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

Richard Schneider Collegiate Professor of Neurosurgery and Professor of Cell and Developmental Biology

Biography

Pedro R. Lowenstein, MD, PhD, is Professor in the Department of Neurosurgery and in the Department of Cell and Developmental Biology. He graduated as MD (Cum Laude) and PhD (Summa Cum Laude) from the University of Buenos Aires, School of Medicine, Argentina. He did postdoctoral work with Dr. J.T. Coyle at Johns Hopkins Hospital and with Dr. P. Somogyi at Oxford University.
 

Research Interests

His research program is composed of four themes: (i) studies on innate immune responses to brain tumors; (ii) studies on the mechanisms by which the co-deletion of 1p/19q increases the sensitivity of low grade brain tumors to chemo- and radiotherapy; (iii) studies on the self-organization of brain tumors, especially one of its main manifestations, the onco-streams; and (iv) novel gene-immunotherapeutic clinical trials for the treatment of malignant brain tumors. The ultimate aim of the lab is to understand the molecular basis of the phenomena to harness their mechanisms to develop novel therapies to treat malignant brain tumors.
In (i) we discovered that the tumor itself releases an agonist that binds to TLR7, activates MyD88, IRF5, and eventual release of Interferon α/β; all these steps are necessary to stimulate innate NK-mediated immune responses against brain gliomas. We are now determining the nature of the TLR7 agonist released by the tumor, if stimulation of TLR7 alone is sufficient to initiate glioma elimination, the cell that responds to the TLR7 agonist, and the mechanisms of eventual stimulation of NK cells.
In (ii) we are currently testing the activity of various genes affected by 1p/19q co-deletion vis-à-vis their effect on tumor growth, and response to chemo- and radiotherapy.
(iii) We have discovered that malignant brain tumor growth is not random. We can recognize a number of neuropathological features which support this notion. The main feature we discovered is called onco-streams and it is present in rodent and human gliomas. Onco-streams are essentially streams of elongated malignant cells which mediate glioma growth, invasion, and facilitate the migration of other non-migrating brain tumor cells. Through the use of laser scanning microdissection we have discovered that oncostreams are different from the rest of the brain. The construction of networks now allows us to understand the molecular basis of oncostream function; this will identify molecular targets whose pharmacological manipulations we will develop into novel treatments.
(iv) Together with Dr. Castro we have developed a novel treatment for brain tumors that is currently being tested in humans. Using the cytokine Flt3L we essentially reconstitute the brain immune system by attracting dendritic cells to the tumor area. Dendritic cells are then exposed to antigens released from dying cells (induced by HSV1-TK + ganciclovir).This work has been translated into an early clinical trial ongoing at the University of Michigan (see ClinicalTrials.gov Identifier: NCT01811992).

 

Publications

Calinescu AA, Yadav VN, Carballo E, Kadiyala P, Tran D, Zamler D, Doherty R, Srikanth M, Lowenstein PR, Castro MG. (2017) Survival and proliferation of neural progenitor derived glioblastomas under hypoxic stress is controlled by a CXCL12/CXCR4 autocrine positive feedback mechanism. Clinical Cancer Research, 2017 Mar 1;23(5):1250-1262. Epub 2016 Aug 19. PMCID: PMC5316506
Koschmann C, Nunez FJ, Mendez F, Brosnan-Cashman JA, Meeker Ak, Lowenstein PR, Castro MG. (2017) Mutated Chromatin Regulatory Factors as Tumor Drivers in Cancer. Cancer Research. 2017 Jan 15;77(2):227-233. Epub 2017 Jan 6. PMCID: PMC5243833.
Kamran N, Kadiyala P, Saxena M, Candolfi M, Li Y, Moreno-Ayala MA, Raja N, Shah D, Lowenstein PR, Castro MG. (2017) Immunosuppressive myeloid cells’ blockade in the glioma microenvironment enhances the efficacy of immune stimulatory gene therapy. Molecular Therapy. 2017 Jan 4;25(1):232-238. PMCID: PMC5363306
Koschmann C, Calinescu AA, Nunez FJ, Mackay A, Fazal-Salom J, Thomas D, Mulpuri L, Kamran N, Mendez F, Dzaman M, Krasinkiewicz J, Doherty R, Lemons R, Li Y, Roh S, Zhao L, Appleman H, Ferguson D, Gorbunova V, Meeker A, Jones C, Lowenstein PR, Castro MG. (2016) ATRX Loss Promotes Tumor Growth and Impairs Non-Homologous End Joining DNA Repair in Glioma. Science Translational Medicine, 2016 March 2;8(328):328ra28. PMCID: PMC5381643.
Baker GJ, Chockley P, Zamler D, Castro MG, Lowenstein PR. (2016) Natural killer cells require monocytic Gr-1(+)/CD11b(+) myeloid cells to eradicate orthotopically engrafted glioma cells. OncoImmunology, 2016 Mar 16:5(6)e1163461 [Available on 2017-03-16] PMCID: PMC4938363
Baker G, Chockley P, Yadav V, Doherty R, Ritt M, Sivaramakrishnan S, Castro MG, Lowenstein PR. (2014) Natural killer cells eradicate galectin-1 deficient glioma in the absence of adaptive immunity. Cancer Research, 74:5079-90. PMCID: PMC4184887.
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. Proceedings of the National Academy of Sciences, USA, 2012 May 15: 109(20):7835-40. Epub April 30, 2012. PMCID: PMC3356634.
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, 20:808-19. PMCID: PMC3321600.
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. Proceedings of the National Academy of Sciences, USA, 107(32):14443-14448. Epub July 26, 2010. PMCID: PMC2922551.
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. Proceedings of the National Academy of Sciences, USA, 2010 March 19;107(10):4716-4721. Epub Jan 19, 2010. PMCID: PMC2842057.
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. Cover article. PMCID: PMC2716973.
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.
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. Cover article. Rviewed 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.
Iannacone M, Sitia G, Isogawa M, Marchese P, Castro MG, Lowenstein PR, Chisari FV, Ruggeri ZM, Guidotto LG. (2005) Platelets mediate cytotoxic T lymphocyte-induced liver damage. Nature Medicine, 11:1167-1169. PMCID: PMC2908083.

A complete list of published work is in MyBibliography:
http://www.ncbi.nlm.nih.gov/sites/myncbi/pedro.lowenstein.1/bibliography...

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