Network-guided Therapeutics to Differentiate Colorectal Cancer Stem Cells.

The curative potential of differentiation therapy has been recognized in hematologic malignancies, but not in solid tumors. Using colorectal cancers (CRCs) as an example, here we outline an unbiased network-based approach to track, differentiate and selectively target cancer stem cells (CSCs). A transcriptomic network is built with the intention to identify therapeutic perturbations that can reinstate the expression of CDX2, a transcription factor whose loss identifies poorly differentiated (CSC-enriched) CRCs, and whose reinstatement is predicted to reduce the risk of death/relapse by 50%. The top candidate target, when engaged with a clinical-grade drug, predictably shifts the network, induces CDX2 and crypt differentiation and shows cytotoxicity with a surprising degree of selectivity towards CDX2-negative models (CRC cell lines, xenotransplants in mice, and patient-derived organoids; PDOs). Potential for effective pairing of therapeutic efficacy (IC50) and biomarker (CDX2-low state) is confirmed in PDOs using multivariate analyses. A 50-gene signature of therapeutic response shows that CDX2-reinstatement therapy is expected to translate into a ~50% reduction in the risk of mortality/recurrence. We conclude that CDX2-reinstatement selectively triggers differentiation and death of colorectal CSCs, and in doing so, this network-guided approach identifies a first-in-class differentiation therapy agent in solid tumors.