Sean Krivitsky ‘27

Figure 1. Visualization of the mitochondria

Unbeknownst to many, the mitochondria plays a significant role in carcinogenesis given the importance of metabolic processes in the formation and maintenance of tumors. CPI-613, more commonly known as devimistat, is a recently developed drug that targets a key metabolic cycle that takes place in the mitochondria of cancer cells, the tricarboxylic acid (TCA) cycle. The TCA cycle is key to many metabolic pathways in the cell, which allows it to not only reduce the effectiveness of catabolic processes in cancer cells, but also to degrade some of the drug-resistant properties held by cancer cells. However, stores of the lipids in some cancer cells prevent devimistat from effectively combating the cancer cells because they bypass the need for the TCA cycle.

Recent research published at the lab of Dr. Paul M. Bingham and conducted by Moises O. Guardado Rivas here at Stony Brook University sought to find an approach that would improve devimistat’s efficiency by targeting the ability of those cancer cells to use their lipid stores for devimistat resistance. These researchers sought to test approaches to improve devimistat efficiency in carcinoma by testing drug response through in vitro cell-based and tumor growth inhibition assays, as well as through steady state metabolomic analysis. First, they were able to confirm the importance of lipids for devimistat resistance by demonstrating increased sensitivity to the drug over longer periods of nutrient depletion. Second, by also demonstrating contributions to the electron transport chain (ETC) made by lipid stores in carcinoma cells, the group was able to ultimately demonstrate an approach to circumventing devimistat resistance during carcinoma treatment. That is, devimistat sensitivity can be achieved by combining devimistat treatment with a clinical approach of potentially applying different fatty acid catabolism inhibitors, such as etomoxir and thioridazine. However, given flaws identified with the non-FDA approved inhibitor etomoxir and promising results supporting the ability of thioridazine in fully resistant tumor xenografts, thioridazine was identified as the more promising inhibitor. 

Ultimately, this research’s overall results point to the importance of developing different clinical approaches to targeting ETC electron flow to improve devimistat efficiency. Their research identifies some inhibitors, such as thioridazine, as potential therapeutics to contribute to inducing devimistat sensitivity in carcinoma cells and further suggests more promising inhibitors to be tested. These results are incredibly important because cancer cell resistance is a prolific issue that limits the efficacy of current treatments.

Works Cited

[1] Guardado Rivas, M. O., Stuart, S. D., Thach, D., Dahan, M., Shorr, R., Zachar, Z., & Bingham, P. M. (2022). Evidence for a novel, effective approach to targeting carcinoma catabolism exploiting the first-in-class, anti-cancer mitochondrial drug, CPI-613. PLOS ONE, 17(6), e0269620. https://doi.org/10.1371/journal.pone.0269620

‌[2] Image retrieved from: https://ndla.no/nn/subject:1:83ce68bc-19c9-4f2b-8dba-caf401428f21/topic:1:1c0aeb24-1a5a-4464-8f27-30fd0472f635/topic:1:0b73bd6e-da2f-47f1-a456-74b4062d9964/resource:be88f5d3-bff8-4c5d-b7b2-73cf33df3fee