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Alitalo

Mayo School of Continuous Professional Development

5th Mayo Clinic Angiogenesis Symposium: Angiogenesis and Tumor Micro-Environment: Basic Science to Clinical Practice

August 17 - 19, 2012 17 - 19, 2012 2012 Depot Renaissance Hotel

Minneapolis, Minnesota

Course Director Debabrata Mukhopadhyay, Ph.D. Course Co-Director Neil Kay, M.D. Honorary Course Director Philip Greipp, M.D.

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TABLE OF CONTENTS

Program Schedule ..........................................................................................................................ii Course Description and Objectives..............................................................................................vii Continuing Education Credit ..................................................................................................... viii Faculty...........................................................................................................................................ix Faculty Disclosure...................................................................................................................... xiii

Educational Grants .......................................................................................................................xv Friday, August 17, 2012 9:00 a.m. Registration 10:00 a.m. Welcome and Introduction Philip Greipp, M.D. Debabrata Mukhopadhyay, Ph.D. Neil Kay, M.D. Folkman Lecture 10:15 a.m. Regulation of the Angiogenic Switch David Cheresh, Ph.D. Section II: Mayo Clinic Lectureship Awards Ceremony Chair: Debabrata Mukhopadhyay, Ph.D. 10:45 a.m. Introduction if lectureship recipients and amount of lectureships Recipients: TBA 11:15 p.m. Pre-Plenary Assessment Utilizing Audience Response Section III: Keynote Lecture Chair: Raghu Kalluri, M.D., Ph.D. 11:25a.m. Angiogenesis and Lymphangiogenesis in Cancer and Cardiovascular Diseases Kari Alitalo, M.D., Ph.D. 12:00 p.m. Lunch Section IV: Regulation of Angiogenesis Chair: Ramani Ramchandran, Ph.D. 1:00 p.m. The Role of Sox and Robo’s in Angiogenesis Ramani Ramchandran, Ph.D.

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1:20 p.m. The Ins and Outs of Angiopoietin/Tie Signalling During Angiogenesis, Vascular Homeostasis and Tissue Regeneration

Hellmut Augustin, Ph.D. 1:40 p.m. Arteriogenic Signaling Cascade Timothy Hla, Ph.D. 2:05 p.m. Molecular Mechanisms of Angiogenesis Michael Simons, M.D. 2:30 p.m. Break 2:50 p.m. Transcriptional Regulation of Vascular Endothelial Differention Saulius Sumanas, Ph.D. 3:10 p.m. Mechanisms of Endothelial cell De-differentiation and Angiogenesis

Kishore Wary, Ph.D. 3:30 p.m. Epigenetic Regulation of Angiogenesis Mukesh Verma, Ph.D. 3:50 p.m. Regulation of Angiogenesis and Metastasis by Thrombospondin-1 Jack Lawler,, Ph.D. 4:10 p.m. Board buses for Blaisdell Manor 5:00 p.m. Reception/Dinner Buffet/ Blaisdell Manor 6:45 p.m. Plenary Lecture Chair: Sudipta Seal, Ph.D. 7:00 p.m. Introducing New Nanotechnologies to Medicine Lodewyk Kock, Ph.D. Distinguished Professor: Microbial Biochemical and Food Biotechnology 7:30 p.m. Adjourn to Social Hour 9:00 p.m. Board buses to return to Depot Renaissance Saturday, August 18, 2102 7:00 a.m. Continental Breakfast and Registration Section V: Angiogenesis and Vascular Biology Chair: Sundaram Ramakrishnan, Ph.D. 8:00 a.m. Control of Vascular Tube Morphogenesis by Hematopoietic Stem Cell Cytokines George E. Davis, M.D., Ph.D. 8:25 a.m. Interactions Between Tumor Cells and Lymphatic Endothelium in Cancer

Progression Michael Detmar, M.D.

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8:50 a.m. Vascular Permeability; VEGF and the Junction Lena Claesson-Welsh, Ph.D. 9:10 a.m. Metabolic Stress, AMPK Cascades and Tumor Angiogenesis Kevin Claffey, Ph.D. 9:30 a.m. In vitro and in vivo signaling mechanisms during endothelial tube formation Jeffrey Essner, Ph.D. 9:50 a.m. Break Section VI: Tumor Microenvironment Chair: Suresh Mohla, Ph.D. 10:10 a.m. How Can Resistance to Angiogenesis Inhibitors be Overcome? Donald M. McDonald, M.D., Ph.D.

10:35 a.m. VEGF-dependent and -independent Angiogenesis Napoleone Ferrara , M.D. * *CME credit is not offered for this presentation. 11:00 a.m. Tumor Microenvironment in Multiple Myeloma: The Role of Angiogenesis Sundaram Ramakrishnan, Ph.D. Section VII: Molecular Mechanisms of Angiogenesis and Lymphangiogenesis Chair: Nancy Emenaker, Ph.D., R.D. 11:20 a.m. Cancer Stem Cells And Tumor Angiogenesis — Molecular Signaling And

Therapeutic Targeting Suyun Huang, M.D., Ph.D. 11:40 a.m. Fox Transcription Factors In Pathological Angiogenesis Tsutomu Kume, Ph.D. 12:00 p.m. microRNA and Pancreatic Cancer Angiogenesis Keping Xie, M.D., Ph.D. 12:20 p.m. Lunch Section VIII: Angiogenesis and Cell Signaling Chair: Yunling Gao, M.D., Ph.D. 1:30 p.m. Dietary Modification of Pathological Angiogenesis Nancy Emenaker, Ph.D.., R.D. 1:55 p.m. Novel Regulators of Vascular Function and Inflammation Tatiana V. Byzova, Ph.D. 2:20 p.m. Regulation of CNS Angiogenesis Calvin Kuo, M.D., Ph.D.

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2:45 p.m. Break 3:10 p.m. Mechanisms by Which Pericyte Derived Myofibroblasts Regulate Tumor Growth Vijay Shah, M.D 3:20 p.m. Mast Cell Mediated Neural Control of Angiogenesis Kalpna Gupta, Ph.D.. 3:40 p.m. Regulation of VEGFR2-mediated Vascular Permeability Suvro Chatterjee, Ph.D. Section IX: Mayo Clinic Travel Awards/Oral Presentations Chairs: Vijay Shah, M.D. and Philip Greipp, M.D. 4:20 p.m. Poster Sessions/Reception 6:00 p.m. Mayo Clinic Young Investigator Presentations 7:00 p.m. Banquet/buffet Sunday, August 19, 2012 7:00 a.m. Continental Breakfast and Registration Section XI: Angiogenesis in the Clinical Setting Chair: Laura Benjamin, Ph.D. 8:00 a.m. Angiogenesis Imaging in Neoplasia Sanjay Misra, M.D. 8:20 a.m. Novel Designs and End Points for Phase II Clinical Trials Sudhakar Akulapalli, MSc., MPhill & Ph.D. 8:40 a.m. The Reactive Oxygen Driven Tumor-Implications for Diagnosis and Treatment Jack Arbiser, M.D., Ph.D. 9:00 a.m. Anti-Angiogenic Therapy: Clinical Challenges Debabrata Mukhopadhyay, Ph.D. 9:20 a.m. The Myeloma Conundrum: Roadmap or Distraction for the Treatment of Cancer? S. Vincent Rajkumar, M.D. 9:40 a.m. Anti-angiogenic Therapy in Melanoma Svetomir Markovic, M.D., Ph.D. 10:00 a.m. Break

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10:30 a.m. Adjuvant Hepatic Arterial Infusional Chemotherapy: Revisiting The Past or A New Era?

Axel Grothey, M.D. 10:50 a.m. Leukemic B Cell Interaction With Its Microenvironment: Implications for Therapy Neil Kay, M.D. Section XII: Mayo Clinic Lectureship Chair: Philip Greipp, M.D. 11:10 a.m. Introduction 11:20 a.m. TBA Shaji Kumar, M.D. 11:50 a.m. The Role of Angiogenesis Inhibitors in Central Nervous System Tumors Jan Buckner, M.D 12:20 p.m. Closing Comments and Adjourn Debabrata Mukhopadhyay, Ph.D.

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Course Description The main goal of our symposium is to bring together basic science and clinical experts in the field of angiogenesis to facilitate the exchange of ideas and science involving basic biology and pathways of angiogenesis and new anti-angiogenic agents that can be used for specific targeting of tumor blood vessels and stroma. Moreover, the clinician scientists will present the results of ongoing clinical trials on anti-angiogenic therapy. Novel genetic and imaging methods to assess tumor vasculature for monitoring the effectiveness of angiogenic response in the pre-clinical and clinical trials will be discussed in this symposium. Overall, the symposium will assist in establishing strong collaborations among leading national, international, and Mayo Clinic experts in the field. Course Objectives Upon completion of this program, participants should be able to:

• Critically assess the role of angiogenesis in different pathological situations. • Analyze the molecular pathways in angiogenesis. • Identify the importance of angiogenesis in cancer progression and metastasis. • Evaluate angiogenesis as a potential target for future cancer therapy. • Establish the therapeutic potential of anti-angiogenic molecules and translate basic

science to clinical applications. • Build a collaborative platform where basic scientists and clinicians can interface.

Intended Audience

• Clinicians involved in cancer-related practice or research • Laboratory scientists • Translational researchers • Industry partners • Graduate or medical students • Postdoctoral fellows or residents • Others with an interest or with backgrounds in cardiovascular biology and developmental

biology, myeloma, cancer, angiogenesis and related clinical trials, lymph angiogenesis, extracellular matrix, and anti-angiogenic therapy in differential tumors.

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Continuing Education Credit College of Medicine, Mayo Clinic, is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. College of Medicine, Mayo Clinic, designates this live activity for a maximum of 18 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.Physicians should only claim credit commensurate with the extent of their participation in the activity. Other health care professionals will be provided a certificate of attendance for requesting credits in accordance with state nursing boards, specialty societies, or other professional associations. CME Record of Attendance A Record of Attendance is provided to you during on-site registration. The Record of Attendance allows course attendees to calculate their own credits of participation in the educational activity. The total number of credits participants can earn per day is noted on the Record of Attendance. Below each day is a line to record the actual number of credits during which you participated in the educational activity. It is recommended that you record your actual credits daily as you proceed through the course. Upon conclusion of the course, please total the number of credits you have recorded on the top half of the form, sign it, and return to the registration desk. The bottom half of the form represents your Record of Attendance, which you must retain for your records. Please make sure the number of credits claimed in both sections coincide. Course Evaluation A course evaluation form will be emailed to you post course. Please complete and return the evaluation electronically. Your feedback is very important to us and will be used for planning future programs. Smoking Policy In keeping with Mayo Clinic policy, smoking is not permitted in any of the meeting rooms or course facilities during Mayo-sponsored activities. Taping of Sessions Audio or visual taping by participants is not permitted.

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Electronic Devices As a courtesy to other attendees, please turn off or place in silent mode all cell phones, pagers, PDA’s, laptop computers, etc. Disclaimer The material presented in this continuing medical education program is made available by the College of Medicine, Mayo Clinic, for educational purposes only. This material is not intended to represent the only, or necessarily the best, methods or procedures appropriate for the medical situation discussed, but rather is intended to present an approach, view, statement or opinion of the authors or presenters that may be helpful or of interest to other practitioners. As an attendee, you agree to participate in this medical education program sponsored by the College of Medicine with full knowledge and awareness that you waive any claim you may have against the College of Medicine or Mayo Clinic for reliance on any information presented in this educational program. The approval of the U.S. Food and Drug Administration is required for procedures and drugs that are considered experimental. Instrumentation systems discussed and/or demonstrated in or at this program may not yet have received FDA approval. All of the proceedings of this program, including the presentation of scientific papers, are intended for limited publication only, and all property rights in the material presented, including common-law copyright, are expressly reserved by the speaker, the College of Medicine or Mayo Clinic. No statement of presentation made is to be regarded as dedicated to the public domain. Any sound reproduction, transcript or other use of the material presented at this course without the permission of the College of Medicine is prohibited to the full extent of common-law copyright in such material. Attendance at this Mayo course does not indicate nor guarantee competence or proficiency in the performance of any procedures that may be discussed or taught in this course. FACULTY Program Directors Debabrata Mukhopadhyay, Ph.D., Mayo Clinic, Department of Biochemistry & Molecular Biology

Philip R. Greipp, M.D., Mayo Clinic, Department of Hematology, Hematology Research

Program Chairperson Neil E. Kay, M.D., Mayo Clinic, Department of Hematology

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Program Planning Committee Philip R. Greipp, M.D. Mayo Clinic Department of Hematology Hematology Research Kalpna Gupta, Ph.D. Medicine – Hematology, Oncology and Transplantation Office University of Minnesota Neil E. Kay, M.D. Mayo Clinic Department of Hematology

Debabrata Mukhopadhyay, Ph.D. Mayo Clinic Department of Biochemistry & Molecular Biology Sundaram Ramakrishnan, Ph.D. Pharmacology University of Minnesota Vijay H. Shah, M.D. Mayo Clinic Department of Gastroenterology/GI Basic Research Center

Mayo Clinic Faculty Jan Buckner, M.D. Philip R. Greipp, M.D. Axel Grothey, M.D. Neil E. Kay, M.D. Shaji Kumar, M.D. Svetomir Markovic, M.D., Ph.D.

Sanjay Misra, Ph.D. Debabrata Mukhopadhyay, Ph.D. S. Vincent Rajkumar, M.D. Vijay H. Shah, M.D.

Guest Faculty Kari Alitalo, M.D., Ph.D. University of Helsinki, Finland Jack Arbiser, M.D., Ph.D. Emory University, School of Medicine Winship Cancer Institute Hellmut Augustin, Ph.D. German Cancer Research Center and Heidelberg University Tatiana V. Byzova, Ph.D. Dept. of Molecular Cardiology Cleveland Clinic Foundation

Suvro Chatterjee, Ph.D. KBC Research Center Anna University, India David Cheresh, Ph.D. Moores UCSD Cancer Center Lena Claesson-Welsh, Ph.D. Uppsala University, Sweden Kevin Claffey, Ph.D. Center for Vascular Biology UCONN Health Center

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George Davis, Ph.D. Medical Pharmacology/Physiology University of Missouri Michael Detmar, M.D. Swiss Federal Institute of Technology Zurich, Switzerland Nancy Emenaker, Ph.D., R.D. Nutritional Science Research Group Division of Cancer Prevention National Cancer Institute Jeffrey Essner, Ph.D. Department of Genetics Iowa State University Napoleone Ferrara, M.D. Genentech, Inc. Yunling Gao, M.D., Ph.D. Division of Cardiovascular Sciences NHLBI, NIH Timothy Hla, Ph.D. Weill Cornell Medical College Suyun Huang, M.D., Ph.D. The University of Texas M.D. Anderson Cancer Center Luisa Iruela-Arispe, Ph.D. Dept. of Molecular, Cell Developmental Biology UCLA Raghu Kalluri, M.D., Ph.D. Harvard Medical School Lodewyk Kock, Ph.D. University of the Free State South Africa Tsutomu Kume, Ph.D. Northwestern University

Calvin Kuo, M.D., Ph.D. Stanford University Jack Lawler, Ph.D. Beth Israel Deaconess Medical Center Harvard Medical School Donald McDonald, M.D., Ph.D. University of California San Francisco Medical Center Suresh Mohla, Ph.D. Division of Cancer Biology, NCI Ramani Ramchandran, Ph.D. Medical College of Wisconsin Sudipta Seal, Ph.D. The University of Texas M.D. Anderson Cancer Saulius Sumanas, Ph.D. Developmental Biology Cincinnati Children’s Hospital

Medical Center Michael Simons, M.D. Yale University Kishore Wary, Ph.D. Department of Pharmacology University of Illinois Mukesh Verma, Ph.D. Epidemiology and Genomics Research National Cancer Institute Keping Xie, M.D., Ph.D. The University of Texas M.D. Anderson Cancer Center Sudhakar Akul Yakkanti, Ph.D. University of Nebraska Medical Center

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DISCLOSURE SUMMARY TO CME PARTICIPANTS

As a provider accredited by ACCME, Mayo School of Continuing Professional Development must ensure balance, independence, objectivity and scientific rigor in its educational activities. Course Director(s), Planning Committee Members, Faculty, and all others who are in a position to control the content of this educational activity are required to disclose all relevant financial relationships with any commercial interest related to the subject matter of the educational activity. Safeguards against commercial bias have been put in place. Faculty also will disclose any off label and/or investigational use of pharmaceuticals or instruments discussed in their presentation. Disclosure of this information will be published in course materials so those participants in the activity may formulate their own judgments regarding the presentation.

Listed below are individuals with control of the content of this program who have disclosed…

Relevant financial relationship(s) with industry: Kari Alitalo, M.D., Ph.D. Circadian Technologies, Ltd. Chairman Vegenics, Ltd. Jack Arbiser, M.D., Ph.D. Naturderm Stock Shareholder Allmera Honoraria Hellmut Augustin, Ph.D. Bayer-Schering Pharma Grant/Research Support Laura Benjamin, Ph.D. Eli Lilly & Co. Full/part-time employee David Cheresh, Ph.D. Targegen, Inc., Kinagen, Inc. Consultant Targegen, Inc., Kinagen, Inc. Stock Shareholder Napoleone Ferrara, M.D. Genetech, Inc. Full/part-time employee Neil E. Kay, M.D. Celgene Consultant Celgene, Callstoga, Cephalon, Genetech, GlaxoSmithKline, Hospira, Novartis, Rigel, Trubion Grant/Research Support Shaji Kumar, M.D. Celgene, Millenium, Genzyme, Novartis Grant/Research Support Calvin Kuo, M.D., Ph.D. NIH Grant/Research Support Donald McDonald, M.D. Pfizer, Exelexis, OSI, Medimmuna Grant/Research Support Sudipta Seal, Ph.D. NSF, NIH Grant/Research Support Simons, Michael, M.D. AnGes, Inc. Consultant

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No relevant financial relationship(s) with industry:

Alex Adjei, M.D., Ph.D. Colleen Allen Jan Buckner, M.D. Tatiana V. Byzova, Ph.D. Suvro Chatterjee, Ph.D. Lena Claesson-Welsh, Ph.D. Kevin Claffey, Ph.D. George Davis, M.D., Ph.D. Michael Detmar, M.D. Nancy Emanker, Ph.D., R.D. Jeffrey Essner, Ph.D. Yunling Gao, M.D., Ph.D. Axel Grothey, M.D. Kalpna Gupta, Ph.D. Timothy Hla, Ph.D. Suyun Huang, M.D. Luisa Iruela-Arispe, Ph.D.

Raghu Kalluri, Ph.D. Lodewyk Kock, Ph.D. Christopher Kontos, M.D. Jack Lawler, Ph.D. Denise Lecy Svetomir Markovic, M.D., Ph.D. Sanjay Misra, M.D. Suresh Mohla, Ph.D. Debabrata Mukhopadhyay, Ph.D. Ramani Ramchandran, Ph.D. Sundaram Ramakrishnan, Ph.D. Saulius Sumanas Ph.D. Vijay H. Shah, M.D. Kishore Wary, Ph.D. Mukesh Verma, Ph.D. Keping Xie, Ph.D. Sudhakar Akulapalli, Ph.D

References to off-label usage(s) of pharmaceuticals or instruments in their presentation: Napoleone Ferrara, M.D. Genentech Bevacizumab Philip R. Greipp, M.D. Celgene R&T S. Vincent Rajkumar, M.D. Celgene Lenalidomide, Pomalidomide

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This course is supported in part by unrestricted educational

grants from the following companies in accordance with ACCME standards:

Lilly USA, LLC

Millennium

Sanofi-Aventis

TEVA