胃癌PDX模型中对Wnt/β-catenin凝聚物调节剂DPTX3186反应的基因组决定因素及其临床开发意义

DPTX3186 is a first-in-class small molecule oral condensate modulator (c-mod) designed to disrupt oncogenic wnt/beta-catenin signaling in tumors selectively. DPTX3186 forces beta-catenin to concentrate within an inactive condensate inside tumor cells, resulting in malignant cell death in vitro and robust single-agent anti-tumor activity in wnt-driven tumor models in vivo . DPTX3186 has an open IND, has been granted Orphan Drug and Fast Track Designations, and is being tested in a combined Phase 1/2 trial focused on gastric cancer. To assess the therapeutic potential of DPTX3186 across gastric cancer and identify biomarkers predictive of high response, we tested DPTX3186 in a diverse panel of well-characterized gastric cancer patient-derived xenograft (PDX) models. Mice implanted with PDX-based tumors were treated with either DPTX3186 or vehicle, with tumor volume and body weight measured for up to 70 days following treatment initiation. Across models, treatment with DPTX3186 resulted in a statistically significant decrease in tumor volume growth, including stasis and regression (as measured by tumor growth inhibition, TGI), and a statistically significant increase in survival, without affecting body weight. Each of the PDX models implanted were characterized in terms of the patients' clinical, genomic, and transcriptomic profiles, enabling analysis of biomarkers that were predictive of increased TGI or survival when comparing DPTX3186 treated mice to vehicle mice. Through these analyses, we identify prevalent and clinically actionable genomic characteristics that predict an increased response to DPTX3186. Specifically, mutations in oncogenes that are associated with greater beta-catenin activity confer greater response to DPTX3186, reinforcing the specificity of the condensate mechanism for wnt-driven tumors. These results demonstrate the promising therapeutic potential of DPTX3186 in gastric cancer, outline our patient selection strategy for the ongoing clinical trial, and provide a roadmap for the clinical selection of high responders to condensate-modulating anti-cancer agents.