Saroj P. Mathupala
Saroj P. Mathupala, Ph.D.
4100, John R. Road
Tumor Bioenergetics and Metabolism
Metabolic Targeting of Tumors
Metabolite-mimetics as Small Molecule Drug Candidates
Highly malignant tumors harbor unique biochemical signatures that distinguish them from the surrounding healthy tissues. In many instances, these tumors switch their metabolic isozyme profile to that of fetal tissues, resulting in changes to metabolic flux across the tumor, while gain-of-function mutations enable the enzymes to alter the metabolite profile both within the tumor and in the tumor microenvironment.
Foremost among metabolic signatures is the tumor's propensity to extract excessive quantities of glucose from blood and convert it into lactic acid. This deviant metabolic behavior is known as the "Warburg Effect," named after its discoverer (Otto Warburg, 1930). In general, the more malignant the tumor, the greater is its capacity for this abnormal metabolism. It is the principle that is harnessed during PET (Positron-Emission Tomography) imaging of malignant tumors with radiolabeled glucose analogs.
Thus, this trait of malignant tumors to produce copious amounts of lactic acid can be investigated for use as an "Achilles' Heel" to target and destroy the tumor (while leaving the surrounding healthy tissue intact) - the long-term objective of our research group. We are currently exploring the potential of using this as a therapeutic tool against the most malignant of brain tumors, glioblastoma multiforme (GBM).
We are pursuing four main pre-clinical research projects, each geared towards the development of molecular therapeutics against GBMs, or the design of sensitive assays for detection or diagnosis of GBMs.
To survive, these malignant tumors need to efflux the lactic acid to the tumor microenvironment, a function facilitated by a family of membrane transporters denoted monocarboxylate transporters (MCTs). One of our goals is to identify the factors that up-regulate these MCT genes in GBMs. The second goal is to identify the metabolites that enable the GBMs to invade the surrounding normal brain tissue in a rapid and diffuse manner. Thirdly, we test small-molecule analogs of metabolite precursors for their ability to block lactic acid efflux. Another goal is to develop highly sensitive fluorescence based cellular assays for rapid detection and grading of tumors, based on their metabolite signatures.
Caruso JP, Koch BJ, Benson PD, Varughese E, Monterey MD, Lee AE, Dave AM, Kiousis S, Sloan AE, Mathupala SP. pH, Lactate, and Hypoxia: Reciprocity in Regulating High-Affinity Monocarboxylate Transporter Expression in Glioblastoma. Neoplasia. 2017;19:121-34.
Mathupala SP, Kiousis S, Szerlip NJ. A Lab Assembled Microcontroller-Based Sensor Module for Continuous Oxygen Measurement in Portable Hypoxia Chambers. PLoS One. 2016;11:e0148923.
Monterey MD, Szerlip NJ, Mathupala SP. Low-cost media formulation for culture of brain tumor spheroids (neurospheres). Biotechniques. 2013;55:83-8.
Colen CB, Shen Y, Ghoddoussi F, Yu P, Francis TB, Koch BJ, Monterey MD, Galloway MP, Sloan AE, Mathupala SP. Metabolic targeting of lactate efflux by malignant glioma inhibits invasiveness and induces necrosis: an in vivo study. Neoplasia. 2011;13:620-32.
Mathupala SP. Metabolic targeting of malignant tumors: small-molecule inhibitors of bioenergetic flux. Recent Pat Anticancer Drug Discov. 20116:6-14. Review.
Education and Training:
1984 B.Sc., Chemistry, University of Colombo, Sri Lanka
1992 Ph.D., Biochemistry and Molecular Biology, Michigan State University, E. Lansing, Michigan
1993-1998 Postdoctoral Fellow, Tumor Bioenergetics and Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland
Cancer Biology Courses Taught:
CB7240 Principles of Cancer Therapy
CB7460 Mechanism of Neoplasia: Alterations to Cellular Signaling
CB7700 Recent Developments in Cancer Biology
Link to Departmental web page: http://neurosurgery.med.wayne.edu/mathupala_research.php