Synthetic Lethal Drug Combinations Targeting Stem Cells in the Evolution of Esophageal Adenocarcinoma
Introduction
Esophageal adenocarcinoma (EAC) is a highly lethal cancer that arises from a 20-year evolution of precursor lesions that in retrograde order include high-grade dysplasia (HGD), low-grade dysplasia (LGD), and "Barrett's esophagus (BE)." An estimated seven million Americans have the relatively indolent BE lesion which typically do not progress; those that do progress to LGD are at high risk to advance to HGD and EAC.
Methods
To clarify the molecular basis of this evolutionary process to EAC, we applied stem cell cloning technology that efficiently captures stem cells of the normal GI tract to patient-matched endoscopic biopsies of EAC, HGD, LGD, and BE. Remarkably, this technology identifies rare (1:1,000 lesional cells) stem cells for each of these lesions, the genomics of which define their phylogenic relationships and the evolution of an epithelial cancer at unprecedented resolution.
Results
These stem cells recapitulate the respective lesions in vitro and in xenograft models, and only the EAC stem cells yield tumors in immunodeficient mice. High-throughput screening efforts to identify leads targeting BE stem cells failed to yield single agents with sufficient selectivity versus normal esophageal stem cells. However, a synthetic lethal strategy has identified a lead combination that eliminated BE stem cells with a three-orders of magnitude safety profile towards stem cells of normal esophageal, gastrointestinal, and hepatic mucosa. Unexpectedly, this same drug combination showed similar nanomolar lethality against stem cells of LGD, HGD, and EAC, hinting that the target is common to these pathogenic stem cells.
Conclusion
Novel drug combinations targeting rare stem cells of esophageal adenocarcinoma and its precursor lesions show potent and durable effects against EAC tumors in immunodeficient mice. These novel drugs show similar and sub-nanomolar effects against stem cells of pancreatic ductal adenocarcinoma and paclitaxel-resistant high-grade serous ovarian cancers in vitro and as xenografts in mice, suggesting the intriguing potential of targeting common features of cancer stem cell future patient care.