Hallmark tumor metabolism becomes a validated therapeutic target

Pursuing alternative targets and repurposing drugs

Other metabolic targets that are being pursued include glutaminase, given the observation of significantly enhanced glutamine uptake in cancer cells. CB-839 is a glutaminase inhibitor that is currently being evaluated in phase 1 and 2 clinical trials. Updated clinical trial data from a phase 1 trial of CB-839 in combination with paclitaxel in patients with advanced/metastatic TNBC were presented at the San Antonio Breast Cancer Symposium last year.²⁶

As of October 2017, 49 patients had been treated with 400 mg, 600 mg, or 800 mg CB-839 twice daily in combination with 80 mg/m² intravenous paclitaxel weekly. Among the 44 patients evaluable for response, the rate of PR was 22% and of disease control, 59%. The one DLT was grade 3 neutropenia at the 400 mg dose. Overall AEs were mostly low grade and reversible.

In recent years, lactate has emerged as more than just a by-product of altered cancer cell metabolism. It is responsible, at least in part, for the highly acidic tumor microenvironment that fosters many of the other hallmarks of cancer. In addition, lactate promotes angiogenesis by upregulating HIF-1α in endothelial cells. Depriving tumor cells of the ability to export lactate is a potentially promising therapeutic strategy. An MCT-1 inhibitor, AZD3965, is being evaluated in early stage clinical trials.

Finally, several drugs that are renowned for their use in other disease settings are being repurposed for cancer therapy because of their potential effects on cancer cell metabolism. Ritonavir, an antiretroviral drug used in the treatment of HIV, is an inhibitor of GLUT-1 and is being evaluated in phase 1 and 2 clinical trials. Meanwhile, long-term studies of metformin, a drug that has revolutionized the treatment of diabetes, have revealed a reduction in the emergence of new cancers in diabetic patients treated who are treated with it, and the drug has been shown to improve breast cancer survival rates. Its precise anticancer effects are somewhat unclear, but it is thought to act in part by inhibiting oxidative phosphorylation. Numerous clinical trials of metformin in different types of cancer are ongoing.^27,2