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Updated: Oct 4, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Defining and Targeting Esophagogastric Cancer Genomic Subsets With Patient-Derived Xenografts
Ryan H Moy1,2,3, Henry S Walch4, Marissa Mattar5
1Department of Medicine, Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY.
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.
Insights
Researchers created patient-derived xenografts (PDXs) to study esophagogastric cancer. These models help test new therapies for specific molecular subtypes, especially in treatment-resistant cases.
Area of Science:
- Oncology
- Genetics
- Translational Research
Background:
- Comprehensive genomic profiling has identified oncogenic drivers and molecular subtypes in esophagogastric cancer.
- The number of clinically actionable alterations remains limited, necessitating better preclinical models.
Purpose of the Study:
- To generate and characterize a large collection of esophagogastric cancer patient-derived xenografts (PDXs).
- To establish preclinical models for testing genomically driven therapeutic strategies.
Main Methods:
- Established a biobank of 98 esophagogastric cancer PDX models from primary tumors and metastases.
- Annotated clinicopathologic features and performed targeted sequencing on PDX and parent tumor pairs.
- Conducted xenograft trials in genomically defined models with identified oncogenic drivers.
Main Results:
- Successfully established 98 PDX models (35.5% engraftment rate) from 276 patient tumors.
- Collection is enriched for human epidermal growth factor receptor 2-positive (HER2+) models (63%), many refractory to trastuzumab.
- Identified predominant oncogenic drivers including TP53 mutations, ERBB2/EGFR alterations, RAS/PI3K pathway genes, CDKN2A/CCNE1, and CDH1.
- Observed antitumor activity with combination strategies in models from treatment-refractory disease.
Conclusions:
- The PDX collection recapitulates esophagogastric cancer heterogeneity.
- This resource aids in investigating tumor progression mechanisms and identifying predictive biomarkers.
- Enables development of therapeutic strategies for molecularly defined esophagogastric cancer subsets.
