Maria G. Castro, PhD, is the R.C. Schneider Professor of Neurosurgery, and Professor of Cell and Developmental Biology, at the University of Michigan Medical School. My research program focuses on epigenetic regulation of cancer progression, uncovering the role of oncometabolites in the brain tumor microenvironment (TME), and the development of new therapies for adult and pediatric gliomas, including DIPG. We are investigating the role of the tumor immune-microenvironment in tumor progression and response to therapeutics, crosstalk between cancer cells and hematopoietic stem/progenitor cells, and mechanisms affecting the migration of immune cells from peripheral lymphoid organs to the tumor microenvironment. The study of these basic immunological mechanisms will lead to clinical implementation. The goal of my program is to develop novel treatments for brain tumors based on immunotherapeutics, a new and exciting approach that targets inhibition of tumor growth and recurrence.
Areas of Interest
- Antigen Processing/Presentation
- Cell Homing/Trafficking
- Cytokine Networks
- Innate Immunity
- T Cell Activation
- Viral Infections in the brain
- Gene Delivery
- Cell Signaling
- Immune Suppression
- T Cell Biology
- Animal Models of Disease
- Vaccine Development
- Gene Therapy
Pediatric and adult brain cancer biology and therapeutics. Epigenetics, cancer metabolism, and signaling networks that mediate tumor progression. Uncovering the role of secreted cancer ligands in hematopoietic stem cell development and anti-tumor immunity. Nanotechnology to develop novel anti-cancer therapies. DNA damage, DNA damage response, and development of novel combination therapies for both adult and pediatric brain tumors, including novel immunotherapeutic approaches.
Current Research Activity
Mutant IDH1 Glioma Project
Glioma genetic models are needed to uncover mechanisms that mediate tumor progression, the interplay with the tumor microenvironment (TME) and response to therapeutics. We have generated the first genetically engineered mutant IDH1 mouse glioma model and isolated primary neurospheres (NS) from the tumors, which exhibit cancer stem cell-like properties. This has enabled us to develop a transplantable mIDH1 glioma model amenable to testing novel therapies. NS are derived from fully immune-competent (C57BL/6) mice, thus allowing examination of the TME and the impact of tumor mutations on the immune response. Our goals are to assess the effect of mIDH1 on transcription (using mRNA-seq) and on global DNA and histone methylation. The mIDH1 glioma model will also be used to identify promoter/enhancer region-specific changes in histone methylation marks (using chromatin immunoprecipitation followed by deep sequencing, or ChIP-seq). We are collaborating with Dr. Mats Ljungman, who pioneered bromouridine sequencing (Bru-seq), to identify and quantify nascent mRNA and gene transcription rates. Uncovering epigenetic patterning of histone 3 hypermethylation and cytosine modifications using next generation sequencing (NGS) technologies will contribute to the identification of novel pathways and gene regulatory networks which will provide novel insights into disease biology and uncover novel therapeutic targets.
Diffuse intrinsic pontine glioma (DIPG) is a brainstem tumor that affects mainly children and for which there is no effective treatment. The most frequent DIPG mutations affect the N-terminal tail of histone variant H3.3 (encoded by H3F3A) and histone variant H3.1 (encoded by HIST1H3B) and result in the change of a lysine to methionine at residue 27, precluding methylation or acetylation of this key regulatory post-translational modification. In addition, six recurrent somatic activating mutations in ACVR1, which encodes for a bone morphogenetic protein (BMP) type-I receptor, have also been identified in DIPG tumors. BMP has very context-specific roles in the brain during development but its role in pediatric cancer remains unknown. We are using the Sleeping Beauty Transposase System to generate spontaneous in vivo tumor models that will allow us to analyze the contributions of these genes to DIPG pathogenesis. This work will elucidate how ACVR1 and H3K27M mutations contribute to DIPG progression and evaluate their impact on tumor response to DNA damaging agents. These studies will uncover novel therapeutic targets to improve prognosis for patients who suffer from DIPG.
The adult and pediatric brain tumor models we have established in our lab are ideal for developing and testing novel immunotherapies as they are implemented in mice with a fully competent immune system. We are using both immune mediated gene therapy strategies and nanoparticle-based vaccination approaches to develop new treatment strategies for these devastating brain cancers.
Our innovative work has led to an FDA-approved gene therapy Phase 1 clinical trial for malignant brain cancer which is currently enrolling patients at the University of Michigan.
Honors & Awards
- Breakout Session Chair/Moderator: “Opportunities and Challenges of Nanomedicine in Neuro-Oncology”, BioInterfaces Institute meeting, Ann Arbor, MI, November 1-2, 2013.
- Member, Program Organizing Committee, American Society of Cell and Gene Therapy, May, 2011 – June, 2013.
- Biography included in 2010-2011 Edition of Sutton Who’s Who in North America by Sutton Who’s Who in Elite Healthcare as an Honored Member.
- Chair and Co-Organizer, Symposium: “New Therapeutic Strategies for Neuro-Ophthalmic Diseases” American Society of Cell and Gene Therapy 14th Annual Meeting, Seattle, WA, May 18-21, 2011.
- Chair, Session 9: “Brain tumors and the immune system”, 2011 FASEB Summer Research Conference: “Translational Neuroimmunology: From Mechanisms to Therapeutics”, Carefree, Arizona, July 31-August 5, 2011.
- Chair, Symposium: “MicroRNA and siRNA Roles in Disease Progression and Development of Novel Therapeutic Targets”, American Society of Cell and Gene Therapy Annual Meeting, May 19-23, 2010.
- Co-Chair, Symposium: “Oral Session 235 – Immunologic & Host Responses in Gene & Cell Therapy, American Society of Cell and Gene Therapy Annual Meeting, Washington, DC, May 19-23, 2010.
- Chair, American Society of Gene and Cell Therapy Neural Disorders Gene Therapy Committee, June 2009 – June 2010.
- “Women of Action Award”, Israel Cancer Research Fund (ICRF) for achievements in the field of: Brain Cancer biology and therapeutics”, Beverly Hills, CA August, 2008.
- Visiting Professor, Wake Forest University School of Medicine, Comprehensive Cancer Center, Brain Tumor Center of Excellence, Winston-Salem, NC, December, 2007.
- The American Brain Tumor Association (ABTA) Mentoring Award to mentor a medical student in 2007 Medical Student Summer Fellowship Program to conduct basic brain tumor research: Recipient – Ms. Sharon Lee, Albany Medical College, Albany, NY.
- The Medallions Group Endowed Chair in Cancer Gene Therapeutics Research, Cedars-Sinai Medical Center, Los Angeles, California, USA, 2006.
- Best Keynote Speaker Award at 2nd International Symposium on CNS Germ Cell Tumors, “Gene therapy strategies of potential application to recurrent primary CNS Germ Cell Tumors, Universal City, CA USA, November 18-21, 2005.
- Biography included in “Who’s Who in American Education”, 2004-2005 6th Edition, outstanding achievements; “Who’s Who in Science and Engineering”, 2003-2004 7th Edition, latest achievements in genetics; “Who’s Who in The World”, 2003 20th Edition, most significant record of achievement; “Who’s Who in America”, 2003 57th Edition, country’s most accomplished women in the 21st century; “Who’s Who in Medicine and Healthcare, 2002-2003 4th Edition, Most Accomplished Healthcare and Medical Professionals Worldwide; “Who’s Who of American Women”, 2002 23rd Edition, Most Accomplished Women from the USA and Canada; Who’s Who” in Medicine and Healthcare, Who’s Who in Science and Engineering and Who’s Who in The World, 2001 Edition for significant record of achievement in the field of Molecular Medicine and Gene Therapy. Published by Marquis, USA.
- Biography included in “One Thousand Great Scientists”, published by International Biographical Centre, Cambridge, England. The bio appeared in the 2002 1st Edition containing a listing of prominent scientists worldwide.
- Biography included in “Dictionary of International Biography", 29th Edition, International Biographical Center, Cambridge CB2 3QP, 2001.
- Siebens Foundation Fellowship Award to attend and present work at The Harold W. Siebens Conference: Cytoreductive Gene Therapy. The Mayo Foundation, May 25th – 27th September, 1999, Rochester, Minnesota, USA, 1999.
- Prize for best basic science presentation: Outcomes of brain tumor gene therapy using conditional cytotoxicity: inflammation, white matter lesions, and transgene expression. Lowenstein, P.R., Morrissey, G., Stone, D., Southgate, T., Dewey, R., Mee, A., Bolognani, F. and Castro, M.G. 19th Annual Meeting of the British Neuro-oncology Group, 24th -25th June 1999, Edinburgh, Scotland, UK, 1999.
- The 'Prof. B Houssay Award' to the best PhD thesis: 'The physiology of ACTH and -MSH secretion in Aves', F. C.Iturriza, M. G. Castro and F. E. Estivariz, 1987.
- Fogarty International Fellowship Award: National Institutes of Health, Bethesda, MD, USA 1986-1989 (Post-Doctoral Award).
BSc Hons (1st Class) Chemistry, School of Biological Sciences, National University of La Plata, Argentina, 1979
M.Sc. - Biochemistry, School of Biological Sciences, National University of La Plata, 1981
M.Sc. - Education Technology, School of Biological Sciences, National University of La Plata, 1986
Ph.D. - Biochemistry, School of Biological Sciences, National University of La Plata, 1986
Institute for Endocrine Studies, School of Medicine, National University of Argentina at La Plata, 1983
Institute for Endocrine Studies, School of Medicine, National University of Argentina at La Plata, 1986
Fogarty International Visiting Research Fellow, Laboratory of Neurochemistry and Neuro-immunology, National Institute of Child Health and Human Development, National Institutes of Health, 1988
Laboratory of Molecular Endocrinology, Department of Biochemistry and Physiology, University of Reading, United Kingdom, 1990
- Candolfi M, Yagiz K, Wibowo M, Ahlzadeh GH, Puntel M, Kamran N, Paran C, Ghiasi H, Lowenstein PR, and Castro MG. (2013) Temozolomide does not impair gene therapy-mediated antitumor immunity in syngeneic brain tumor models. Clinical Cancer Research (accepted for publication pending minor revisions).
- MineharuY, Muhammad AG, Yagiz K, Candolfi M, Kroeger KM, Xiong W, Puntel M, Lui C, Levy E, Lugo C, Kocharian A, Allison J, Curran M, Lowenstein PR, and Castro MG. (2012) Gene therapy-mediated reprogramming tumor infiltrating T cells using IL-2 and inhibiting NF-kB signaling improves the efficacy of immunotherapy in a brain cancer model. Neurotherapeutics, 2012 October; 9(4):827-43. PMCID: PMC3480576.
- 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 April 30, 2012. PMCID: PMC3356634.
- Mineharu Y, King G, Muhammad AKM, Bannykh S, Kroeger K, Liu C, Lowenstein PR, Castro MG (2011) Engineering the brain tumor microenvironment enhances the efficacy of dendritic cells' vaccination: implications for clinical trials design. Clinical Cancer Research, 17(14), 4705-4718. Epub June 1, 2011. PMCID: PMC3205808.
- King GD, Muhammad AG, Larocque D, Kelson KR, Xiong W, Liu C, Sanderson NS, Kroeger KM, Castro MG, Lowenstein PR. (2011) Combined Flt3L/TK gene therapy induces immunological surveillance which mediates an immune response against a surrogate brain tumor neo-antigen. Molecular Therapy, 2011 Oct; 19(10):1793-801. Epub April 19, 2011. PMCID: PMC3188756.
- 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.
- Candolfi M, Xiong W, Yagiz K, Liu C, Muhammad AK, Puntel M, Foulad D, Zadmehr A, Ahlzadeh GE, Kroeger KM, Tesarfreund M, Lee S, Debinski W, Sareen D, Svendsen CN, Rodriguez R, Lowenstein PR, Castro MG. (2010) Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics. The Proceedings of the National Academy of Sciences, USA, 107(46):20021-20026. Epub Oct. 28, 2010. PMCID: PMC2993419.
- Candolfi M, Yagiz K, Foulad D, Ahlsadeh GE, Tesarfreund M, Muhammad AKM, Puntel M, Kroeger KM, Liu C, Lee S, Curtin J, King GD, Lerner J, Sato K, Mineharu Y, Xiong W, Lowenstein PR, Castro MG. (2009) Release of HMGB1 in response to pro-apoptotic glioma killing strategies: efficacy and neurotoxicity. Clinical Cancer Research 15(13):4401-4414. Portrayed on the highlights section of Cancer Research. PMCID: PMC2769255.
- Curtin JF, Liu N, Candolfi M, Xiong W, Assi H, Yagiz Y, Edwards MR, Michelsen KS, Kroeger KM, Liu C, Muhammad AKM, Clark MC, Arditi M, Comin-Anduix B, Ribas A, Lowenstein PR, Castro MG. (2009) HMGB1 mediates endogenous TLR2 activation and brain tumor regression. PLoS Medicine 6(1); e10. PMCID: PMC2621261.
- 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.
- 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
- 2011-2014 Gutless Adenovirus Mediated Gene Therapy for Glioma; Sponsor: NIH
- 2011-2014 Gutless Adenovirus Mediated Gene Therapy for Glioma S1: 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