Defining and Targeting Esophagogastric Cancer Genomic Subsets With Patient-Derived Xenografts

Abstract

PURPOSE Comprehensive genomic profiling has defined key oncogenic drivers and distinct molecular subtypes in esophagogastric cancer; however, the number of clinically actionable alterations remains limited. To establish preclinical models for testing genomically driven therapeutic strategies, we generated and characterized a large collection of esophagogastric cancer patient–derived xenografts (PDXs). MATERIALS AND METHODS We established a biobank of 98 esophagogastric cancer PDX models derived from primary tumors and metastases. Clinicopathologic features of each PDX and the corresponding patient sample were annotated, including stage at diagnosis, treatment history, histology, and biomarker profile. To identify oncogenic DNA alterations, we analyzed and compared targeted sequencing performed on PDX and parent tumor pairs. We conducted xenotrials in genomically defined models with oncogenic drivers. RESULTS From April 2010 to June 2019, we implanted 276 patient tumors, of which 98 successfully engrafted (35.5%). This collection is enriched for PDXs derived from patients with human epidermal growth factor receptor 2–positive esophagogastric adenocarcinoma (62 models, 63%), the majority of which were refractory to standard therapies including trastuzumab. Factors positively correlating with engraftment included advanced stage, metastatic origin, intestinal-type histology, and human epidermal growth factor receptor 2–positivity. Mutations in TP53 and alterations in receptor tyrosine kinases ( ERBB2 and EGFR), RAS/PI3K pathway genes, cell-cycle mediators ( CDKN2A and CCNE1), and CDH1 were the predominant oncogenic drivers, recapitulating clinical tumor sequencing. We observed antitumor activity with rational combination strategies in models established from treatment-refractory disease. CONCLUSION The Memorial Sloan Kettering Cancer Center PDX collection recapitulates the heterogeneity of esophagogastric cancer and is a powerful resource to investigate mechanisms driving tumor progression, identify predictive biomarkers, and develop therapeutic strategies for molecularly defined subsets of esophagogastric cancer.

Patient-derived xenograft models in cancer therapy: technologies and applications

“… 118 (59%) N/A N/A Duodenal cancers (N/A) 25 (86%) Biliary ductal cancers (N/A) 17 (35%) Kawashima et al 245 Acute myeloid leukemia (M0-M6, AML with MRC, tAML from MPN) 105 (66%) N/A Lower event-free survival rate and poor responses to chemotherapy. Moy et al 246 Esophagogastric cancer (diffuse, mixed, intestinal) 98 (N/A) Metastases, stage IV disease, HER2 expression, intestinal subtype N/A Jung et al 28 Lung squamous cell carcinoma (N/A) 82 (59%) Tumor engraftment failure was correlated with the preoperative chemotherapy initiation. Poor overall survival or relapse free survival.…”

Patient-derived tumor models: a suitable tool for preclinical studies on esophageal cancer

“…A biobank or biobank of PDX tumor models is required for the systematic application of PDX models in drug development. Researchers have recently established a library of PDX models containing EC and gastric cancer and annotated the clinical characteristics of each PDX model and their corresponding patient samples, thus providing an invaluable resource for exploring the tumor biology and genomic targets of EC [55].…”

Promising preclinical patient-derived organoid (PDO) and xenograft (PDX) models in upper gastrointestinal cancers: progress and challenges

“…Notably, PDXs had become a successful tool for drug discovery in GC cancer. Ryan et al constructed a comprehensive PDX collection of gastroesophageal cancer, including 46 (47%) GC adenocarcinomas, 25 gastroesophageal junction adenocarcinomas (26%), 21 oesophageal adenocarcinomas (32%), and three squamous cell carcinomas (3%), and then evaluated the antitumour activity of rational combination strategies [59]. Song et al established patient-derived cell lines with peritoneal carcinomatosis, transformed them into orthotopic mouse models, identified major expression and activation traits, and then recapitulated the molecular and phenotypical features of donors [60].…”