Colorectal cancer is the second leading cause of cancer-related deaths worldwide and stands as the third most diagnosed cancer. Patients with advanced colorectal cancer present very poor survival rate at 5 years (5-15%), largely due to resistance to current treatment options and secondary effects linked to treatment toxicity. The development of optimized drug combinations could decrease treatment resistance and secondary effects. In this study, we have assessed the efficacy of four optimized combination treatments of low-dose drugs, previously developed in the lab, on a 3D organoid co-culture model, harboring mutations associated with an advanced colorectal cancer. Our results showed that the four optimized drug combinations reduce cell metabolic activity of organoids alone and in coculture with tumor associated endothelial cells, as well as exhibit anti-angiogenic activity in vitro.