Understanding Autophagy to Enhance Clinical Discovery: The 2016 Dr. Paul Janssen Award Symposium
Thursday, September 22, 2016
The New York Academy of Medicine
Advances in the molecular and genetic characterization of autophagy have significantly expanded our understanding of cellular homeostasis. The pioneering discoveries of Dr. Yoshinori Ohsumi into the molecular mechanisms and physiological significance of this essential cellular function laid the foundation for understanding the synthesis and degradation of critical intracellular components. Dr. Ohsumi's groundbreaking research demonstrated that autophagy is a crucial process for cellular maintenance, repair, and energy generation under stress conditions, including starvation. Employing a diverse set of molecular and biochemical techniques, he demonstrated that ubiquitin signaling targets cellular components to the lysosome for recycling. These discoveries have great potential to improve treatments for diseases, as more recent studies have found that autophagy plays a role in development, response to bacterial and viral infections, immunity, cancer, and Alzheimer's disease. For his extensive characterization of the underlying mechanisms of autophagy and its potential clinical impact, Dr. Ohsumi will receive the 2016 Dr. Paul Janssen Award for Biomedical Research.
This symposium will honor Dr. Yoshinori Ohsumi, who will reflect on his initial work on the key players in autophagy, and share his vision for future advancements in the field. Following his award lecture, fellow prominent scientists at the forefront of autophagy research will discuss emerging concepts and technologies.
This symposium will be hosted at the New York Academy of Medicine.
Featuring
Yoshinori Ohsumi, PhD
Tokyo Institute of Technology
Registration
Symposium registration is free. Although on-site registration may be possible on the day of the event, pre-registration is highly encouraged due to space limitations.
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Agenda
* Presentation times are subject to change.
Thursday, September 22, 2016 | |
8:00 AM | Registration and Breakfast |
9:00 AM | Welcome and Introductory Remarks |
Session I: Elucidating the Underlying Cellular Processes of Autophagy | |
9:15 AM | 2016 Dr. Paul Janssen Award for Biomedical Research Announcement |
9:30 AM | Dr. Paul Janssen Award for Biomedical Research Lecture |
10:20 AM | Coffee and Networking Break |
Session II: Understanding the Molecular Landscape of Autophagy: From Basic Mechanisms to Human HealthSession Chair: Sonya Dougal, PhD, The New York Academy of Sciences | |
10:50 AM | Beclin 1: From Discovery to Development of a Potential Therapeutic Therapy Agent |
11:20 AM | Ouroboros, Autophagy, Cell Health and Cell Death |
11:50 AM | Chaperone-Mediated Autophagy in the Fight Against Aging and Age-Related Diseases |
12:20 PM | Discovery of Autophagy Inhibitors |
12:50 PM | Panel Discussion: The Future of Autophagy Research
|
1:15 PM | Luncheon |
2:15 PM | Adjourn |
Speakers
Yoshinori Ohsumi, PhD
Tokyo Institute of Technology
Eric H. Baehrecke, PhD
University of Massachusetts Medical School
Eric H. Baehrecke obtained his PhD from the University of Wisconsin–Madison, and was a Howard Hughes Medical Institute Fellow of the Life Sciences Research Foundation at the University of Utah during his postdoctoral studies. He was on the faculty of the University of Maryland from 1995–2007, and is currently a Professor in the Department of Molecular, Cell and Cancer Biology at the University of Massachusetts Medical School. His team studies the regulation and function of autophagy in cell health and cell death.
Ana Maria Cuervo, MD, PhD
Albert Einstein College of Medicine
Ana Maria Cuervo, MD, PhD is the Robert and Renee Belfer Chair for the Study of Neurodegenerative Diseases, Professor in the Departments of Developmental and Molecular Biology and of Medicine of the Albert Einstein College of Medicine and Co-Director of the Einstein Institute for Aging Studies. She obtained her MD degree and a PhD in Biochemistry and Molecular Biology from the University of Valencia (Spain) in 1990 and 1994, respectively, and received postdoctoral training at Tufts University, Boston. In 2002, she started her laboratory at the Albert Einstein College of Medicine, where she continues her studies into the role of protein-degradation in neurodegenerative diseases and aging.
Dr. Cuervo's group is interested in understanding how altered proteins can be eliminated from the cells through the lysosomal system (autophagy) and how malfunction of autophagy in aging is linked to age-related disorders such as neurodegenerative and metabolic diseases.
Dr. Cuervo is the recipient of prestigious awards such as the P. Benson Award in Cell Biology, the Keith Porter Fellow in Cell Biology, the Nathan Shock Memorial Lecture Award, the Vincent Cristofalo Rising Start in Aging Award, the Bennett J. Cohen award in basic aging biology, the Marshall Horwitz Prize for excellence in research and the Saul Korey Prize in Translational in Medicine Science. She also delivered the Robert R. Konh Memorial Lecture, the NIH Director's Lecture, the Roy Walford Endowed Lecture, the Feodor Lynen Lecture, the Margaret Pittman Lecture, the IUBMB Award Lecture, the David H. Murdoxk Lecture, the Gerry Aurbach Plenary Lecture, the SEBBM L'Oreal-UNESCO for Women in Science, and the Harvey Lecture. She is currently co-Editor-in-Chief of Aging Cell and Associate Editor of Autophagy. She has also twice received the LaDonne Schulman Teaching Award. Dr. Cuervo has served as member of the NIA Scientific Council and is currently member of the NIH Council of Councils.
Beth Levine, MD
University of Texas Southwestern Medical Center, Howard Hughes Medical Institute (HHMI)
Dr. Levine is internationally recognized as a leading authority in the field of autophagy. Dr. Levine received an AB from Brown University, an MD from Cornell University Medical College, and completed her postdoctoral training in Infectious Diseases/Viral Pathogenesis at the Johns Hopkins University School of Medicine. In 1993, she joined the faculty at Columbia University College of Physicians & Surgeons where she became Associate Professor of Medicine. In 2004, she became the Jay P. Sanford Professor and Chief of the Division of Infectious Diseases at UT Southwestern Medical Center. In 2011, she became the Director of a newly created Center for Autophagy Research at UT Southwestern and the Charles Cameron Sprague Distinguished Chair in Biomedical Science. Since 2008, she has been a Howard Hughes Medical Institute Investigator.
Dr. Levine's laboratory has made fundamental discoveries that have helped to open up a new field of biomedical research—the role of autophagy in human health and disease. Her laboratory identified the mammalian autophagy gene, beclin 1, and defined a role for beclin 1 and the autophagy pathway in tumor suppression, antiviral immunity, development, cell death regulation, lifespan regulation, and exercise-induced metabolic effects. Dr. Levine has received numerous awards for her research including the 2008 Edith and Peter O'Donnell Award in Medicine from The Academy of Medicine, Engineering and Science of Texas, election to the National Academy of Sciences in 2013, and the 2014 American Society of Clinical Investigation Stanley J. Korsmeyer award.
Matthias Versele, PhD
Janssen Research & Development
Matthias Versele is a biology team leader in the oncology discovery group in Beerse (Belgium). He currently leads drug discovery teams focusing on hematological malignancies, primarily B-cell lymphomas and multiple myeloma; he is involved in identifying new drug targets for the hematologic disease area stronghold; and he is the preclinical lead in support of the clinical development of Ibrutinib (Imbruvica). His main research interests are kinase signaling and stress response mechanisms relevant to tumor biology (unfolded protein response, autophagy).
Matthias joined Janssen in 2006, after his post-doctoral training at UC Berkeley (CA), working on the molecular mechanisms through which septin filament formation is coordinated with cell cycle progression and cell morphology. Matthias completed his PhD in biochemistry at the KU Leuven (Belgium) in 2000, studying nutrient sensing and signaling mechanisms controlling stress resistance and cell growth.
Additional speakers to be announced.
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Abstracts
Looking Back on My 28 Years of Autophagy Research
Yoshinori Ohsumi, PhD, Tokyo Institute of Technology
More than a half-century has passed since C. de Duve coined the term "autophagy" for the degradation process of cytosolic proteins and organelles in the lysosome. However, studies at a molecular level failed to yield significant advances in our understanding of this pathway. After a long gestation period, now autophagy has become major field of biology and is expanding day by day. I used to study biochemically the yeast vacuole, and found transport systems and novel proton-pump, v-type ATPase, on the membrane.
In 1988 I decided to launch into the lytic function of the yeast vacuole and soon found intensive autophagy induced by nutrient starvation under a light microscope. Soon a genetic effort to address the machinery of autophagy led to the discovery of many autophagy-defective mutants. The ATG genes identified can be classified into unique sets of proteins exclusively involved in autophagosome formation. Our primary objective was to understand the unique membrane dynamics during autophagy by structural and functional analyses of the 18 Atg proteins essential for autophagy. These Atg proteins concertedly assemble to form a dot structure, the PAS, and function to generate a unique isolation membrane. Recent progress in our understanding of the molecular mechanism of the PAS formation will be presented.
Autophagy degrades not only proteins but also various cytoplasmic constituents. Metabolites derived from degradation process may exert a large influence on metabolism, which means degradation is not simply the inverse reaction of synthesis. The late steps of autophagy must be uncovered to obtain a complete understanding of autophagy. The historical landmarks underpinning the explosion of autophagy research are discussed with a particular focus on the contribution of yeast as a model organism.
Ouroboros, Autophagy, Cell Health and Cell Death
Eric H. Baehrecke, Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School
Autophagy is a catabolic process that targets cytoplasmic components for degradation by the lysosome. Autophagy is an important cellular response to stress, and plays essential roles in development, immunity, cancer and neurodegeneration. Thus, autophagy is considered a promising target for disease therapies. Pioneering studies of yeast led to the identification of conserved core factors that regulate autophagy, but the role of autophagy in specific cell contexts within multi-cellular organisms has not been rigorously studied. Recent studies of how autophagy is regulated and contributes to distinct cell fates will be presented.
Chaperone-mediated Autophagy in the Fight against Aging and Age-related Diseases
Ana Maria Cuervo, Department of Developmental and Molecular Biology; Institute for Aging Studies, Albert Einstein College of Medicine
Autophagy is an essential cellular process that contributes to protein quality control along with chaperones and other proteolytic pathways. Of the different types of autophagy that co-exist in mammalian cells, failure of two of them, macroautophagy and chaperone-mediated autophagy, has been shown to result in major alterations of proteostasis and often cellular toxicity and death. Chaperone-mediated autophagy (CMA) activity decreases with age and in different human disorders such as neurodegenerative and metabolic disorders. We have recently developed a series of mouse models with systemic or tissue-specific blockage of CMA to gain a better understanding of the contribution of reduced CMA to the phenotype of aging. Analysis of these models has revealed that added to the previously known role of CMA as part of the cellular response to stress, this type of autophagy is also required in the regulation of important cellular processes such as metabolism of lipids and carbohydrates, cell cycle, cell reprograming and cellular differentiation. In this talk, I will describe how phenotypic characterization of these mice is allowing us to link CMA deficiency with different age related diseases.
Discovery of Autophagy Inhibitors
Matthias Versele, Janssen R&D, Oncology Discovery and Discovery Sciences, Belgium
Adaptation to nutrient deprivation in the tumour microenvironment depends on the appropriate regulation of protein elongation rate through activation of the atypical kinase, eukaryotic elongation factor 2 kinase (eEF2K). We have discovered potent, low nM inhibitors of eEF2K, with remarkable selectivity across the protein kinome. These compounds inhibit the phosphorylation of eEF2 in nutrient-starved or metabolically stressed cells, and increase protein elongation rates through stabilization of the ribosomal elongation complex under stress. Coupling these inhibitors to an affinity matrix to identify all protein binding partners from cell lysates, revealed that a subset of the eEF2K inhibitors also bind with low nM affinity to the class III phosphatidylinositol-3-kinase, VPS34, but not to class I or II PI3Ks, and pull down the entire beclin-UVRAG-VPS34 complex. Proteomic and biochemical screening of the compound set enabled deconvolution of potent EF2K versus VPS34 inhibitors. Inhibition of VPS34 results in abrogation of autophagic flux, as indicated by rapid and massive accumulation of p62, and impairs survival in specific subsets of tumor cell lines, consistent with a pro-survival role for autophagy in those models. Interestingly, a whole-genome pooled RNAi screen in a KRAS/PI3KCA mutant colorectal cancer cell line revealed that reduction of beclin levels significantly increased sensitivity to VPS34 inhibition. Our work has provided the first potent inhibitors to unravel the functional relevance of eEF2K and VPS34 in adaptation to cellular stress, and to examine the utility of inhibiting these kinases in nutrient-deprived and/or autophagy-addicted tumours.
Increasing evidence suggest that autophagy enhances the processing and presentation of tumor antigens. Thus, beyond autophagy inhibition, novel therapeutic approaches to stimulate autophagy and improve the efficacy of cancer immunotherapy will be discussed.
Coauthors: Claire Moore3, Christopher G. Proud3, Cindy Rockx1, Inez Van de Weyer1, Kurt Van Baelen1, Stephanie Blencke4, Sebastian K. Wandinger4, Gaston Diels1, Didier Berthelot1, Marcel Viellevoye1, Bruno Schoentjes1, Berthold Wroblowski1, Lieven Meerpoel1, and William N. Hait2.
1. Janssen R&D, Oncology Discovery and Discovery Sciences, Belgium
2. Janssen R&D, Raritan, New Jersey
3. South Australian Health & Medical Research Institute, Adelaide, Australia
4. Evotec, Munchen, Germany
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