OMB No. 0925-0001 and 0925-0002 (Rev. 09/17 Approved Through 03/31/2020)

NAME:  MAHER, Elizabeth A

eRA COMMONS USER NAME (credential, e.g., agency login):  EMAHER

POSITION TITLE:  Associate Professor

EDUCATION/TRAINING

A. Personal Statement

The focus of my research is translational imaging and metabolism related to brain tumors. The fundamental concept driving my research is that the model systems we use to study biological mechanisms is likely to be most clinically translatable when using patient tumors in vivo or mouse models that retain as much patient-specific relevance as possible.  My training as a neuro-oncologist, former medical director of neuro-oncology and current Director of the Brain Tumor Imaging and Metabolism Group at UT Southwestern, gives me a unique perspective on the clinical problem and access to the technology and expertise that is necessary for defining the metabolic machinery that drives these aggressive tumors in the brain. As a physician-scientist at UT Southwestern Medical Center, seeing patients and developing clinical trials in addition to running a translational research program in glioma, I have established outstanding collaborations with a wide range of surgeons, basic scientists and translational scientists.

B. Positions and Honors

Positions and Employment

1988-1989     Post-Doctoral Fellow, University of Medicine and Dentistry, New Jersey

1993-1994     Intern (Internal Medicine), The Toronto Hospital, Toronto, Ontario

1994-1996     Resident (Internal Medicine), The Toronto Hospital, Toronto, Ontario

1996-1999     Clinical Fellow, Dana-Farber Cancer Institute, Department of Adult Oncology, Boston, MA

1997-1998     Research Fellow, Children's Hospital, Department of Neurology, Boston, MA

1998-1999     Research Fellow, Dana-Farber Cancer Institute, Department of Adult Oncology, Boston, MA

1998-1999     Clinical Fellow, Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston

1999-2005     Instructor in Medicine, Harvard Medical School, Center for Neuro-Oncology, Dana-Farber Cancer Institute. Boston, MA

1. 2008. Assistant Professor of Medicine and Neurology, UT Southwestern Medical Center, Dallas, TX

2008-present  Associate Professor of Medicine and Neurology, UT Southwestern Medical Center, Dallas, TX

2009-2013     Medical Director of the Neuro-Oncology Program, UT Southwestern Medical Center, Dallas

2012-present  Director, Chrystal Charity Ball Center for Pediatric Brain and Neurological Diseases, UT Southwestern Medical Center, Dallas, TX

2013-present  Director of Translational Research, Neuro-Oncology Program, UT Southwestern Medical

                       Center, Dallas, TX

Honors and Awards:

1993               Prize in Medical Ethics and Jurisprudence, McGill University Faculty of Medicine

1993               Williams Prize in Medicine and Clinical Medicine, McGill University Faculty of Medicine

1994               Sopman Humanitarian Award, The Toronto Hospital

2001               V Foundation Basic-Clinical Research Award (Co-Principal Investigator)

2004               Goldhirsh Foundation Brain Tumor Research Award – 3 yr (Principal Investigator)

2009               NIH Challenge Grant (PI) 2 year

C. Contribution to Science

1. 1. Insights into brain tumor metabolism through patient studies in vivo. Starting with an NIH Challenge Grant in 2009, on which I was the PI, I have been developing/applying new methods in intermediary metabolism to the study of brain tumor metabolism in patients. Based on the premise that we needed to examine tumor tissue in its native microenvironment in order to get a better understanding of the metabolic pathways driving tumor growth, I wrote a translational protocol to enable us to study patients going to the operating room for brain tumor resection. To date, 100 patients have been enrolled and infused with ¹³C-glucose or ¹³C-acetate during the 2 - 2 1/2 hours leading up to tumor resection. We have modified the protocol to now include any age patient (includes pediatrics) and all tumor types (brain and non-CNS). This has been highly successful and provided exciting insights into brain metabolism including the demonstration that glucose and acetate are oxidized in the citric acid cycle of primary brain tumors and brain metastases. These patient studies have dovetailed with studies in human orthotopic tumor models in glioblastoma and brain metastases, which were developed in collaboration with Dr. Robert Bachoo. Mechanistic studies related to substrate utilization have helped to further the understanding of brain tumor bioenergetics.

1. 1. Marin-Valencia I, Yang C, Mashimo T, Cho S, Baek H, Yang XL, Rajagopalan KN, Maddie M, Vemireddy V, Zhao Z, Cai L, Good L, Tu BP, Hatanpaa KJ, Mickey BE, Matés JM, Pascual JM, Maher EA, Malloy CR, Deberardinis RJ, Bachoo RM. Analysis of tumor metabolism reveals mitochondrial glucose oxidation in genetically diverse human glioblastomas in the mouse brain in vivo. Cell Metab. 2012 Jun 6; 15(6):827-37. PubMed PMID: 22682223; PubMed Central PMCID: PMC3372870.
   2. Marin-Valencia I, Cho SK, Rakheja D, Hatanpaa KJ, Kapur P, Mashimo T, Jindal A, Vemireddy V, Good LB, Raisanen J, Sun X, Mickey B, Choi C, Takahashi M, Togao O, Pascual JM, Deberardinis RJ, Maher EA, Malloy CR, Bachoo RM. Glucose metabolism via the pentose phosphate pathway, glycolysis and Krebs cycle in an orthotopic mouse model of human brain tumors. NMR Biomed. 2012 Oct; 25(10):1177-86. PubMed PMID: 22383401; PubMed Central PMCID: PMC3670098.
   3. Maher EA, Marin-Valencia I, Bachoo RM, Mashimo T, Raisanen J, Hatanpaa KJ, Jindal A, Jeffrey FM, Choi C, Madden C, Mathews D, Pascual JM, Mickey BE, Malloy CR, DeBerardinis RJ. Metabolism of [U-13 C]glucose in human brain tumors in vivo. NMR Biomed. 2012 Nov; 25(11):1234-44. PubMed PMID: 22419606; PubMed Central PMCID: PMC3406255.
   4. Mashimo T, Pichumani K, Vemireddy V, Hatanpaa KJ, Singh DK, Sirasanagandla S, Nannepaga S, Piccirillo SG, Kovacs Z, Foong C, Huang Z, Barnett S, Mickey BE, DeBerardinis RJ, Tu BP, Maher EA, Bachoo RM. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell. 2014 Dec 18;159(7):1603-14. PubMed PMID: 25525878; PubMed Central PMCID: PMC4374602.
2. Brain tumor imaging and the development of 2Hydroxyglutarate (2HG) MR spectroscopy in patients with IDH-mutant gliomas. Patients with IDH-mutant tumors produce high levels of the oncometabolite, 2HG. Approximately 75% of WHO grade II and III gliomas and secondary glioblastomas are IDH mutated. Recognizing the potential for development of 2HG as a biomarker for the IDH-mutant gliomas, I collaborated with physicists and MR spectroscopists in the Advanced Imaging Research Center at UT Southwestern Medical Center to develop the method for detection of 2HG in clinical patients. Our method was published in Nature Medicine in 2012 as a technical report. It is the first non-invasive imaging biomarker of a genetic mutation to be developed. Since then, we have completed a longitudinal study of 136 patients from my clinical practice who have IDH mutations and demonstrated that 2HG is an excellent biomarker and tumor marker. The paper describing this work was published in Journal Clinical Oncology and establishes the technique for clinical practice.  The method has been adopted by major brain tumor centers internationally and we are working to make the methodology available on MR scanners for routine use in clinical practice. This work has led to additional studies of brain tumors and we are currently working on several metabolites that have the potential to be important biomarkers.
   1. Choi C, Ganji SK, DeBerardinis RJ, Hatanpaa KJ, Rakheja D, Kovacs Z, Yang XL, Mashimo T, Raisanen JM, Marin-Valencia I, Pascual JM, Madden CJ, Mickey BE, Malloy CR, Bachoo RM, Maher EA. 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nature Medicine 2012 Jan 26;18(4):624-9. PubMed PMID: 22281806; PubMed Central PMCID: PMC3615719.
   2. Choi C, Ganji S, Hulsey K, Madan A, Kovacs Z, Dimitrov I, Zhang S, Pichumani K, Mendelsohn D, Mickey B, Malloy C, Bachoo R, Deberardinis R, Maher E. A comparative study of short- and long-TE ¹H MRS at 3 T for in vivo detection of 2-hydroxyglutarate in brain tumors. NMR Biomed. 2013 Oct;26(10):1242-50. PubMed PMID: 23592268; PubMed Central PMCID: PMC3733061.
   3. Choi C, Ganji SK, Madan A, Hulsey KM, An Z, Zhang S, Pinho MC, DeBerardinis RJ, Bachoo RM, Maher EA. In vivo detection of citrate in brain tumors by 1H magnetic resonance spectroscopy at 3T. Magn Reson Med. 2014 Aug;72(2):316-23. PubMed PMID: 24123337; PubMed Central PMCID: PMC4236907.
   4. Choi C, Raisanen JM, Ganji SK, Zhong S, McNeil SS, An Z, Madan A, Hatanpaa KJ, Vemireddy V, Sheppard CA, Oliver D, Hulsey KM, Tiwari V, Mashimo T, Battiste J, Barnett S, Madden CJ, Patel TV, Pan E, Malloy CR, Mickey BE, Bachoo RM, Maher EA.  Prospective longitudinal analysis of 2-hydroxyglutarate magnetic resonance spectroscopy identifies broad clinical utility for the management of patients with IDH-mutant glioma.  Journal of Clinical Oncology 2016 34(33):4030-4039 PubMed PMID:  28248126;  PubMed Central PMCID: PMC5477829
3. Brain Metastasis. I have a long interest in brain metastases from the perspective of a clinical neuro-oncologist and an investigator studying primary and metastatic brain tumors. I am the lead author on the White Paper generated from The Biology of Brain Metastasis Workshop (held in Bethesda, MD, Jan 30 – Feb 1, 2008). For the past several years I have been working with our multidisciplinary group of experts in intermediary metabolism looking at substrate utilization in brain metastases from the most common subgroups (breast, lung, renal cell, and melanoma). I have taken the lead on developing human orthotopic brain metastases tumor models and, to date, we have generated and characterized 30 tumor models that were generated from individual patients, passaged intracranially, and never cultured. These models have been validated molecularly and metabolically to be very similar to the patient that they were each derived from. In addition to providing a new resource for studying brain metastasis, these models provide the first ever orthotopic model for preclinical testing of new drugs for brain metastases. We are planning to make them available to the scientific community in the near future.
   1. Maher EA, Mietz J, Arteaga CL, DePinho RA, Mohla S. Brain metastasis: opportunities in basic and translational research. Cancer Res. 2009 Aug 1;69(15):6015-20. PubMed PMID: 19638593.
   2. Marin-Valencia I, Cho SK, Rakheja D, Hatanpaa KJ, Kapur P, Mashimo T, Jindal A, Vemireddy V, Good LB, Raisanen J, Sun X, Mickey B, Choi C, Takahashi M, Togao O, Pascual JM, Deberardinis RJ, Maher EA, Malloy CR, Bachoo RM. Glucose metabolism via the pentose phosphate pathway, glycolysis and Krebs cycle in an orthotopic mouse model of human brain tumors. NMR Biomed. 2012 Oct;25(10):1177-86. PubMed PMID: 22383401; PubMed Central PMCID: PMC3670098.
   3. Mashimo T, Pichumani K, Vemireddy V, Hatanpaa KJ, Singh DK, Sirasanagandla S, Nannepaga S, Piccirillo SG, Kovacs Z, Foong C, Huang Z, Barnett S, Mickey BE, DeBerardinis RJ, Tu BP, Maher EA, Bachoo RM. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell. 2014 Dec 18;159(7):1603-14. PubMed PMID: 25525878; PubMed Central PMCID: PMC4374602.

D. Additional Information:  Research Support and/or Scholastic Performance

RP180634  (Bachoo)                                                                                                                                                                          03/01/18 – 2/28/21                       

Cancer Prevention & Research Institute of Texas                 

Understanding metabolic regulation of pediatric glioma through mouse modeling and patient tumor interrogation in vivo.

Project Goal: To determine the metabolic phenotype, bioenergetic substrates and metabolic pathways that underlie pediatric glioma growth and invasion.

2R01CA154843-A1   (Maher)                                                                                                                                               04/01/18 - 3/31/23

NIH-NCI

Understanding the role of IDH in malignant gliomas

Project Goal:  To understand the differences in metabolic pathways that drive IDH mutant and IDH WT gliomas with respect to the transition from low to high grade disease and response to targeted inhibition of IDH.

Kleberg Foundation    (Maher)                                                                                                                                              07/01/17 – 6/30/20                             

Matching IDH driver status to treatment timing in glioma

Project Goal:  To determine whether the IDH mutant enzyme is a driver in low grade gliomas in stable phase.

1 R01 CA 184584-01(Choi)                                                                                                                                                   09/01/14-08/31/19                                          

NIH-NCI                                                       

Clinical development of cancer-specific MRS biomarkers in malignant gliomas

Major Goal: To examine the disease specification of 2HG in vivo.

AG120-C-002 (Maher)                                                                                                                                                                       04/08/14-4/4/24                       

Novella Clinical (Agios Pharmaceuticals      

Phase 1 Study of Orally Admin AG-120 in Subjects with Advanced Solid Tumors, including Glioma, with an IDH1 Mutation

Major Goal: To determine the safe dose of AG-120 in patients with IDH1 mutant tumors.

AG221-C-003 (Maher)                                                                                                                                                                       01/29/15-01/29/20                                

Novella Clinical (Agios Pharmaceuticals)                             

Phase 1/2 Dose Escalation Study of AG-221 in Subjects with Advanced Solid Tumors and with Angioimmunoblastic T-cell Lymphoma that Harbor an IDH2 Mutation

AG881-C-002 (Maher)                                                                                                                                                                       04/08/14-4/4/24                       

Novella Clinical (Agios Pharmaceuticals)                                                     

A Phase 1, Multicenter, Open-Label, Dose-Escalation and Expansion, Safety, Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of Orally Administered AG-881 in Patients with Advanced Solid Tumors, Including Gliomas, with an IDH1 and/or IDH2

AG221-C-003 (Maher)                                                                                                                                                                       01/29/15-01/29/20           

Novella Clinical                                             

Phase 1/2 Dose Escalation Study of AG-221 in Subjects with Advanced Solid Tumors and with Angioimmunoblastic T-cell Lymphoma that Harbor an IDH2 Mutation

Major Goal: To determine the safe dose of AG-221 in patients with an IDH2 mutation

Completed Research Support

5R01CA154843-04 (Maher)                                                                                                                                                  04/01/15-03/31/17      

NIH-NCI                                                       

Defining Metabolic Phenotype of Low Grade Gliomas in Vivo

Major Goal: To define the metabolic phenotype of low grade gliomas using infused ¹³C-glucose and ¹³C-NMR.

RP130629-01(Maher)                                                                                    06/01/13-05/31/17

Cancer Prevention and Research Institute of Texas (CPRIT)                                                           

Genotype and metabolic phenotype in pediatric brain cancer

Major Goal:  Identify major metabolic pathways which support pediatric brain tumor growth.

RP130629-02  (Maher)                                                                                                                                                                       06/01/13-50/31/17                                               

Cancer Prevention & Research Institute of Texas     

Genotype and Metabolic Phenotype in Pediatric Brain Tumors

RC 1NS070675 (Maher)                                                                                                                                                                     09/30/09-08/31/11

NIH-NINDS

NIH Challenge Grant                                                                                                                                     

Genetic and Metabolic Phenotype in Glioma