Abstract 2670: Drug combinations against Barrett's stem cells show efficacy across advanced lesions in esophageal cancer

Abstract We have applied a single cell cloning technology to patient-matched endoscopic biopsies of Barrett's esophagus and co-existing lesions of low-grade dysplasia (LGD), high-grade dysplasia (HGD), and esophageal adenocarcinoma (EAC). In vitro differentiation and xenografting of these clones yields epithelia with histology corresponding to the origin of these clones, and the EAC clones yield aggressive tumors in vivo. In addition, genomic analyses of these clones reveals their phylogenetic relationships based on common and accumulating mutations. In efforts to identify drugs that would target the Barrett's stem cells for preemptive therapeutics, we performed parallel screens of small molecule libraries against Barrett's stem cells and patient-matched normal esophageal stem cells. Synthetic lethal strategies ultimately yielded drug combinations that showed low nanomolar efficacy against Barrett's stem cells that spared normal esophageal stem cells even at micromolar concentrations. The synthesis of new compositions of matter corresponding to these leads has identified powerful analogs that not only selectively eliminate stem cells of Barrett's esophagus but show similar efficacy in vitro against stem cells of LGD, HGD, and EAC. In vitro, these drug combinations show broad efficacy against Barrett's and EAC, with nanomolar elimination of 20 of 23 Barrett's cases and 6 of 7 EAC cases. In tumors derived from xenografting EAC clones, these new drug combinations show robust activity marked by tumor shrinkage and a profound loss of tumor cell clonogenicity. We foresee the potential of these synthetic lethal drug combination both as topical delivery for premetastatic lesions in the distal esophagus and perhaps as systemic applications for advanced EAC cases. Citation Format: Wa Xian, Jennifer Lin, Mona Oraei, Frank McKeon, Shan Wang, Jaffer Ajani, Christopher Crum, William Bachovchin, Melina Khorrami, Amber Su, Melika Khorrami, Shumei Song, Jeremy Siegelman, Matt Vincent, Khek Yu Ho, Yusuke Yamamoto. Drug combinations against Barrett's stem cells show efficacy across advanced lesions in esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2670.