Executive Summary : | Colorectal cancer is the third most commonly diagnosed malignancy and the second leading cause of cancer deaths globally. The standard treatment paradigm includes surgery, radiation, chemotherapy, and targeted therapies, but these often lead to drug resistance and relapse. To target quiescent cancer stem cells, cytodifferentiation therapeutic approaches like Retinoic differentiation therapy have been employed. The success of ATRA in APL has led researchers to harness the therapeutic potential of ATRA in solid tumors, either as a single drug or adjuvant along with chemotherapy. In colorectal cancer, the APC mutation accounts for about 80% and alters key genes of the RA signaling pathway. This leads to decreased ability to enzymatically synthesize ATRA by inhibiting RDH expression and enhanced degradation of ATRA via overexpression of CYP26A1. Retinoid-based treatment is ineffective in APC-mutant colorectal tissues due to lower intracellular ATRA levels activating RA signaling. Various synthetic retinoids, ATRA analogues, RAMBAs, RAR agonists, and antagonists have been developed to increase intracellular levels of ATRA and prevent its metabolism. Talarazole, a potent inhibitor of CYP26A1, has been under clinical trials but discontinued due to its inefficacy.
Bioconjugation chemistry has been employed to rationally design bifunctionalized retinamides to improve differentiation therapy in colorectal cancer. The coupling of carboxylate esters of ATRA and amino compounds of RAMBA in forming retinamides presents a promising avenue for developing novel anticancer drugs with enhanced therapeutic potential and minimal side effects. |