Glutamine Antagonism and Its Utlity [sic] as a Therapeutic Modality in Cancer




Rosales, Tracy Ibarra

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Glutamine metabolism is important in cancer as it fuels the TCA cycle, plays a role in redox homeostasis, and contributes to the production of nucleotides, amino acids, and lipids for survival, making glutamine metabolism a promising target in cancer therapy. The work outlined in this dissertation focuses on understanding the mechanism of the broad glutamine metabolism inhibitor, 6-diazo-5-oxo-L-norleucine (DON) and its prodrug, JHU-083, while comparing them to the effects of CB-839, a specific glutaminase inhibitor. DON is one of the oldest and well-known glutamine antagonists and can effectively limit tumor growth in a preclinical setting. Unfortunately, DON was removed from early phase clinical trials due to unacceptable toxicity in the gastrointestinal tract (GI). Thus, DON prodrugs were recently developed to be inactive until cleaved by cathepsins enriched in the tumors or by plasma esterases, bypassing toxicity in the GI tract. Using isotope tracer studies in cancer cells and mouse xenograft models, I found that DON and JHU-083 mainly inhibit glutamine-derived nitrogen labeling in purines but unexpectedly does not limit the contribution of glutamine-derived carbon labeling of tricarboxylic acid (TCA) cycle metabolites. Additionally, I found that DON and JHU-083 can limit the levels of purines but not the levels of most TCA cycle metabolites. These findings suggest that these drugs are poor inhibitors of glutaminase in the cancer cell lines tested and that DON and JHU-083 mainly target purine metabolism. Recognizing DON and JHU-083 as effective purine metabolism inhibitors can offer insight into which cancer patients could benefit from these drugs. Relapsed small-cell lung cancer (SCLC) is characterized by an upregulation of de novo purine biosynthesis and have few durable therapies. Using metabolic tracing and untargeted metabolomics, I found that DON can inhibit purine metabolism in treatment-naïve and chemoresistant pairs of SCLC. In a mouse xenograft model of relapsed SCLC, JHU-083 induces a delay in tumor growth without overt side effects. My work provides an opportunity to explore JHU-083 as an anti-cancer therapy for diseases that depend on purine biosynthesis.

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