CB-839 has the potential to be an important new therapeutic agent with a novel mechanism of action for the treatment of a broad range of cancers.
Genetically mandated alterations in the fundamental metabolic pathways of tumors often cause a dramatic rise in the uptake of the nutrients glucose and glutamine. Removal of glutamine leads to a substantial reduction in cell growth or induces cell death in certain types of cancer cells, indicating that these cells are dependent on, or “addicted” to, glutamine. Normal cells do not show this pronounced dependence on glutamine. The enzyme glutaminase, which converts glutamine to glutamate, has been identified as a critical choke point in the utilization of glutamine by cancer cells. CB-839 is a potent, selective, reversible and orally bioavailable inhibitor of human glutaminase.
Inhibition of glutaminase also results in accumulation of glutamine in tumors. Glutamine, which is frequently depleted in the tumor microenvironment due to uptake by tumor cells, has been shown to be an important nutrient for T-cell growth. CB-839 could potentially have an impact on the treatment of cancer by first starving the tumor cell, and second facilitating the activation of T-cells in the nutrient-deprived tumor microenvironment.
In preclinical studies, CB-839 has been shown to halt the growth of or kill cancer cells across a range of tumor types. The compound has demonstrated antitumor activity in several different tumor models in animals. In preclinical toxicology studies, CB-839 was well tolerated in animals at doses above those shown to inhibit tumor growth. CB-839 has also shown strong synergy with immunomodulatory agents and several kinase inhibitors that target growth factor pathways.
Calithera’s clinical program seeks to identify cancers that will be most sensitive to CB-839 to allow the greatest benefit for patients and to pursue the most efficient path to regulatory approval. Based on our preclinical data, we believe several specific tumor types will be sensitive to glutaminase inhibition and benefit from treatment with CB-839.
Calithera is currently conducting multiple Phase 1b combination trials of CB-839 in solid tumors. CB-839 administered as a single agent has resulted in clinical responses in renal cell cancer and acute myeloid leukemia and clinical benefit in several other tumor types. Calithera is currently enrolling patients in a series of combination Phase 1b cohorts in specific solid tumor types of CB-839 in combination with standard therapies and immune-oncology agents. Phase 2 trials in renal cell carcinoma and triple negative breast cancer are planned to begin in 2017.
Results of Calithera’s preclinical and clinical studies of CB-839 have been presented at several scientific conferences and these data may be viewed on our Publications page.