By Julia Chivu, Class of 2024
Figure 3 Woman ingesting a pill.
A new drug has been developed to target the metabolism of cancer. Associate Professor Paul M. Bingham and Research Assistant Professor Zuzana Zachar from Stony Brook University developed a unique class of anticancer drugs–including the first-in-class and FDA-approved drug CPI-613. A first-in-class drug produces new treatment options or outcomes by exploring an unprecedented mechanism of action. CPI-613, also referred to as devimistat, was designed to better understand the mitochondrial tricarboxylic acid (TCA) cycle metabolism, which is responsible for energy production and transfer, found in carcinoma cells.
CPI-613 treatment on four different carcinoma lines resulted in an increase in transported glucose from the growth medium to the affected cells. This homeostatic response occurs because it is difficult for ATP production to properly occur in the TCA cycle when glycolytic resources cannot be broken down. Therefore, CPI-613 inhibits the regulation of energy production in tumor cells. While it was found that this anticancer drug can block off energy-generating pathways, some energy pathways are resistant to the actions of the drug. In particular, the fatty acid beta-oxidation pathway was found to avoid the TCA cycle and lead electrons straight into the electron transport chain. These electrons are supplied from lipids which are broken down by peroxisomes and transported to the mitochondria. Consequently, the electrons found in the lipids contribute to carcinoma CPI-613 resistance.
As a result of the findings of the preclinical study and previous information about the drug, CPI-613 is currently being tested in a clinical trial. In addition, the drug may be able to effectively treat cancer when combined with other drugs. For instance, thioridazine and crizotinib are candidates that could potentially be combined with CPI-613 to better target the difficulties associated with the energy fatty acid pathway. The unique functions of the candidates are able to target parts of the peroxisome-to-mitochondria pathway that CPI-613 has difficulty treating on its own.
 M. Guardado Rivas, et al., Evidence for a novel, effective approach to targeting carcinoma catabolism exploiting the first-in-class, anti-cancer mitochondrial drug, cpi-613. PLoS ONE 17, 1-30 (2022). doi: 10.1371/journal.pone.0269620.
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