Mioara Larion, Ph.D.

Mioara Larion, Ph.D.
Investigator

Our research focuses on understanding the metabolic signatures of glioblastomas in comparison with normal cells in order to exploit them for therapeutic applications. We are particularly interested in IDH-mutated glioblastoma and our goal is to characterize these tumors using in vitro and in vivo metabolomics.

Areas of Expertise
1) metabolomics, 2) nuclear magnetic resonance, 3) mass spectrometry, 4) hyperpolarized MRI

Contact Info

Mioara Larion, Ph.D.
Center for Cancer Research
National Cancer Institute
Building 37, Roon 1136A
Bethesda, MD 20892
Ph: 240-760-6825
Fax: 240-541-4466
mioara.larion@nih.gov

Glioblastoma multiforme (GBMs) is the most common and aggressive brain tumor.  Despite years of research and clinical trials, the median survival remains about 14.6 months, underlying an urgent need for better treatment.  Although profiling of mutations, gene and protein expressions have contributed significantly to the understanding of tumor biology, little is known about the metabolic signatures of different GBM types.  Metabolomics report on the set of metabolites present within a cell, tissue or organism by identifying and quantifying the steady state cellular metabolites.  Since metabolic reprograming is emerging as a hallmark of cancer, a detailed characterization of patient’s tumor metabolic state together with the results of other omics has the potential to provide a better understanding of tumorigenesis.  Metabolomics can also be used as a cancer diagnosis tool since specific metabolic signatures correlate with different glioblastoma subtypes therefore helping in the  characterization of tumor stage, type or prognosis.  Most importantly a comprehensive analysis of differentially expressed metabolites between normal and cancer cells offers avenues towards identification of potential pathways to be targeted for therapeutics.

My laboratory is focused on understanding the metabolic changes in brain tumors such as GBMs.  In particular, we are interested in revealing the metabolic alterations of isocitrate dehydrogenase (IDH1)-mutated GBMs and in exploiting these deregulations for therapeutic applications.  We will identify and quantify metabolic changes in GBMs using mass spectrometry and nuclear magnetic resonance (MRI) spectroscopy-based metabolomics.  In addition, using specific isotope labeling and 13C-hyperpolarized MRI, we will track metabolic fluxes in the pursuit of the following goals: 1) Describe the metabolic flux in patients with glioblastoma containing or not an IDH mutation. 2) Identify and quantify novel metabolic changes in urine, blood, cerebrospinal fluid and brain tissue of patients with GBMs. 3) Produce patient-derived xenographs in mice for further metabolomics characterization. 4) Identify and quantify novel metabolic changes in patient-derived GBM cells expressing endogenous or exogenous IDH mutations.

Another area of my laboratory is to discover and develop novel therapeutics for glioblastoma patients with IDH mutation.  Variants of IDH are identified in more than 80% of glioblastomas (GBMs), more than 20% of acute myeloid leukemias (AMLs), neurometabolic disorders and other types of cancers.  Although specific inhibitors of D-2HG formation by variant-IDH have been identified, they targeted a single variant of IDH, potentially limiting their use in treating the many other variant-IDH-associated tumors.  Cancer-associated somatic mutations in IDH lead to accumulation of D-2HG (up to 30 mM), which is normally kept at low concentrations (~10 μM) in healthy cells by the housekeeping enzyme D-2Hydrohyglutarate dehydrogenase (D-2HGDH).  D-2HG inhibits -keto dependent dioxygenases, which are involved in epigenetic modulation of gene expression.  Deregulating of these epigenetic controls is thought to lead to tumorigenesis.  We are interested in discovering new       ways to decrease D-2HG concentration in vivo via it’s recycling to -ketoglutarate. Our aim is to screen and characterize activators of D-2HGDH using a combination of biophysical techniques.

Scientific Focus Areas:
Cancer Biology, Molecular Biology and Biochemistry, Neuroscience, Structural Biology

Selected Publications

  1. The Role of Intrinsically Disordered Regions of GCK to It’s Kinetic Cooperativity Effect.
    Larion M, Miller B, and Brüschweiler R.
    Intrinsically Disordered Proteins. 3: 1-4, 2015. [ Journal Article ]
  2. Whittington AC, Larion M, Bowler JM, Ramsey KM, Brüschweiler R, and Miller BG.
    Proc Natl Acad Sci U S A. 112(37): 11553-8, 2015. [ Journal Article ]
  3. Larion M, Hansen AL, Zhang F, Bruschweiler-Li L, Tugarinov V, Miller BG, and Brüschweiler R.
    Angew Chem Int Ed Engl. 54(28): 8129-32, 2015. [ Journal Article ]
  4. Larion M, Salinas RK, Bruschweiler-Li L, Miller BG, and Brüschweiler R.
    PLoS Biol. 10(12): e1001452, 2012. [ Journal Article ]
  5. Larion M, Salinas RK, Bruschweiler-Li L, Brüschweiler R, and Miller BG.
    Biochemistry. 49(37): 7969-71, 2010. [ Journal Article ]

Dr. Mioara Larion received her B.Sc. in Biochemistry from Cuza University, Lasi, Romania in 2002.  She moved to Florida State University where she received a M.Sc. in Biophysics in 2005 working on saturation transfer electron paramagnetic resonance methods and their sensitivity to molecular motion upon increasing the field.  In 2009, Dr. Larion received her Ph.D. in Biochemistry working on divergent evolution of function in bacterial kinases and the origin of kinetic cooperativity in human pancreatic glucokinase in the laboratory of Prof. Brian Miller.  After obtaining her Ph.D in 2009, she was awarded the AHA postdoctoral fellowship to work with Prof. Rafael Brüschweiler on biophysical characterization of glucokinase and PHHI-like variants.  Her work helped understand the mechanism of glucokinase’s activation for design of better anti-diabetic therapeutics.  Her major interest is in metabolomics of brain tumors.

Name Position
Alejandra Cavazos Saldana Postbaccalaureate Fellow
Tyrone M. Dowdy Laboratory Technician (Contr)
Adrian Lita Ph.D. Research Fellow
Victor Ruiz Rodado Ph.D. Postdoctoral Fellow (Visiting)