Faculty, Staff and Student Publications
Publication Date
1-17-2025
Journal
Clinical Cancer Research
Abstract
Purpose: Biliary tract cancers, which are rare and aggressive malignancies, are rich in clinically actionable molecular alterations. A major challenge in the field is the paucity of clinically relevant biliary tract cancer models that recapitulate the diverse molecular profiles of these tumors. The purpose of this study was to curate a collection of patient-derived xenograft (PDX) models that reflect the spectrum of genomic alterations present in biliary tract cancers to create a resource for modeling precision oncology.
Experimental design: PDXs were derived from biliary tract cancer samples collected from surgical resections or metastatic biopsies. Alterations present in the PDXs were identified by whole-exome sequencing and RNA sequencing. PDXs were treated with approved and investigational agents. Efficacy was assessed by change in tumor volume from baseline. Event-free survival was defined as the time to tumor doubling from baseline. Responses were categorized at day 21: >30% decrease in tumor volume = partial response, >20% increase in tumor volume = progressive disease, and any non-partial response/progressive disease was considered stable disease.
Results: Genomic sequencing demonstrated key actionable alterations across this cohort, including alterations in FGFR2, isocitrate dehydrogenase I, ERRB2, PIK3CA, PTEN, and KRAS. RNA sequencing demonstrated fusions and expression of antibody-drug conjugate targets, including TROP2, HER2, and Nectin4. Therapeutic matching revealed objective responses to approved and investigational agents that have been shown to have antitumor activity clinically.
Conclusions: In this study, we developed a catalog of biliary tract cancer PDXs that underwent comprehensive molecular profiling and therapeutic modeling. To date, this is one of the largest collections of biliary tract cancer PDX models and will facilitate the development of personalized treatments for patients with these aggressive malignancies.
Keywords
Humans, Biliary Tract Neoplasms, Precision Medicine, Animals, Xenograft Model Antitumor Assays, Mice, Biomarkers, Tumor, Exome Sequencing, Disease Models, Animal, Female, Male, Mutation
DOI
10.1158/1078-0432.CCR-24-1233
PMID
39513959
PMCID
PMC11739782
PubMedCentral® Posted Date
11-8-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons