Colorectal cancer (CRC) is one of the leading causes of
cancer deaths worldwide. The initiation and progression of CRC is a multi-step process that proceeds via precursor lesions to
carcinoma, with each stage characterized by its distinct molecular and tissue microenvironment changes. Precursor lesions of CRC,
aberrant crypt foci, and
adenoma exhibit drastic changes in genetic, transcriptomic, and proteomic profiles compared to normal tissue. The identification of these changes is essential and provides further validation as an initiator or promoter of CRC and, more so, as lesion-specific druggable molecular targets for the precision
chemoprevention of CRC. Mutated/dysregulated signaling (
adenomatous polyposis coli, β-
catenin,
epidermal growth factor receptor, V-Ki-ras2 Kirsten rat
sarcoma viral oncogene homolog (KRAS),
tumor protein53, Akt, etc.), inflammatory (
cyclooxygenase-2, microsomal
prostaglandin E synthase-1,
inducible nitric oxide synthase, and other pro-inflammatory mediators), and metabolic/
growth factor (
fatty acid synthase, β-Hydroxy β-methylglutaryl-
CoA reductase, and
ornithine decarboxylase) related targets are some of the well-characterized molecular targets in the precision
chemoprevention of CRC. In this review, we discuss precursor-lesion specific targets of CRC and the current status of pre-clinical studies regarding clinical interventions and combinations for better efficacy and safety toward future precision clinical
chemoprevention. In addition, we provide a brief discussion on the usefulness of secondary precision chemopreventive targets for tertiary precision
chemoprevention to improve the disease-free and overall survival of advanced stage CRC patients.