A research team announced on Apr. 6 a new therapeutic approach for colorectal cancer that targets a genetic vulnerability found in most patients. The study focuses on the adenomatous polyposis coli (APC) gene, which is mutated in about 60% to 85% of colorectal cancer cases.
This development is significant because restoring APC function directly with drugs has proven difficult. Instead, the researchers used a synthetic lethal strategy to find genes that, when inhibited, would kill only cells lacking the APC gene while sparing healthy ones.
Through bioinformatics and laboratory tests, the enzyme aldehyde dehydrogenase 2 (ALDH2) was identified as a promising target. The team found that disulfiram—a medication already approved for treating alcoholism—can inhibit ALDH2 and reduce the growth of APC-deficient cancer cells without harming normal cells. "The findings reveal that the ALDH2 inhibitor disulfiram, a drug traditionally used to treat alcoholism, significantly reduces the proliferation of APC-deficient cancer cells while sparing healthy cells with wild-type APC," according to the researchers.
Mechanistically, loss of APC leads to higher levels of reactive oxygen species inside tumor cells. Inhibiting ALDH2 causes even more buildup of these molecules, activating pathways that result in programmed cell death or apoptosis. Laboratory experiments showed that disulfiram treatment caused cancer cells to stop dividing and led to slower tumor growth in animal models. Adding small amounts of copper ions further increased this anti-tumor effect.
These results point toward personalized medicine approaches for gastrointestinal cancers by using APC deficiency as a biomarker for selecting patients who might benefit from ALDH2 inhibition therapy. Because disulfiram is already an approved drug, this strategy could offer a faster and less expensive way to develop new treatments if future clinical trials confirm its safety and effectiveness.
