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.
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.
His research program is composed of four themes:
Studies on innate immune responses to brain tumors
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.
Studies on the mechanisms by which the co-deletion of 1p/19q increases the sensitivity of low grade brain tumors to chemo- and radiotherapy
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.
Studies on the self-organization of brain tumors, especially one of its main manifestations, the onco-streams
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.
Novel gene-immunotherapeutic clinical trials for the treatment of malignant brain tumors.
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 Student
- Neuroimmunology of Malignant Brain Tumors: Innate Mechanisms
- Cellular and Molecular Mechanisms of Glioma Progression: Identification of Novel Therapeutic Targets
Yadav VN, Altshuler D, Kadiyala P, Zamler D, Dunn P, Koschmann C, Castro MG, Lowenstein P. Molecular ablation of tumor blood vessels inhibits therapeutic effects of radiation and anti-angiogenesis. Neuro-Oncology, 2018 Sep 3;20(10):1356-1367. PMCID: PMC6140787.
Nunez F, Mendez FM, Kadiyala P, Alghamri MS, Savelieff MG, Garcia-Fabiani MB, Haase S, Koschmann C, Calinescu AA, Kamran N, Patel R, Carney S, Guo MZ, Edwards M, Ljungman M, Qin T, Sartor MA, Tagett R, Venneti S, Brosnan-Cashman J, Meeker A, Gorbunova V, Zhao L, Kremer DM, Zhang L, Lyssiotis CA, Jones L, Herting CJ, Ross JL, Hambardzumyan D, Hervey-Jumper S, Figueroa ME, Lowenstein PR*, Castro MG*. IDH1R132H acts as a tumor suppressor in glioma via epigenetic upregulation of the DNA damage response. Science Translational Medicine 2019 Feb 13;11(479). PMCID: PMC6400220. (*Corresponding authors) Accessible online: https://www.biorxiv.org/content/10.1101/389817v1 Comba A, Dunn PJ, Argento AE, Kadiyala P, Ventosa M, Zamler DB, Patel P, Zhao L, Nunez FJ, Castro MG, Lowenstein PR. The Proto-Oncogene Fyn Inhibits the Anti-Glioblastoma Immune Response, bioRxiv. doi: https://doi.org/10.1101/608505.
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
A complete list of published work is in MyBibliography: