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

Richard C. Schneider Professor of Neurosurgery
Professor of Cell and Developmental Biology
Accepting Students

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

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 self-organized. 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).

 

Research Opportunities for Rotating Students

I. Innate immunity to brain tumors
II. The effects of chromosomal deletions on tumor malignity
III. Self-organization in cancer

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, 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.
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, 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. Reviewed by: Science, 313[issue 5790, August 25, 2006] p. 1020; Cell [October 20, 2006]; Journal of Cell Biology [September 11, 2006]. Cited in Faculty of 1000 Medicine. PMCID: PMC1997281.
Dewey RA, Morrissey G, Cowsill C, Stone D, Dodd NJF, Bolognani F, Southgate TD, Klatzmann D, Castro MG, Lowenstein PR. (1999) Chronic brain inflammation and persistent HSV1-TK expression in survivors of syngeneic glioma treated by adenovirus-mediated gene therapy: Implications for clinical trials. Nature Medicine, November, 1999;5(11), 1256-1263. Cover article. PMID 10545991. Note: A “News and Views” article was written about this paper: T. Kielian and W.F. Hickey, Inflammatory thoughts about glioma gene therapy, Nature Medicine, 5:1237-1238, 1999. – A comment on this work presented at the 2nd meeting of the American Society for Gene Therapy, Washington, DC, USA, 1999 was published on the Web by Bio Med Net: L. Spinney, “Gene therapy for glioblastoma may inflame the brain”.

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