cinader Award for research excellence and contributions to immunology from the Canadian Society for Immunology. She has published more than 180 papers. Her research focuses on multiple myeloma and she is actively researching the nature of the myeloma stem cell. She is also developing novel technology focused on better diagnosis and monitoring tools for the clinic.

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Biographies Faculty

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David T. Scadden, MD Massachusetts General Hospital, Harvard Stem Cell Institute Dr. Scadden received his MD from Case Western Reserve School of Medicine and received an honorary AM from Harvard Medical School in 2004. He completed his internship and residency at Brigham and Women's Hospital in Boston, MA. In addition, Dr. Scadden completed fellowships in hematology and medical oncology at the Brigham and Women's Hospital and the Dana-Farber Cancer Institute, Harvard Medical School. Dr. Scadden is currently a Professor of Medicine at Harvard Medical School and holds the Gerald and Darlene Jordan Chair of Medicine at Harvard University. He also serves as the Cochair of the Department of Stem Cell and Regenerative Biology at Harvard University, the Codirector and Cofounder of the Harvard Stem Cell Institute, Director of the Center for Regenerative Medicine, and Director of the Hematologic Malignancies Program at Massachusetts General Hospital. Dr. Scadden has been the recipient of many awards. Most recently in 2007, he became a member of the National Heart, Lung, and Blood Institute Board of External Experts at the National Institutes of Health (NIH) and a member of the Institute of Medicine of the National Academy of Sciences. His research is currently funded through several grants from the NIH. Dr. Scadden has coauthored more than 100 publications in peer-reviewed journals and has been an invited speaker at numerous national and international meetings. His research is focused on hematopoietic stem cell biology.

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Biographies Participants

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P. Leif Bergsagel, MD, FRCP(C) Mayo Clinic Dr. Bergsagel received an undergraduate degree in mathematics, and a graduate degree in medicine from the University of Toronto. He completed a residency in internal medicine at the University of Toronto. He completed a fellowship in medical oncology at the National Cancer Institute in Bethesda, MD. After working for 9 years at Cornell University, he moved to the Mayo Clinic where he is currently an Associate Professor of Medicine. He is also a Scientific Advisory Board Member for the Multiple Myeloma Research Foundation (MMRF). His research is currently funded by a Specialized Program of Research Excellence (SPORE) in Multiple Myeloma grant from the National Cancer Institute and an R01 from the National Institutes of Health. His numerous awards include the 2007 Senior Investigator Award from the MMRF and the 1998 Translational Research Award from The Leukemia & Lymphoma Society. Dr. Bergsagel has coauthored many publications in peer-reviewed journals and has spoken at numerous national and international meetings. His research is focused on understanding the molecular pathogenesis of multiple myeloma. His seminal contributions to myeloma research include: identifying recurrent immunoglobulin gene translocations; identifying and cloning the t(11;14), t(4;14), t(14;16), t(6;14), and t(14;20) translocation breakpoints; identifying recurrent MYC translocations and p18 inactivations; developing a comprehensive molecular classification of myeloma; identifying cyclin D dysregulation as a universal event in the pathogenesis of myeloma; identifying promiscuous mutations that activate the NF B pathway; and developing a faithful mouse model of myeloma.

Laurence Elias, MD Geron Corporation Dr. Elias received his MD from Stanford University, where he also pursued his postgraduate specialty training in internal medicine and hematology. After completing his training, he worked his way through the academic ranks and became a Professor and Chief of Hematology and Medical Oncology at the University of New Mexico Cancer Center. Dr. Elias also served as Medical Director at Chiron Corporation, where he worked on several oncology products including aldesleukin. He is currently the Executive Director for Oncology Clinical Development at Geron Corporation. Dr. Elias is a member of several professional organizations including the American Society of Hematology, the American Society of Clinical Oncology, and the American Association for Cancer Research.

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Biographies Participants

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Joseph R. Garlich, PhD Semafore Pharmaceuticals Inc. Dr. Garlich has over 20 years of experience as a scientist, successful inventor, and Director of Drug Discovery and Development. He cofounded Semafore Pharmaceuticals (formerly known as ComChem Technologies) in 2000 and has since directed all of the company's scientific research activities, including scientific strategy, drug discovery, and preclinical drug development efforts. Dr. Garlich has served as the principal investigator for 6 peer-reviewed grants awarded to Semafore totaling over $4.5 million. Dr. Garlich also served as President of the company until 2007. Previously, Dr. Garlich worked for 5 years developing and leading the combinatorial chemistry capabilities at Dow-Elanco, a joint venture between Dow and Lilly. Before that, he spent 11 years in the pharmaceutical division of Dow Chemical, where he invented and developed multiple drug candidates including Skeletal Targeted Radiation (STR) for treating multiple myeloma, which was subsequently licensed to NeoRx Corporation and tested in phase III studies; and the bone cancer drug Quadramet ®, approved by the US Food and Drug Administration (FDA) for hematologic and other bone-related disorders. Dr. Garlich is an inventor on 23 US patents and author of numerous publications and presentations. In addition to multiple industry memberships and organizational affiliations, he has been a reviewer of grants for the National Cancer Institute's Small Business Innovation Research (SBIR) program on multiple occasions, and is an Adjunct Professor at Purdue University School of Pharmacy. Dr. Garlich received his PhD in organic chemistry at the University of Missouri and was a postdoctoral fellow in the Department of Medicinal Chemistry at the University of Florida School of Pharmacy.

David S. Grayzel, MD Infinity Pharmaceuticals, Inc. Dr. Grayzel is Vice President, Clinical Development and Medical Affairs at Infinity Pharmaceuticals, Inc., in Cambridge, MA. Dr. Grayzel joined Infinity from Dyax Corp., a biopharmaceutical company focused on antibody and protein therapeutics. At Dyax, he was Director of Corporate Development and Business Operations, responsible for marketing and commercialization strategy for therapeutic products in the development pipeline, including late-stage clinical trials as well as business initiatives for in-licensing of targets, out-licensing of late-stage compounds, and codevelopment partnerships. Dr. Grayzel obtained his medical degree at Harvard Medical School where, working in the Department of Genetics investigating familial inheritance of cardiovascular disease, he assisted in identifying the gene causing Holt-Oram Syndrome. He completed his internship and residency training in internal medicine at Massachusetts General Hospital. Prior to his medical training, Dr. Grayzel was a Curriculum Director at Stanford University Medical Center, creating their first case-based medical ethics curriculum. He holds a BA with honors from Stanford University.

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Biographies Participants

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Lori Hazlehurst, PhD H. Lee Moffitt Cancer Center & Research Institute Dr. Hazlehurst received her PhD from the University of Vermont. She completed postdoctoral fellowships at the University of Arizona and the University of South Florida. Dr. Hazlehurst is currently an Assistant Professor at the H. Lee Moffitt Cancer Center & Research Institute. Dr. Hazlehurst is a member of the Institutional Review Board for the University of South Florida and a member of the university's Cancer Biology Graduate Admissions Committee. She is a member of the American Association for Cancer Research and a grant reviewer for the Italian Association for Cancer Research. Her research is currently funded by a grant from the Leukemia Research Foundation, one R01 grant which she is the PI and one R01 grant where she is the Co-PI from the National Institutes of Health, a grant from Merck Inc., and a grant from Genzyme Corporation. Dr. Hazlehurst has coauthored several publications in peer-reviewed journals. Her research focuses on studying de novo drug resistance associated with anthracyclines and anthracenediones.

Michael Kuehl, MD National Cancer Institute Dr. Kuehl completed his MD at Harvard Medical School. He then became a research fellow at the Albert Einstein College of Medicine. Dr. Kuehl has been a researcher at the National Cancer Institute (NCI) in Bethesda, MD, since 1982. He is currently the Chief of the Molecular Pathogenesis of Myeloma Section of the Genetics Branch and Deputy Chief of the Genetics Branch of the Center for Cancer Research at the NCI. Dr. Kuehl has published several peer-reviewed articles and his research is focused on studying the genetic changes that occur during the pathogenesis of premalignant multiple gammopathy of undetermined significance (MGUS) and multiple myeloma.

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

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Noopur Raje, MD Massachusetts General Hospital Dr. Raje received her MD from BJ Medical College at Pune University in India. She completed a residency in internal medicine at Massachusetts General Hospital followed by a fellowship in hematology and oncology at Dana-Farber Cancer Institute in Boston, MA. Dr. Raje is currently the Director of the Center for Multiple Myeloma at Massachusetts General Hospital and an Assistant Professor of Medicine at Harvard Medical School. Dr. Raje has been the recipient of numerous awards including two senior research awards from the Multiple Myeloma Research Foundation and a career development award from the American Society of Clinical Oncology (ASCO). She is a member of many professional organizations including the American Society of Hematology, ASCO, and the British Society for Haematology. Dr. Raje has authored more than 70 articles published in several peer-reviewed publications and has spoken at numerous scientific meetings. Her research is focused on understanding the biology of myeloma, especially developing novel treatment strategies to target the tumor cell and its microenvironment.

John D. Shaughnessy, Jr, PhD University of Arkansas for Medical Sciences Dr. Shaughnessy completed his PhD in molecular biology at the University of Maryland. He then completed a postdoctoral fellowship at the National Cancer Institute (NCI) in Bethesda, MD. Dr. Shaughnessy is currently the Chief of the Division of Basic Sciences and the Director of the Lambert Laboratory of Myeloma Genetics at the Myeloma Institute for Research and Therapy at the University of Arkansas for Medical Sciences (UAMS) and a Professor of Medicine at UAMS. Dr. Shaughnessy's research is funded by the Steve and Nancy Grand Fund and two P0I grants from the NCI. He serves on the scientific advisory boards for Novartis and Millennium Pharmaceuticals, Inc. He is a member of many professional organizations including the American Society of Hematology, the American Association for the Advancement of Science, and the American Society of Clinical Oncology. Dr. Shaughnessy has published more than 100 articles in several peer-reviewed publications including the International Journal of Cancer, Oncogene, Nature Genetics, Cell, and Blood. Dr. Shaughnessy has been an invited speaker at numerous national and international meetings. His research is focused on the genetics and cell biology of hematopoietic cell development.

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Biographies Participants

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Peter Sportelli Keryx Biopharmaceuticals, Inc. Mr. Sportelli is the Director of Oncology and Development for Keryx Biopharmaceuticals, Inc., a }mid-sized biotechnology company focused on cancer and diabetes. He has more than 16 years of experience in various roles and responsibilities in the pharmaceutical/biotechnology industry, with a focused interest on multiple myeloma (MM) over the past 8 years. Mr. Sportelli is currently responsible for the development of Keryx's oncology pipeline including their oral Akt inhibitor, perifosine, which is currently being tested in multiple phase I and II clinical trials for patients with relapsed/refractory MM. He has worked extensively with US and international MM investigators, as well as with members of the Multiple Myeloma Research Foundation and the Multiple Myeloma Research Consortium on the preclinical and clinical development of perifosine, particularly in combination with other novel agents including bortezomib and lenalidomide. He is also working with investigators exploring the preclinical activity of Keryx's second oncology compound UCN-01 in myeloma cell lines. UCN-01 is a novel kinase inhibitor targeting primarily Chk1 and PDK1. Prior to joining Keryx in 2004, Mr. Sportelli led the commercial team for Millennium Pharmaceuticals, Inc., and was instrumental in the successful launch and ongoing development of Velcade® for use in MM. Mr. Sportelli is a graduate of the University of Delaware.

Attaya Suvannasankha, MD Indiana University School of Medicine Dr. Suvannasankha completed her MD at the Chulalongkorn University in Bangkok, Thailand. She then completed an internship at the Prince of Songkhla University and a residency in internal medicine at Albert Einstein Medical Center in Philadelphia, PA. Dr. Suvannasankha completed a medical oncology/hematology fellowship at the Roswell Park Cancer Institute of the State University of New York at Buffalo. She is currently an Assistant Professor in Clinical Medicine in the Hematology/Oncology Division in the Department of Medicine at The Indiana University School of Medicine. Dr. Suvannasankha's research is currently funded by the Multiple Myeloma Research Foundation (MMRF). She is a member of the American Society of Hematology, the American Society of Clinical Oncology, and the Thai Medical Council. Dr. Suvannasankha has published several peer-reviewed publications and presented at multiple cancer meetings. Her research interests include hematologic malignancies and multiple myeloma.

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Biographies Participants

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Brian G. Van Ness, PhD Institute of Human Genetics, University of Minnesota Dr. Van Ness completed his PhD in Biochemistry at the University of Minnesota. He then completed his postdoctoral fellowship at the Fox Chase Cancer Center in Philadelphia, PA. Dr. Van Ness is currently a Professor and Head of the Department of Genetics, Cell Biology & Development, and is the Director of the Division of Medical Genomics in the Institute for Human Genetics at the University of Minnesota. Dr. Van Ness has received several awards including the Damon Runyon-Walter Winchell Cancer Fund Fellowship, the Searle Scholar Award, and the 2006 International Myeloma Foundation Honoree, co-director Bank On A Cure. He is also a member of several professional societies including the American Society of Hematology, the Eastern Cooperative Oncology Group, and the American Association for the Advancement of Science. Dr. Van Ness has coauthored more than 100 publications in peer-reviewed journals and has given presentations at numerous national and international meetings. His research focuses on defining genetic deregulation contributing to lymphoid malignancies including multiple myeloma.

Multiple Myeloma Research Foundation

Carole Asher, MPA Multiple Myeloma Research Foundation Carole Asher is the Grants Coordinator at the Multiple Myeloma Research Foundation (MMRF), where she is responsible for managing research operations, including the disbursement of funding. Carole has more than 15 years of experience in policy and public health administration, including both writing and managing grants for federal, state, and municipal agencies, as well as corporate and private foundations. Prior to joining the MMRF, she served as Grants Manager for the Yale-Griffin Prevention Research Center. In New York, Carole was the Departmental Administrator of Sociomedical Sciences at Columbia University Medical Center where she oversaw a portfolio of 90 funded programs. She was the Grants Manager at Brooklyn Hospital, where she developed policies and procedures to increase the volume and scope of grant funding by streamlining the application process and providing technical assistance to investigators. Carole has served on the Centers for Disease Control's Breast Cancer Consumer and Advocacy Council and coauthored the Standard of Care Manual for the Avon Breast Care Foundation. She holds a bachelor's degree in political science and a master's degree in public administration with a concentration in health policy and management from New York University.

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

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Multiple Myeloma Research Foundation

Joan B. Levy, PhD Multiple Myeloma Research Foundation

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Joan B. Levy, PhD, is the Associate Director of Research at the MMRF, where she is responsible for the planning and implementation of its research agenda. Dr. Levy has more than 20 years of experience in oncology and osteoporosis research in both pharmaceutical and academic settings. Before joining the MMRF, Joan was Technical Director at The Binding Site, supporting use of Freelite, a diagnostic assay for multiple myeloma. In addition, she worked at Bayer Pharmaceuticals Corporation in West Haven, CT, for nine years. In that capacity, she was engaged in target identification, compound validation, and project leadership in the fields of cancer and osteoporosis research. She has contributed to the delivery of novel drug candidates for clinical studies in each of these indications. Joan earned her PhD at The University of Vermont and then completed two postdoctoral fellowships at The Rockefeller University and later at the State University of New York at Stony Brook. Her two academic appointments were at the New York University Medical Center and Yale University, studying various aspects of cell signaling pathways involved in the pathogenesis of cancer and development of osteoporosis.

Louise M. Perkins, PhD Multiple Myeloma Research Foundation Louise M. Perkins, PhD, is the Director of Research at the MMRF where she is responsible for the strategic development and execution of the MMRF's research agenda. Dr. Perkins brings more than 16 years of pharmaceutical research experience from two major companies to the MMRF. Prior to joining the MMRF, she was the Director of Cancer Research at Bayer Pharmaceuticals in West Haven, CT, where she contributed to advancing novel targeted therapies toward clinical study, including Nexavar® and other innovative signal transduction inhibitors. While at Bayer, she also served as the Director of Research Licensing and was responsible for oncology licensing activities in support of cancer research programs. Prior to joining Bayer, she led a cancer research group at the Schering­Plough Research Institute in Kenilworth, NJ. In this role, she participated in several early-stage research programs including novel target-finding research using human genomics data. Dr. Perkins graduated from the University of Michigan with a PhD and MS in biological chemistry and conducted postdoctoral studies at Princeton University in the Department of Molecular Biology. She earned her BS in zoology from the University of North Carolina at Chapel Hill.

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Abstracts Stem Cell Interaction With the Microenvironment

Bone Cells and the Stem Cell Niche

G. David Roodman, MD, PhD University of Pittsburgh Medical Center Hematopoietic stem cells are thought to reside in discrete niches within the bone marrow. These niches maintain stem cell quiescence; protect stem cells from apoptosis and depletion of stem cell reserves, and inhibit differentiation. Electron microscopic studies have demonstrated that the bone marrow has a hierarchical structure in which pluripotent stem cells are close to the endosteal surface while more differentiated progenitors are more centrally located. Osteoblasts play a critical role in the stem cell niche by supporting the expansion and survival of pluripotent stem cells through adhesive interactions between osteoblasts and stem cells and production of signals that regulate stem cell growth. These adhesive interactions involve cadherins and integrins that bind hematopoietic stem cells to osteoblasts. In addition, interactions between cytokines and chemokines produced by osteoblasts and their respective receptors on hematopoietic stem cells are also required to maintain stem cells. A crucial chemokine in this process is chemokine stromal cell-derived factor-1 (SDF-1), which is produced by osteoblasts and increased by treatment with parathyroid hormone (PTH). SDF-1 attracts hematopoietic stem cells to the niche. SDF-1 also attracts osteoclast precursors to the niche and increases osteoclast formation in combination with Rank ligand. Osteoclasts in turn secrete metalloproteinase 9 (MMP-9) and cathepsin K into the niche to degrade SDF-1 and thereby mobilize stem cells into the circulation. Increasing osteoclast activity results in increased mobilization of stem cells. In addition to SDF-1, annexin II is another important protein involved in stem cell homing. Annexin II is a calcium-binding protein, which is produced by both osteoblasts and osteoclasts. Annexin II binds a specific annexin II receptor present on hematopoietic stem cells and marrow stromal cells, to enhance homing. Mice lacking annexin II have increased stem cell mobilization and decreased stem cell homing. Further, blocking annexin II with either an antibody or a blocking peptide decreases stem cell engraftment in lethally irradiated mice. Further, we have reported that osteoclasts produce annexin II that induces production of granulocyte monocyte colony-stimulating factor (GM-CSF) and Rank ligand to increase osteoclast formation. This increase in osteoclast formation and release of annexin II should enhance stem cell mobilization. Myeloma stem cells likely home to the bone marrow using similar mechanisms as hematopoietic stem cells. Ghobrial and coworkers have shown that SDF-1 plays an important role in myeloma cell homing to the marrow, and blocking its receptor, CXCR4, prevents myeloma cell homing to its receptor marrow. Whether myeloma cells usurp the hematopoietic stem cell niche or use other sites is unclear. More likely, myeloma stem cells use the same niches as hematopoietic stem cells to inhibit both osteoblast and hematopoietic stem cell activity and induce lytic bone disease and suppress hematopoiesis.

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Abstracts

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Stem Cell Interactions With the Microenvironment

Mechanisms Regulating Stem Cell Localization

David T. Scadden, MD Massachusetts General Hospital, Harvard Stem Cell Institute The niche hypothesis proposes that all stem cells require interaction with a specialized, anatomically distinct local environment for their persistence and function. Stem cells in the hematopoietic system interact with the local environment in an apparently transient manner with clear evidence for movement into and out of a number of environments in development and in maintenance of the adult mammal. Regulation of stem cell trafficking and engraftment in the niche is critical for the support of hematopoiesis and likely plays a role for both normal and malignant stem cell populations. We have explored mechanisms regulating stem cell localization and recently defined a previously unrecognized requirement for activation of the G s signaling pathway. Further, we have defined components within the microenvironment that regulate normal stem cells and pharmacologic agents capable of altering that regulation in a directed manner. Distinctive effects of such interventions on normal and malignant cells may provide a novel niche-targeted basis for anti-cancer therapies.

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Abstracts

(continued)

Stem Cell Interaction With the Microenvironment

Establishing a 3-Dimensional Tissue Culture Model to Examine the Effects of Novel Therapies for Multiple Myeloma

Linda M. Pilarski, PhD; Julia Kirshner, PhD; and Andrew R. Belch, MD University of Alberta and Cross Cancer Institute We have developed a unique 3-dimensional (3-D) tissue culture model that recapitulates the human bone marrow (BM) microenvironment, within which proliferation and expansion of the multiple myeloma (MM) clone occurs. Cells from the BM aspirates are grown in a fibronectin/laminin/collagen rich extracellular matrix (ECM) designed to reconstruct in vitro endosteum and central marrow. Proliferation and redistribution of cells within ECM result in stratification of cells within 3-D cultures. This mimics the individual niches seen in vivo. The MM clone undergoes expansion in 3-D cultures as measured by real-time quantitative polymerase chain reaction (rqPCR) for genomic clonotypic VDJ sequences. Malignant B cells and plasma cells (PC) proliferate in these cultures and chromosomal analysis reveals that their progeny harbor abnormalities identical to those that mark the malignant clone before culture. MM clonal expansion of 2-fold to 15-fold in 3-D has been confirmed in BM or mobilized blood from about 60 MM patients. Based on labeling of ex vivo cells with CFSE, a cytoplasmic dye that is reduced in intensity by 50% at each cell division, MM B cells and PC proliferate. However, a set of non-proliferating, label-retaining cells (LRC) in 3-D cultures concentrate at a putative endosteum-marrow junction, comparable to the in vivo localization of hematopoietic progenitor cells (HPC). This suggests that MM cancer stem cells (MM-CSC) from MM BM or mobilized blood remain in dormant stasis as they "transit" through 3-D cultures, retaining their in vivo properties and localizing to the 3-D endosteal niche. MM-CSC are released from dormancy in colony-forming unit (CFU) assays where MM-CSC form clonal colonies composed entirely of malignant cells with the clonotypic VDJ sequence; for multiple MM patients, over half of the CFU colonies from LRC were clonotypic, as quantified by patient-specific rqPCR of individual plucked colonies. MM-CSC are drug resistant, as predicted from the ultimate failures of essentially all therapeutic strategies in MM. All of the progeny in clonotypic colonies were clonotypic lymphocytes. LRC include both normal HPC and malignant MM-CSC. Only CD20+ LRC have clonogenic capabilities. The properties of CD20+ MM-CSC include quiescence, drug resistance, ability to generate clonotypic progeny, and self renewal. This is the first report that ex vivo clonotypic MM cells, particularly clonally validated MM-CSC, proliferate ex vivo, making the 3-D culture/CFU model ideally suited for analyzing the therapeutic impact of novel drugs on all compartments of the MM clone, particularly the cancer stem cell compartment of multiple myeloma.

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Abstracts

(continued)

Animal Models and Stem Cells

Defining the Myeloma Stem Cell

Joshua Epstein, DSc University of Arkansas for Medical Sciences Investigators have debated the existence of the "myeloma stem cell" for over two decades, a controversial issue stemming from the perceived lack of proliferative capacity of the recognizable myeloma plasma cell. Candidate cells that have specific phenotypes and express certain genes have been described in primary myeloma tumors and myeloma cell lines as the myeloma stem cell by their ability to grow in vitro under certain conditions or to grow and produce myeloma-like symptoms in highly specialized mice. Myeloma-like diseases were generated in mice genetically altered to express certain oncogenes as markers for the properties of the myeloma stem cells. Yet defining the myeloma stem cell as the cell that can grow in culture or that can cause myeloma in an animal leaves unanswered questions: "Do the cells that conform to these parameters constitute a defined compartment of self-renewing cells, a defining property of stem cells, or do they represent a transitory proliferative state? Is a cell's ability to grow in an environment that is totally different from its natural environment sufficient to attest to its stemness?" Following the observation that when a human bone (myeloma patient biopsy core) was present, myeloma cell lines injected IV into SCID mice homed preferentially to the human bone and not to the murine hematopoietic organs -- their site of homing when a human bone was not present -- we developed the SCID-Hu model for primary human myeloma. Initial work established, for the first time, a model that consistently supported the growth of myeloma cells isolated to a high degree of purity from fresh bone marrow aspirates. This model helped prove that, given the right microenvironment, myeloma plasma cells are capable of sustained proliferation, and that no other cells in the patient's bone marrow or blood are able to produce myeloma in this model or are required for sustained myeloma cell growth. Myeloma growth was totally restricted to and dependent on the human bone marrow microenvironment, and was associated with typical myeloma manifestations, including osteolytic bone disease. These observations underscore the importance of the microenvironment to the disease process, by heavily influencing the properties of tumor cells, including their ability to proliferate. Diligence demands the validation of all candidate stem cells under conditions as close as possible to those of the patients' microenvironment, and not simply relying on the ability of cell subpopulations to grow under certain conditions. Although fetal bones were used in the SCID-Hu model, gene expression studies reveal that the expression profile of 62 microenvironment-associated genes in fetal bones is similar to that seen in myeloma bone marrow core biopsies and vastly different from normal biopsies. These studies may also indicate that changes in the bone marrow microenvironment (at least in patterns of gene expression) precede dissemination of the disease, and likely its progression.

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Abstracts

(continued)

Animal Models and Stem Cells

Identification of a Myeloma Tumor Stem Cell in a Faithful Congenic Mouse Model

Marta Chesi, PhD, and P. Leif Bergsagel, MD, FRCP(C ) Mayo Clinic ­ Scottsdale An unresolved issue in cancer biology is whether a tumor's growth is sustained by most of its cells, or by a rare population with self-renewing capacity. Experimental evidence in favor of the existence of a rare cancer stem cell comes from xenogenic transplantation experiments in which only a minor fraction of human leukemic cells can repopulate the tumor in severely immuno-deficient NOD/SCID mice. Against this theory are congenic transplantation experiments in which as few as 1 to 100 cells of several types of leukemia and lymphoma from genetically modified mice can reconstitute the tumor in recipient mice. Although the latter experiments suggest that the inability of the bulk of human tumor cells to proliferate in a mouse may simply be due to the inability of the murine microenvironment to efficiently support human leukemic cell growth, it is still possible that for more mature and differentiated tumors, like multiple myeloma (MM), self-renewing capacity is retained only by the small fraction of the less differentiated tumor subpopulation. We believe that we are now in the unique position of exploring this possibility, by utilizing the Vk*MYC transgenic mouse model of MM. In Vk*MYC mice, sporadic activation of an MYC transgene is dependent on the somatic hypermutation process and drives the progression of benign monoclonal gammopathy (to which C57BL/6 mice are prone) to an indolent but fully malignant MM that faithfully recapitulates the biological and phenotypic features of human MM. In particular, the mice develop a slowly progressive bone marrow-confined accumulation of non-proliferative monoclonal or oligoclonal plasma cells (B220- CD138+) associated with anemia, and bone disease. Starting at about 18 months of age, about a third of the Vk*MYC mice develop an aggressive B220+/- CD138+ plasmablastic disease (clonally related to the preceding MM), with extramedullary growth including at times enlargement of lymph nodes and spleen. A preliminary congenic transplantation experiment of unfractionated or CD138+ bone marrow cells selected by immunomagnetic beads from Vk*MYC mice with indolent MM demonstrated that the monoclonal gammopathy could successfully be transferred by both fractions. Interestingly, some of the unfractionated transplant recipients died abruptly two months after transplant, without developing gammopathy. In one informative case, we could identify an abnormal B220+ CD138+ population within spleen and lymph nodes. We don't know at this time if this population is clonally related to the MM of the donor mouse. To help clarify this possibility in the future, we propose exploiting a unique feature of MM in the Vk*MYC mice. We have shown that antigen-specific MM can be induced in Vk*MYC mice by two rounds of immunization with T-dependent antigens, like NP (hydroxy-nitrophenyl). If there is a MM stem cell with a B-cell phenotype, we can identify it very specifically by cell surface expression of an Ig receptor for NP using NP-bio. Further congenic transplantation experiments using serially diluted fractionated cells from NP-immunized mice (ie, surface anti­NP Igs+ versus sIg- CD138+) will determine which fraction can reconstitute the tumor, if a fully differentiated MM cell retains self-renewing capacity or if a myeloma tumor stem cell is required for tumor growth.

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Abstracts

(continued)

Animal Models and Stem Cells

Examining the Role of Stem Cells in Normal Lung and Lung Cancer

Carla Kim, PhD Children's Hospital Boston Adult stem cells, the self-renewing cells that maintain multiple types of specialized cells within a tissue, are likely to be a target cell population in cancer and pulmonary disease. We identified the first lung stem cell population, named bronchioalveolar stem cells (BASCs). BASCs can self-renew and give rise to bronchiolar and alveolar lung cell lineages in culture, and proliferate in response to bronchiolar and alveolar damage in vivo. BASCs are critically affected by an oncogenic K-ras mutation and may be the cell-of-origin in a mouse model of lung cancer. We have recently developed an experimental system to determine whether a stem cell population exists within lung cancers and whether these cells may resemble normal BASCs. Our data suggest that BASCs and more specialized alveolar cells from tumors are equally sufficient to function as murine lung cancer stem cells. Finally, approaches taken to understand the genes that regulate BASC self-renewal will also be discussed.

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Abstracts

(continued)

Targeting the Cancer Stem Cell

Self-renewal in Multiple Myeloma

William Matsui, MD The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Aberrant regulation or acquisition of cellular self-renewal is required for the initiation and propagation of cancer. In several malignancies, the potential for self-renewal appears to be restricted to minority populations of cancer stem cells (CSC), and we have found that self-renewal within multiple myeloma is restricted to tumor stem cells that resemble mature B cells rather than plasma cells. The cellular pathways that control the self-renewal of CSC are largely unknown, but the biologic similarities between CSC and normal adult stem cells suggest that self-renewal is regulated by conserved mechanisms. We have studied whether specific cellular processes that regulate normal stem cells during development or tissue homeostasis can serve as targets within myeloma stem cells. One of these is the Hedgehog signaling pathway required for axial patterning within the developing embryo. Another is telomerase that maintains the terminal ends of linear DNA during DNA replication. We will present data examining these two processes in myeloma stem cells.

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Abstracts

(continued)

Targeting the Cancer Stem Cell

A Closer Look at Leukemia Stem Cells

Craig T. Jordan, PhD James P. Wilmot Cancer Center University of Rochester Medical Center A malignant stem cell population is thought to drive the growth and perpetuation of several forms of human leukemia. In particular, myeloid leukemias have been extensively characterized with regard to stem cell and progenitor cell involvement. Leukemia stem cells (LSCs) appear to retain many characteristics of normal hematopoietic stem cells as evidenced by a hierarchical developmental pattern, a mostly quiescent cell cycle profile, and an immunophenotype very similar to normal stem cells. Defining unique properties of LSCs is required to elucidate the molecular mechanisms driving stem cell transformation, and to develop therapeutic strategies that target the LSC population. Recent studies indicate that LSCs are selectively sensitive to specific classes of apoptotic stimuli. Agents that induce certain forms of oxidative stress, while simultaneously inhibiting LSC-specific survival mechanisms, may provide novel strategies for therapeutic intervention. In this presentation, emerging concepts in the field will be described, with a particular emphasis on molecular and cellular characteristics of leukemia cells and how such features may be exploited to preferentially ablate malignant stem cells.

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Abstracts

(continued)

Targeting the Cancer Stem Cell

Harnessing the Immune System to Target Stem Cell Genes in Myeloma

Madhav Dhodapkar, MD The Rockefeller University The immune system has long been thought of as a potential barrier to cancer, and can represent a useful approach for early detection and prevention. However, while the nature of antigens recognized by the immune system in cancer patients has been extensively studied, less is known about the targets of the immune response in preclinical stages of cancer. Monoclonal gammopathy of undetermined significance (MGUS) represents a precursor lesion to myeloma and is much more common than its malignant counterpart. Recently, we developed tools to evaluate the nature of antigenic targets in preneoplasia. Our studies suggest that the targets of spontaneous immune responses in preneoplastic MGUS may differ from those in multiple myeloma (MM). The majority of MGUS patients, but not MM patients or healthy donors, mount an immune response against SOX2, a gene critical for pluripotency in human embryonal stem cells. The detection of intranuclear SOX2 marks the putative clonogenic compartment in MGUS, and anti-SOX2 T cells effectively inhibit the growth of these tumors. The detection of these T cells predicts exceptionally good clinical outcome and prolonged survival in patients with early plasma cell tumors. These data support the hypothesis that immune targeting of critical stem cell-associated pathways may be of therapeutic benefit in myeloma.

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Abstracts

(continued)

Clinical Trials Based on Cancer Stem Cells

Targeting Myeloma Stem Cells With Anti-CD20 Antibodies

Andrzej J. Jakubowiak, MD, PhD University of Michigan Comprehensive Cancer Center A number of studies suggest that multiple myeloma, similar to other malignancies, may consist of a heterogeneous population of malignant cells. Within the population of myeloma cells, only a small subset of cells appear to have self-renewal potential. These cells, described as myeloma stem cells (MSCs), have a phenotype similar to memory B cells, including the lack of CD138 expression and the presence of CD20. In contrast, the majority of malignant myeloma cells are CD138+ and CD20-, similar to mature plasma cells. It has been proposed that current antimyeloma therapies have the potential to eliminate only the differentiated malignant plasma cells, effectively reducing the tumor burden. However, self-renewing MSCs, which are responsible for relapses after treatment, are not eliminated. These findings provide the rationale for a treatment strategy to eliminate the MSC using anti-CD20 antibodies. Preclinical studies showed that anti-CD20 antibodies inhibit in vitro clonogenic growth of malignant myeloma cells. To evaluate the clinical effects of anti-CD20 treatment, several investigators used Rituxan® (rituximab), an unlabeled anti-CD20 antibody, which, in most part, showed no clear effects. Recently, we initiated a phase II clinical trial with I-131 radiolabeled anti-CD20 antibody (Bexxar®) as a consolidation treatment for multiple myeloma. We hypothesized that Bexxar would be more efficacious than unlabeled antibody in eradication of highly radiosensitive myeloma cells by direct and crossfire effects. To be eligible for Bexxar treatment, patients must have measurable disease in plateau of at least partial response (PR) lasting at least 6 weeks. To date, 7 patients have been treated with Bexxar in this trial. We will present the details of the study design, the approach to the evaluation of the effects of Bexxar treatment, including its effect on the clonogenic myeloma cells, and preliminary results of the study.

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Abstracts

(continued)

Clinical Trials Based on Cancer Stem Cells

TBD

Franziska Michor, PhD Memorial Sloan-Kettering Cancer Center

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

Abstracts

(continued)

Clinical Trials Based on Cancer Stem Cells

Role of Activated Marrow-Infiltrating Lymphocytes on Myeloma Stem Cells

Ivan Borrello, MD The Johns Hopkins University Despite the recent advances in novel therapies targeting multiple myeloma, the disease remains incurable. The putative identification of a myeloma stem cell opens possibilities to both a better understanding of the biology of this disease as well as the development of therapeutic targets aimed at eradicating or at least suppressing stem cell outgrowth if long-term cures are to be achieved. Immunotherapy offers the benefit of imparting a non-crossreactive therapy with the added benefit of inducing long-term antitumor responses. Our laboratory has been examining the role of marrow-infiltrating lymphocytes (MILs) in myeloma. Upon activation with antiCD3/CD28 beads, MILs possess a significant antitumor effect as measured by their ability to proliferate as well as kill mature autologous CD138+ plasma cells. Furthermore, utilizing the human myeloma cell line, H929 (containing both CD138+ and CD138- populations), injected into NOD/SCID matched mice, we have been able to demonstrate that the adoptive transfer of HLA­matched activated MILs 30 days after tumor transfer was able to completely eradicate the myeloma, whereas activated peripheral blood lymphocytes (PBLs) only resulted in a slight delay in tumor outgrowth compared with the control mice. Attempting to understand the breadth of antigen recognition, we asked whether activated MILs were also capable of recognizing and possibly impairing myeloma stem cell outgrowth. In a clonogenic assay in which bone marrow from myeloma patients was depleted of CD34+ cells, CD138+ cells, and CD3+ cells and then plated on methylcellulose, we were able to demonstrate that the addition of activated MILs impaired the outgrowth of mature plasma cells more efficiently than the addition of either activated PBLs or unactivated MILs. These findings suggest broad antigenic recognition of activated MILs that also includes recognition of antigens present on myeloma stem cells. These findings also underscore the potential role of MILs in the therapeutic setting. Studies are currently underway to identify the myeloma stem cell-specific tumor antigens.

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

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CANCER STEM CELL RESEARCH STRATEGIES: APPLICATIONS TO MULTIPLE MYELOMA An MMRF Roundtable January 27­28, 2008

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