A new study published in Genes & Disease reports on Mar. 30 that researchers have identified a potential precision treatment for colorectal cancer by targeting a genetic vulnerability present in the majority of cases.
Colorectal cancer is the fourth leading cause of cancer death worldwide, and more than 60% of cases involve mutations in the adenomatous polyposis coli (APC) gene. Despite its prevalence, APC has been difficult to target directly with therapies. The research team from Nanjing Normal University focused instead on finding another gene whose inhibition would be especially harmful to cells already lacking APC function, while sparing normal cells.
Through bioinformatics screening across synthetic lethality databases, the scientists identified aldehyde dehydrogenase 2 (ALDH2) as a partner gene. ALDH2 helps neutralize toxic aldehydes and manage reactive oxygen species (ROS), which are unstable molecules that can trigger cell death if present in excess. The study found that colorectal cancer cells deficient in APC already experience high oxidative stress and elevated ROS levels.
The team used disulfiram, a compound known to block ALDH2's activity, to further increase ROS levels in these vulnerable cells. This led to activation of cell death pathways specifically in APC-deficient tumor cells but not in those with intact APC genes. Laboratory experiments showed reduced proliferation and increased apoptosis among treated tumor cells, especially when copper ions were added alongside disulfiram to enhance its effect. Animal models confirmed that this combination significantly reduced tumor size only in tumors lacking functional APC.
The findings suggest disulfiram could be repurposed as a precision oncology agent for patients with specific genetic profiles. Since testing for APC mutations is already part of standard colorectal cancer diagnosis, identifying eligible patients would not require new procedures. However, the authors said clinical trials are necessary before this approach can be used with patients due to differences between animal models and human responses.
