Related Experiment Video
Updated: Sep 22, 2025
Spectrophotometric Screening for Potential Inhibitors of Cytosolic Glutathione S-Transferases
Published on: October 10, 2020
Glutaminase inhibition in renal cell carcinoma therapy
Aleksandra M Raczka1,2, Paul A Reynolds1,2
1School of Medicine, University of St Andrews, St Andrews KY16 9TF, UK.
Abstract:
Receptor tyrosine kinase inhibitors have been a standard first-line therapy for renal cell carcinoma (RCC) for over a decade. Although they stabilize the disease, they are unable to remove all tumor cells, leading to relapse. Moreover, both intrinsic and acquired resistance to therapy are a significant health burden. In order to overcome resistance, several combination therapies have been recently approved by the FDA. Another approach takes advantage of altered metabolism in tumor cells, which switch to alternative metabolic pathways to sustain their rapid growth and proliferation. CB-839 is a small molecule inhibitor of kidney type glutaminase (GLS). GLS is often upregulated in glutamine addicted cancers, enhancing glutamine metabolism for the production of energy and the biosynthesis of various cellular building blocks. CB-839 is currently in clinical trials for several tumors, including clear cell (cc)RCC, both as monotherapy and in combination with the approved therapeutic agents everolimus, cabozantinib and nivolumab. Early results of Phase 1/2 clinical trials look promising, especially for CB-839 plus cabozantinib, and all combinations seem to be well tolerated. However, cancer cells can activate compensatory pathways to overcome glutaminolysis inhibition. Therefore, genetic and metabolomic studies are crucial for the successful implementation of CB-839 alone or in combination in subgroups of ccRCC patients.
Insights
Receptor tyrosine kinase inhibitors stabilize but do not cure renal cell carcinoma (RCC). Targeting cancer cell metabolism with CB-839, a glutaminase inhibitor, shows promise in clinical trials, especially in combination therapies.
Area of Science:
- Oncology
- Cancer Metabolism
- Pharmacology
Background:
- Receptor tyrosine kinase inhibitors are standard first-line therapy for renal cell carcinoma (RCC) but lead to relapse due to resistance.
- Tumor cells alter metabolism to sustain growth, presenting a therapeutic vulnerability.
- Intrinsic and acquired resistance to current RCC therapies pose a significant health burden.
Purpose of the Study:
- To investigate the efficacy of CB-839, a glutaminase inhibitor, in treating renal cell carcinoma (RCC).
- To evaluate CB-839 as monotherapy and in combination with existing RCC treatments.
- To explore novel therapeutic strategies for overcoming resistance in clear cell RCC (ccRCC).
Main Methods:
- Clinical trials (Phase 1/2) of CB-839 in various tumor types, including clear cell RCC (ccRCC).
- Combination therapy studies involving CB-839 with everolimus, cabozantinib, and nivolumab.
- Investigating the role of glutamine metabolism and glutaminase (GLS) inhibition in cancer.
Main Results:
- Early clinical trial results for CB-839, particularly in combination with cabozantinib, are promising for ccRCC.
- All evaluated combinations of CB-839 with approved agents were well-tolerated.
- CB-839 targets upregulated glutamine metabolism in "glutamine-addicted" cancer cells.
Conclusions:
- CB-839 demonstrates potential as a therapeutic agent for ccRCC, both alone and in combination therapies.
- Further research, including genetic and metabolomic studies, is needed to identify patient subgroups who will benefit most from CB-839.
- Understanding compensatory pathways is crucial for optimizing glutaminase inhibition strategies in ccRCC.
More Related Videos
11:27Modeling Spontaneous Metastatic Renal Cell Carcinoma mRCC in Mice Following Nephrectomy
Published on: April 29, 2014
06:51Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
Published on: July 21, 2018
