Utilizing Patient-Derived Xenografts to Model Precision Oncology for Biliary Tract Cancer
Timothy P DiPeri1, Kurt W Evans2, Stephen Scott2
1Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
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.
Insights
Researchers developed a new collection of patient-derived xenograft models for biliary tract cancers. These models reflect diverse genomic alterations, aiding precision oncology and personalized treatment development for this rare cancer.
Area of Science:
- Oncology
- Genomics
- Translational Research
Background:
- Biliary tract cancers are rare, aggressive malignancies with actionable molecular alterations.
- A significant challenge is the lack of relevant models for studying these diverse tumors.
Purpose of the Study:
- To create a comprehensive collection of patient-derived xenograft (PDX) models for biliary tract cancers.
- To establish a resource for precision oncology by reflecting the spectrum of genomic alterations.
Main Methods:
- PDX models were established from patient samples (surgical resections or biopsies).
- Whole-exome and RNA sequencing were used for molecular profiling.
- PDX models were treated with targeted agents to assess therapeutic efficacy.
Main Results:
- Identified key actionable genomic alterations (FGFR2, IDH1, ERBB2, PIK3CA, PTEN, KRAS) and fusions/expression of ADC targets (TROP2, HER2, Nectin4).
- Demonstrated objective responses to approved and investigational agents in therapeutic matching studies.
Conclusions:
- Developed a catalog of molecularly profiled biliary tract cancer PDX models.
- This collection represents a significant resource for advancing personalized treatments for biliary tract cancers.
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