School of Medicine

Wayne State University School of Medicine

Glioma Bioenergetics Research: Saroj Mathupala, PhD

Saroj P. Mathupala, PhD
Principal Investigator

Assistant Professor, Neuro-Oncology
Department of Neurosurgery
Wayne State University School of Medicine

Assistant Professor, Neuro-Oncology
Karmanos Cancer Institute

E-mail: smathupala@med.wayne.edu
Phone: (313) 576-8352
Fax:      (313) 576-8306

 

Education and Training

  • BSc. (Hon.), Chemistry, University of Colombo, Sri Lanka
  • PhD, Biochemistry and Molecular Biology, Michigan State University, E. Lansing, Michigan (Advisor, Prof. J. Greg Zeikus)
  • Postdoctoral Fellow, Tumor Bioenergetics & Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland (Advisor, Prof. Peter L. Pedersen)

Research Interests
Malignant brain tumors are usually detected during late stages of their progression - and they are heterogeneous – carrying many genetic mutations that enable them to withstand most clinical interventions including chemotherapy and radiotherapy. However, these highly aggressive tumors harbor several deviant biochemical features that are absent in the surrounding healthy brain tissue. Foremost is the tumor’s propensity to engross excessive amounts of glucose from blood and metabolize it into lactic acid. In general, the more aggressive the tumor, the greater is its capacity for producing lactic acid.

This trait exposes a potential vulnerability in tumors that can be targeted, to destroy the tumor while leaving the surrounding healthy brain tissue intact - the long-term objective of our research group. We are currently exploring the potential of using this as a therapeutic tool against glioblastoma multiforme (GBMs), the most malignant of brain tumors.
 
We have used RNA interference techniques and small molecule inhibitors to target the plasma membrane proteins responsible for transport of lactic acid from tumors. In pre-clinical studies, we grew human brain tumors in brains of immunodeficient (nude) rats and then applied test drugs that inhibit lactic acid efflux via miniature pumps to show that we can selectively kill the tumors without harming healthy brain tissue. We also showed that such tumors become 10-fold more radiosensitive due to disruption of metabolic pathways crucial for tumors to protect themselves against radiation damage. The studies have now been extended to a clinical trial to treat canine glioma, with the aim of translating the findings to a human clinical trial.

A: Day 01 - human brain tumor cells are implanted in nude rat brain

B: Day 14 - a cannula is placed in the growing brain tumor and connected to a miniature osmotic pump primed with a test drug that inhibits lactic acid efflux. The pump is placed under the skin between shoulder blades and will work for just 28 days and pump drug into the tumor at 0.25 microliters per hour.

C: Day 56 - complete necrosis of the tumor – pump has shut down 14 days before, but tumor has not regrown. The empty cavity is filled with CSF (cerebrospinal fluid).

D: Day 120 – No regrowth of the tumor. Animal survives.

E: The growth of an untreated tumor 20 days after implanting tumor.
 

Ref: Colen et al. (2011), Neoplasia 13: 620-632
 

Current and future research will involve both proteomic and metabolomic approaches using 3D brain tumor spheroid cultures and orthotopic nude rat human brain tumor models to identify additional metabolic targets in brain tumors, and to further enhance the efficacy of our previous findings. 


Former and Current Students
The projects are undertaken by both neurosurgery residents (as partial fulfillment of their Ph.D. requirements), and by research associates, medical students/graduate students and undergraduates. 

Neurosurgery Residents:    
Richard Rhiew, MD PhD 2002-2004
Chaim Colen, MD PhD 2003-2005
Todd Francis, MD PhD 2006-2010
     
Medical Students:    
Praveen Sateesh Yr. III Medical Student 2002 Summer
Chantel Njiwaji Yr. III Medical Student 2004 Summer
Andrew Lozen Yr. IV Medical Student 2008 Summer
Charles Kraftchak Yr. IV Medical Student 2008 Summer
Amy Buth Yr. I MD/PhD Student 2008-2011
Ajal Dave Yr. IV Medical Student  
     
Research Associates & Graduate Students:    
Pingyang Yu, MD Research Associate 2002-2006
Akannsha Singh, MBBS Graduate Student 2005-2007
Philip Benson, MS Research Assistant 2008-2009
Michael Monterey,BS Research Assistant 2009-2012
     
Undergraduate Students:    
Noah Heilbrun Kalamazoo College 2000 & 2002 Summers
Scott Gallagher University of Michigan 2001 Summer
Khari Wilson Grambling State University 2003 Summer
Sharon Lu Yale University 2003 & 2004 Summers
Brandon Koch Rollins College 2005-2009 Summers
Mouli Mandalaparty Wayne State University 2009 Summer
James Caruso University of Michigan 2009-2013
Bhavika Chepuri Wayne State University 2009-2012
Elsa Varughese Wayne State University 2009-2012
Jane Harness University of Michigan 2011 Summer
Alexandra Chrumka Stanford University 2012 Summer
Bridget Reno Wanye State University 2012-
     
Collaborators:    
Dr. Andrew E. Sloan, Associate Professor, Department of Neurological Surgery, Case Western Reserve University Medical School, Cleveland, Ohio.
Dr. Sandeep Mittal, Assistant Professor, Department of Neurosurgery, and Chief, Neuro-oncology, Karmanos Cancer Institute, Wayne State University School of Medicine.
Dr. Nicholas Szerlip, Assistant Professor, Department of Neurosurgery, Wayne State University School of Medicine, Karmanos Cancer Institute.
     
Research Funding:    
American Cancer Society (IRG) 2000-2002
LEARN Foundation, Michigan 2002-2006
National Cancer Institute/National Institutes of Health (R01) 2006-2013
Fund for Medical Research and Education (FMRE), Wayne State University School of Medicine 2004-2006
2013-2014
Marvin E. Klein, MD, Charitable Trust 2005-2014