Pedro Lowenstein, M.D., Ph.D.

Professor, Neurosurgery
Professor, Cell and Developmental Biology
734-764-0851

Biography

Pedro R. Lowenstein, MD, Ph.D. is a Professor of Neurosurgery and Cell and Developmental Biology at the University of Michigan.  He received his M.D./Ph.D. from the School of Medicine, University of Buenos Aires, Argentina.  The focus of his research program is to discover the cellular, molecular, and mathematical basis underlying the growth patterns of malignant brain tumors, and the interactions between cancer cells with the tumor microenvironment, in both experimental models and in human patients. Another focus of his research program aims to harness the new information obtained on the mechanisms of tumor growth for therapeutic intent. Specifically, he will utilize nanoparticles targeted to peri-tumoral blood vessels to block GBM invasion. Recent work discovered that both rodent and human glioma cells and glioma stem cells disperse from the primary tumor inoculum by growing along peri-tumoral blood vessels. We predict that eliminating the vessels which support GBM growth and invasion will elicit long term survival of tumor bearing animal, and thus, this approach could become a future therapy for GBM. The long term goal will be to translate this strategy into early phase clinical trials.  In this regard, Dr. Lowenstein’s pioneering work in gene therapy for glioblastoma multiforme has been approved by the FDA and a Phase I clinical trial will commence at the University of Michigan imminently.

Areas of Interest

  • Antigen Processing/Presentation
  • Cell Homing/Trafficking
  • Cytokine Networks
  • Innate Immunity
  • T Cell Activation
  • Viral Infections in the brain
  • Gene Delivery
  • Apoptosis
  • Hematopoiesis
  • Cell Signaling
  • Immune Suppression
  • Cancer
  • T Cell Biology
  • Animal Models of Disease
  • Vaccine Development
  • Gene Therapy
 

Research Focus

The focus of Dr. Lowenstein's research program is to discover the cellular, molecular, and mathematical basis underlying the growth patterns of malignant brain tumors, the molecular and cellular mechanisms that mediate tumor immune escape and the interactions between cancer cells with the tumor microenvironment, in both experimental models and in human patients suffering from malignant brain tumors. His group has shown that galectin-1 knockdown in cancer cells causes the eradication of intracranial glioma in RAG1-/- mice lacking mature B- and T-cells by sensitizing tumor cells to NK cytotoxicity. Conversely, in NK cell depleted RAG1-/- mice, and severely immunocompromised NOD-scid IL2Rg null mice, galectin-1 deficient glioma cells progress killing the host with 100% efficiency. C57BL/6J mice with intact B- and T-cells enable galectin-1 deficient glioma growth only when NK cells are depleted. The data indicate that adaptive immunity is not required for galectin-1 deficient glioma rejection. Investigation is underway into therapeutic galectin-1 suppression to improve outcomes in patient survival by heightening NK immune surveillance.

Current Research Activity

  • “Endogeous glioma models:  use of lentivirus vectors to express genetic lesions encountered in human tumors: role in tumorigenesis, invasion and the immune microenvironment.”
  • “Role of Galectin 1 signaling in glioma models: role in cancer cells’ invasion, tumor progression and NK cells’ mediated cytotoxicity.”
  • “Human Glioblastoma Stem Cells: investigations in human GBM specimens and isolated human GBM stem cells in culture. Immune mediated mechanisms in GBM stem cells’ migration.”
  • “Role of angiogenesis in brain tumor invasion and immune cell migration: molecular and cellular mechanisms”.

Honors & Awards

  • Co-Organizer, 2011 FASEB Summer Research Conference: “Translational Neuroimmunology: From Mechanisms to Therapeutics”, Carefree, Arizona, July 31-August 5, 2011
  • Chair/Organizer, Methods Workshop: “Scientifically Significant Challenges for the Future of Translational Medicine: A View from the Trenches”, American Association for Cancer Research (AACR) 101st Annual Meeting, Washington, DC, April 17-21, 2010
  • Nominated Member, College of CSR Reviewers, Center for Scientific Review, National Institutes of Health, Bethesda, MD, from 2010
  • Honorary Professor, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina, from 2010
  • Elected to the Association of American Physicians (AAP), 2006
  • Chair, Neural Disorders Committee, American Society for Gene and Cell Therapy (ASGCT); Member, Publications Committee, American Society for Gene and Cell Therapy (ASGCT), 2005
  • Awarded “The Bram and Elaine Goldsmith Chair in Molecular Medicine and Gene Therapy”; Gene Therapeutics Research Institute, Cedars Sinai Medical Center; University of California at Los Angeles (UCLA), 2003
  • Founding Editor, Current Gene Therapy, Bentham Science Publishers, P.O. Box 1673, 1200 R Hilversum, The Netherlands, selected & included in Index Medicus & MEDLINE, 2001
  • Editor-in-Chief, Current Gene Therapy, Bentham Science Publishers, P.O. Box 1673, 1200 R Hilversum, The Netherlands, selected & included in Index Medicus & MEDLINE, 2001-2003
  • Research Fellow, The Lister Institute of Preventive Medicine, “Gene therapy of human neurological disorders”, 1993-2001
  • Awarded the ‘Brain Bursary’, to give the Annual Brain Bursary Lecture: “Gene therapy: molecular therapeutics for neurological diseases”. University College, London, UK, 4th April, 2000
  • Junior Research Fellow, Wolfson College, Oxford, 1988-1990.
  • Visiting Fogarty Fellow, NINDS, Laboratory of Neurochemistry (Dr. Harold Gainer), National Institutes of Health, Bethesda, Maryland, USA, 1987.
  • NIH Fogarty International Center Postdoctoral Fellowship, The Johns Hopkins University, School of Medicine, Baltimore, Department of Psychiatry (Dr. Joseph Coyle), MD, USA, 1984-1986.
  • Biography included in “Who’s Who in America”, “Who’s Who in Medicine and Healthcare” and “Who’s Who in the World” published by Marquis, USA 2003 Editions.
  • Biography included in “Who’s Who in American Education”, published by Marquis, USA 2004-2005 6th Edition
  • Referenced in the “Who’s Who in Science”, 2001 Edition.
  • First Prize. Best Dissertation submitted to the School of Medicine, University of Buenos Aires, Academic Year 1984.
  • Bursary awarded from the Wellcome Trust and The British Pharmacological Society to assist the attendance to the 9th International Congress of Pharmacology, London, July 29 - August 3, 1984. 

Credentials

Medical Degree

M.D. (Cum laude), School of Medicine, University of Buenos Aires, Argentina, 1981

Post-Graduate Degree

Ph.D. (Medical Sciences [Summa cum laude]) for thesis “Studies on the molecular basis of the mechanism of action of benzodiazepines in the pineal gland and the central nervous system”, School of Medicine, University of Buenos Aires, Argentina, 1984

Post-Doctoral Fellowship

Department of Psychiatry, The John Hopkins University School of Medicine, 1986

Post-Graduate Employment

Medical Research Council (MRC) Research Scientist, MRC Anatomical Neuropharmacology Unit, Department of Pharmacology, Oxford University, United Kingdom, 1990

Board Certification/Licensures

Education Council for Foreign Medical Graduates (ECFMG) Certification, USA, 1983

State of Michigan, Board of Pharmacy, Research Laboratory Controlled Substance License, 2013

Representative Publications

  1. Sanderson NS, Puntel M, Kroeger KM, Bondale NS, Swerdlow M, Iranmanesh N, Yagita H, Ibrahim A, Castro MG, Lowenstein PR.  (2012) Cytotoxic immunological synapses do not restrict the action of interferon-γ to antigenic target cells.  The Proceedings of the National Academy of Sciences, USA, 2012 May 15: 109(20):  7835-40.  Epub 2012 April 30.  PMCID: PMC3356634
  2. Zirger JM, Puntel M, Bergeron J, Wibowo M, Moridzadeh R, Bondale N, Barcia C, Kroeger KM, Liu C, Castro MG, Lowenstein PR. (2012) Immune-mediated Loss of Transgene Expression From Virally Transduced Brain Cells Is Irreversible, Mediated by IFNγ, Perforin, and TNFα, and due to the Elimination of Transduced Cells. Molecular Therapy 2012 Jan 10:808-819. Epub 2012 Jan 10.  PMCID: PMC3321600
  3. Larocque D, Sanderson NRS, Bergeron J, Curtin J, Girton J, Wibowo M, Bondale N, Kroeger KM, Yang J, Lacayo LM, Reyes KC, Farrokh C, Pechnick RN, Castro MG, Lowenstein PR, (2010) Exogenous fms-like tyrosine kinase 3 ligand overrides brain immune privilege and facilitates recognition of a neo-antigen without causing autoimmune neuropathology. The Proceedings of the National Academy of Sciences, USA, 107(32):14443-14448. Epub July 26, 2010.  PMCID:  PMC2922551.
  4. Yang J, Sanderson N, Wawrowsky K, Castro MG, Lowenstein PR. (2010) Kupfer-type immunological synapse characteristics do not predict anti-brain tumor cytolytic T-cell functions in vivo. The Proceedings of the National Academy of Sciences, USA, 107(10):4716-4721. Epub Jan 19, 2010. PMCID:  PMC2842057.
  5. Barcia C Jr, Gomez A, Gallego-Sanchez JM, Perez-Valles A, Castro MG, Lowenstein PR, Barcia C Sr, Herrero M-T. (2009) Infiltrating CTLs in human glioblastoma establish immunological synapses with tumorigenic cells. American Journal of Pathology, 175:786-798.  Portrayed on the cover.  PMCID: PMC2716973.
  6. Barcia C, Wawrowsky K, Barrett R, Liu C, Castro MG, Lowenstein PR. (2008) In vivo polarization of IFN-{gamma} at Kupfer and non-Kupfer immunological synapses during the clearance of virally infected brain cells. Journal of Immunology, 180:1344-1352.  PMCID: PMC2629497.
  7. Barcia C, Thomas CE, Curtin JF, King GD, Wawrowsky K, Candolfi M, Xiong WD, Liu C, Kroeger K, Boyer O, Kupiec-Weglinski J, Klatzmann D, Castro MG, Lowenstein PR. (2006) In vivo mature immunological synapses forming SMACs mediate clearance of virally infected astrocytes from the brain. Journal of Experimental Medicine, 203:2095-2107.  Work portrayed on journal cover, highlighted in the journal; reviewed by Science, 313[issue 5790, August 25, 2006] p. 1020; reviewed by Cell [October 20, 2006], and Journal of Cell Biology [September 11, 2006]; cited in Faculty of 1000 Medicine.  PMCID: PMC1997281.
  8. Iannacone M, Sitia G, Isogawa M, Marchese P, Castro MG, Lowenstein PR, Chisari FV, Ruggeri ZM, Guidotti LG (2005) Platelets mediate cytotoxic T lymphocyte-induced liver damage. Nature Medicine 11(11):1167-1169.  PMCID:  PMC2908083.
  9. Grande-Perez A, Lazaro E, Lowenstein PR, Domingo E, Manrubia SC. (2005) Suppression of viral    infectivity through lethal defection. The Proceedings of the National Academy of Science USA, 102: 4448-4452.  PMCID: PMC555496
  10. Grande-Perez A, Sierra S, Castro MG, Domingo E, Lowenstein PR. (2002) Molecular indetermination in the transition to error catastrophe: systematic elimination of lymphocytic choriomeningitis virus through mutagenesis does not correlate linearly with large increases in mutant spectrum complexity.  The Proceedings of the National Academy of Sciences, USA, 99: 12938-12943.  PMCID: PMC130564.

Grants

  • 2013-2015  Inhibiting glioma invasion using targeted nanoparticles; Sponsor: NIH
  • 2013-2018  Mechanisms of glioma growth and invasion - Novel therapeutic strategies; Sponsor: NIH
  • 2013-2015  A non-randomized, open-label dose-finding trial of combined cytotoxic and immune stimulatory strategy for the treatment of resectable primary malignant glioma; Sponsor: Phase ONE
  • 2012-2017  Novel gene therapy strategies for Canavan disease; Sponsor: NIH (University of Massachusetts Medical Center)
  • 2011-2014  Gutless Adenovirus Mediated Gene Therapy for Glioma; Sponsor: NIH
  • 2011-2014  Brain immune response: Cellular & Molecular Mechanisms; Sponsor: NIH
  • 2011-2016  Crosstalk between glioma cells & immune cells in the tumor microenvironment: Therapeutic implications; Sponsor: NIH
  • 2011-2013  Gene Therapy and the Brain: Neuroimmune Interactions; Sponsor: NIH
  • 2011-2013  Engineering the Brain Immune System for Tumor Therapy; Sponsor: NIH

Published Articles via PubMed

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