Phosphatidylserine Asymmetry and Cell Survival

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Phosphatidylserine Asymmetry and Cell Survival

Tuesday, May 1, 2012

The New York Academy of Sciences

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Phosphatidylserine (PS) is a membrane lipid that regulates multiple biological processes. It is normally positioned in the inner leaflet of the plasma membrane but translocates to the outer, extracellular-facing surface to signal clearance of apoptotic cells, to quell unwanted inflammatory reactions and immunity, and to stimulate hemostasis and complement activation at sites of injury. PS exposure can be subverted by cells that become malignant or infected by viruses as a ploy to escape host defenses. This symposium will highlight recent developments in the understanding of PS regulation and its exploitation to create novel therapeutics for cancer and viral diseases. Alan Schroit (UT Southwestern) will introduce the topic and discuss how PS asymmetry is regulated in resting cells and the physiologic and pathologic consequences of its loss. David Ucker (University of Illinois at Chicago) will describe how PS exposure suppresses inflammatory and immune responses to cells undergoing apoptosis at the end of their natural lifespan. Ari Helenius (ETH Hönggerberg) will discuss how viruses use macropinocytosis and apoptotic mimcry to enter host cells. Chris Reutelingsperger (University of Maastricht) will discuss the use of annexin A5 to image apoptosis for detecting cardiopulmonary lesions and monitoring tumor responses to therapy. He will also discuss the use of annexin A5 for drug delivery. Finally, Philip Thorpe (UT Southwestern) will discuss clinical trials with bavituximab, an antibody that targets PS-expressing tumor vasculature and reactivates host immunity.

This event will also be broadcast as a webinar.

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Agenda

* Presentation times are subject to change.


Tuesday, May 1, 2012

1:00 PM

Welcome and Introduction
Jennifer Henry, PhD, The New York Academy of Sciences
George Zavoico, PhD, MLV

1:10 PM

Maintenance of Membrane Phospholipid Asymmetry and its Physiologic Significance
Alan Schroit, PhD, UT Southwestern Medical Center

1:50 PM

Innate Apoptotic Immunity and the Specific Apoptotic Externalization of Glycolytic Enzyme Molecules
David Ucker, PhD, University of Illinois at Chicago

2:30 PM

PS in Virus Entry
Ari Helenius, PhD, ETH Hönggerberg, Switzerland

3:10 PM

Coffee Break

3:40 PM

Phosphatidylserine Targeting with Annexin A5 for Diagnosis and Treatment of Human Disease
Chris Reutelingsperger, PhD Maastricht University, The Netherlands

4:20 PM

Targeting Tumor Vasculature and Reactivating Tumor Immunity with Bavituximab
Philip E. Thorpe, PhD, UT Southwestern Medical Center

5:00 PM

Close

Speakers

Organizers

Kenneth P. Olive, PhD

Columbia University Medical Center

Dr. Kenneth P. Olive began his doctoral studies in 1998 with Tyler Jacks at the MIT Center for Cancer Research, investigating the neomorphic effects of mutant p53 in a mouse model of Li-Fraumeni Syndrome. While at MIT, he also helped develop a conditional mutant model of advanced lung adenocarcinoma. After graduating in 2005, Dr. Olive began a postdoctoral fellowship in the laboratory of David Tuveson at the University of Pennsylvania, later moving with the lab to the University of Cambridge in England. There he built a translational research facility for studying novel anticancer therapeutics in genetically engineered mouse models of pancreatic cancer. His studies into chemoresistance and the effects of Hh pathway inhibitors on drug delivery in pancreatic cancer were published in Science in 2009, and have led to multiple clinical trials to evaluate the approach in patients with metastatic pancreatic cancer. In 2010, Dr. Olive joined the faculty of the Columbia University Herbert Irving Comprehensive Cancer Center, where he has established a laboratory dedicated to translational science and experimental therapeutics in pancreatic ductal adenocarcinoma.

Philip Thorpe, PhD

UT Southwestern Medical Center

George Zavoico, PhD

MLV

George B. Zavoico, PhD, is Managing Director, Research, and a Senior Equity Research Analyst at MLV & Co, a boutique investment bank and institutional broker-dealer based in New York. He has over 7 years of experience as a life sciences analyst writing research on publicly traded equities. Prior to MLV, he was an equity analyst with Westport Capital Markets and Cantor Fitzgerald. Prior to working as an analyst, Dr. Zavoico established his own consulting company serving the biotech and pharmaceutical industries by providing competitive intelligence and marketing research, due diligence services, and guidance in regulatory affairs. He also wrote extensively on healthcare and the biotech and pharmaceutical industries for periodicals targeting the general public and industry executives. Dr. Zavoico began his career as a Senior Research Scientist at Bristol-Myers Squibb Co., moving on to management positions at Alexion Pharmaceuticals, Inc. and T Cell Sciences, Inc. (now Celldex Therapeutics, Inc.). He has a BS in Biology from St. Lawrence University and PhD in Physiology from the University of Virginia and has held post-doctoral positions at the University of Connecticut Health Sciences Center and Brigham and Women's Hospital and Harvard Medical School.

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Ari Helenius, PhD

ETH Hönggerberg, Zurich, Switzerland

Educated as a biochemist, Ari Helenius obtained his PhD in 1973 in the University of Helsinki, Finland. After a six year period in the newly founded European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, he became Professor in the Department of Cell Biology, Yale School of Medicine. In 1997, he moved to his current position as professor of biochemistry in ETH Zurich. His research has involved membrane biology, cell biology, virology, infectious disease biology, protein biochemistry, and glycobiology. In most of the studies, animal viruses—their structure, function, and host cell interactions—have been a central theme.

Philip Thorpe, PhD

UT Southwestern Medical Center

Philip Thorpe is a professor of pharmacology and holds the Serena S. Simmons Distinguished Chair at the University of Texas Southwestern Medical Center in Dallas, Texas. His expertise is in drug targeting, vascular targeting and most recently, antiviral research; his work has been published more than 200 times, including publications in Nature, Nature Medicine, Science, and Proceedings of the Natural Academy of Sciences. He is an inventor on more than 240 issued and pending US and international patents. His long-standing collaboration with Peregrine Pharmaceuticals Inc, Tustin, CA, has culminated in the company developing bavituximab, a therapeutic antibody directed against the lipid, phosphatidylserine. Professor Thorpe has been awarded the American Cancer Society Award of Excellence, the Texas State Legislature Award, and the Pierce Immunotoxin Award. He received his Ph.D. from the Clinical Research Centre, London, U.K. He was formerly director of the Drug Targeting Laboratory at the Imperial Cancer Research Fund, London.

Chris Reutlingsperger, PhD

University of Maastricht, The Netherlands

Chris Reutelingsperger studied Biochemistry at the University of Utrecht and received his Ph.D. in Biochemistry of Thrombosis and Haemostasis from the Maastricht University (1987). He discovered annexin A5 and is inventor of the annexin A5 affinity assay to determine apoptosis in vitro and in vivo in animal models and in patients. He was senior investigator of the Royal Dutch Academy of Sciences. Currently he is appointed Professor of Biochemistry and Apoptosis at Maastricht University. He founded and is chairman of the Board of the Virtual Laboratory Euregional PACT II, which is a cross-border collaboration between Universities of Maastricht, Leuven, Antwerp, Ghent and Aachen to develop innovative cancer diagnostics and therapeutics. He (co)-authored more than 150 peer-reviewed scientific papers and is inventor of 8 patents.

Alan Schroit, PhD

UT Southwestern Medical Center

Alan Schroit is Adjunct Professor of Pharmacology at the University of Texas Southwestern Medical Center in Dallas, Texas. He received his Ph.D. degree in Immunology from the Hadassah-Hebrew University Medical, Jerusalem, Israel and completed his postdoctotal training in lipid biochemistry at the Carnegie Institution of Washington in Baltimore, Maryland. His research has focused on the chemistry, biology and pathology of phosphatidylserine (PS) exposure in the outer leaflet of cells. His studies have led to the first observations that PS is constitutively expressed on the surface of many tumor cells and serves as a recognition ligand for phagocytosis by macrophages. Dr. Schroit was a founding Director of the Gulf Coast Consortia for Membrane Biology and was formerly John Q. Gaines Professor for Cancer Biology and Deputy Chair of the Department of Cancer Biology at the M D Anderson Cancer Center in Houston, Texas.

David Ucker, PhD

University of Illinois at Chicago

David Ucker is Professor of Microbiology and Immunology at the University of Illinois College of Medicine in Chicago. He received his Ph.D. in Biochemistry and Biophysics from the University of California at San Francisco in 1981, and focused on studies of Molecular Immunology during his postdoctoral training at M.I.T. and Harvard. He has a long-standing interest in the molecular and cellular biology of physiological cell death (apoptosis) and in the immunological consequences of apoptosis. Those interests have led to the characterization of the phenomenon of "innate apoptotic immunity," and to the identification of novel apoptotic recognition determinants involved in triggering that response. Professor Ucker is the elected chair of the upcoming Gordon Research Conference on Apoptotic Cell Recognition and Clearance. He has served as a member of several NIH and VA grant review panels, as a reviewer and editor for numerous scientific journals, and has received honors and recognition from a variety of scientific and educational societies.

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Abstracts

Maintenance of membrane phospholipid asymmetry and its physiologic significance
Alan Schroit, PhD, UT Southwestern Medical Center

Many studies have established the unifying concept that plasma membrane phospholipids are asymmetrically distributed across the plasma membrane bilayer. In the vast majority of normal eukaryotic cells, essentially all of the phosphatidylserine (PS) and most of the phosphatidylethanolamine resides in the cells’ inner membrane leaflet while the choline-containing phospholipids, phosphatidylcholine and sphingomyelin, are principally localized in the outer membrane leaflet. This distribution can be altered in response to a variety of external and internal stimuli that result in specific biological responses. For example, Ca2+ influx into apoptotic cells results in the redistribution of PS to the cell surface where it marks the dying cells for physiologic clearance by phagocytes through pathways that avoid inflammatory and immune responses. PS also participates in pathologic responses that mimic apoptotic cell responses in which its presence is subverted by viruses and tumor cells as a ploy for infection and immune evasion. This lecture will focus on the maintenance of PS asymmetry and the physiologic and pathologic significance of its redistribution to the cell surface.
 

Innate Apoptotic Immunity and the Specific Apoptotic Externalization of Glycolytic Enzyme Molecules
David Ucker, PhD, University of Illinois at Chicago

Apoptotic cells are recognized by phagocytes and neighboring cells, and trigger a profound repertoire of affirmative signaling and effector responses associated generally with the suppression of inflammation and immune responsiveness, even in the absence of engulfment. We have termed this response "Innate Apoptotic Immunity" (IAI). The anti-inflammatory effects elicited upon the specific recognition of apoptotic cells result primarily from the triggering of transcriptional responses (especially the repression of inflammatory cytokine gene expression) in cells that interact with them. IAI is responsible for the lack of inflammation associated normally with the clearance of apoptotic cells, and its failure has been linked to inflammatory and autoimmune pathologies (including systemic lupus erythematosis and rheumatic diseases). We have shown that essential determinants for apoptotic recognition are surface-exposed and protease-sensitive molecules which are evolutionarily-conserved and expressed ubiquitously in viable cells. Employing comprehensive proteomic approaches to characterize these determinants, we identified components of the glycolysis pathway that become externalized on the apoptotic cell surface. Glycolytic enzyme externalization is a common, early, and caspase-dependent aspect of apoptotic cell death specifically. The further characterization of these apoptosis-associated externalized glycolytic molecules will be discussed.
 

PS in Virus Entry
Ari Helenius, Institute of Biochemistry, ETH Zurich

Macropinocytosis has emerged as a major endocytic mechanism in the infectious cell entry of animal viruses. The process differs fundamentally from other endocytic mechanisms involved in virus internalization. By activating growth factor receptors or other signaling molecules, plasma membrane-bound viruses trigger the activation of signaling pathways that cause a transient, global change in cell behavior. Manifestations of the change include the actin-dependent formation of membrane protrusions, the elevation of non-specific uptake of fluid, and the internalization of surface-bound ligands including viruses. The penetration of the viruses into the cytosol is generally triggered by the low pH in macropinosomes. Recent studies show that this strategy is used by a variety of enveloped and non enveloped viruses. In the case of vaccinia virus ('mature viruses'), we have demonstrated that the phosphatidylserine (PS) exposed in the viral envelope is required to trigger the response by activating EGFR and other receptor tyrosine kinases. The second infectious form of the virus, the so called 'enveloped viruses', also trigger macropinocytosis but without involvement of PS.
 

Phosphatidylserine targeting with annexin A5 for diagnosis and treatment of human disease
Chris Reutelingsperger, Cardiovascular Research Institute Maastricht, The Netherlands

Annexin A5 (anxA5) is a structurally and biophysically well-characterized member of the annexin multigene family. It associates rapidly with cell surfaces expressing phosphatidylserine (PS) and it forms a 2-dimensional network on the cell surface by homotypic protein-protein interactions. The 2-dimensional network creates the driving force for its internalization into the PS-expressing cell. These properties have turned anxA5 into a successful and broadly applied Molecular Imaging agent to measure PS-expressing cells in vitro and in vivo in animal models and in patients.
 
The Molecular Imaging experience with anxA5 created a strong rationale for utilization of this member of the annexin family as vector for targeted drug delivery. My lecture will highlight the Molecular Imaging experience and present recent developments of our lab to employ anxA5 as targeting vector for treatment of atherosclerosis and cancer. Both pathologies are characterized by presence of PS expressing cells and respond to treatments based on PS-targeting with anxA5 constructs that enhance efferocytosis (atherosclerosis) and exhibit cytotoxic activity (cancer).
 

Targeting Tumor Vasculature and Reactivating Tumor Immunity with Bavituximab
Philip E. Thorpe, PhD, University of Texas Southwestern

Bavituximab is a therapeutic monoclonal antibody that is in clinical trials in cancer patients. It targets phosphatidylserine, which becomes exposed on blood vessels in solid tumors in response to hypoxia and other stresses. Phosphatidylserine is also exposed on tumor cells that are responding to therapy and on exosomes shed by the tumor cells. Phosphatidylserine is a powerfully immunosuppressive lipid and its exposure in tumors contributes to the immunosuppressed state of the tumor microenvironment. Bavituximab treatment reactivates tumor immunity. It causes myeloid derived suppressor cells to differentiate into tumoricidal M1 macrophages that destroy the tumor vasculature and tumor cells by antibody-dependent cellular cytotoxicity. It also causes immature dendritic cells in tumors to acquire costimulatory molecules, enabling them to present tumor antigens and generate tumor-specific cytotoxic T-cells.
 

Additional abstracts coming soon.

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