(UroToday.com) In the Top Abstracts session of the 2021 International Kidney Cancer Symposium (IKCS): North America meeting, Dr. Kaushik presented work examining the role of glutamine metabolism in clear cell renal cell carcinoma (ccRCC).
Dr. Kaushik began by emphasizing that metabolic is a hallmark of cancer, driven by mutations in oncogenes and tumor suppressors which lead to tumor growth and cancer progression. In the context of renal cell carcinoma, VHL loss leads to an increase in glycolysis and decrease in oxidative phosphorylation (termed the Warburg effect) which leads to ccRCC.
The most convincing evidence for the biologic importance of this process comes from human infusion studies in which radiolabelled glucose, through the Warburg effect, leads to lactate production. Patient-derived xenographs can be used to identify fuel source for TCA cycle. These studies have identified that the majority of renal cell carcinomas incorporate carbon from glutamine and have a high associated glutamine metabolism. Thus, targeting of glutaminase (with CB-839) can allow insights into the underlying metabolism of these tumors. Notably, the investigators observed a generally cytostatic, rather that cytocidal, effect.
However, the majority of tumors have variable response and glutaminase appears to be dispensable in ccRCC, hypothesized to be due to other metabolic processes, particularly with differing fuel sources feeding the TCA cycle. Given the amidotransferases which may act on purines, pyrimidines, hexosamine biosynthesis, the NAD cycle, and asparagine to feed the TCA cycle, targeting of these enzymes with JHU-083 may allow a novel approach. Treatment with JHU-083 decreases glutamine metabolism and suppresses tumor growth.
Upon treatment with CB-839 with suppression of glutamine metabolism, ccRCC tumors fuel the TCA using aspartate. Thus, co-targeting of both glutamine and aspartate metabolism is likely necessary, with concomitant targeting of
both carbon and nitrogen pathways.
