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Updated: Oct 7, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Patient-derived xenograft models capture genomic heterogeneity in endometrial cancer
Vanessa F Bonazzi1,2, Olga Kondrashova3, Deborah Smith4,5,6
1School of Biomedical Sciences, Queensland University of Technology located at the Translational Research Institute, Brisbane, QLD, Australia.
Background:
Endometrial cancer (EC) is a major gynecological cancer with increasing incidence. It comprises four molecular subtypes with differing etiology, prognoses, and responses to chemotherapy. In the future, clinical trials testing new single agents or combination therapies will be targeted to the molecular subtype most likely to respond. As pre-clinical models that faithfully represent the molecular subtypes of EC are urgently needed, we sought to develop and characterize a panel of novel EC patient-derived xenograft (PDX) models.
Methods:
Here, we report whole exome or whole genome sequencing of 11 PDX models and their matched primary tumor. Analysis of multiple PDX lineages and passages was performed to study tumor heterogeneity across lineages and/or passages. Based on recent reports of frequent defects in the homologous recombination (HR) pathway in EC, we assessed mutational signatures and HR deficiency scores and correlated these with in vivo responses to the PARP inhibitor (PARPi) talazoparib in six PDXs representing the copy number high/p53-mutant and mismatch-repair deficient molecular subtypes of EC.
Results:
PDX models were successfully generated from grade 2/3 tumors, including three uterine carcinosarcomas. The models showed similar histomorphology to the primary tumors and represented all four molecular subtypes of EC, including five mismatch-repair deficient models. The different PDX lineages showed a wide range of inter-tumor and intra-tumor heterogeneity. However, for most PDX models, one arm recapitulated the molecular landscape of the primary tumor without major genomic drift. An in vivo response to talazoparib was detected in four copy number high models. Two models (carcinosarcomas) showed a response consistent with stable disease and two models (one copy number high serous EC and another carcinosarcoma) showed significant tumor growth inhibition, albeit one consistent with progressive disease; however, all lacked the HR deficiency genomic signature.
Conclusions:
EC PDX models represent the four molecular subtypes of disease and can capture intra-tumor heterogeneity of the original primary tumor. PDXs of the copy number high molecular subtype showed sensitivity to PARPi; however, deeper and more durable responses will likely require combination of PARPi with other agents.
Insights
New endometrial cancer (EC) patient-derived xenograft (PDX) models represent all four molecular subtypes. These models show sensitivity to PARP inhibitors (PARPi), suggesting potential for targeted therapies in EC treatment.
Area of Science:
- Gynecologic Oncology
- Cancer Genomics
- Translational Research
Background:
- Endometrial cancer (EC) is a significant gynecological malignancy with rising incidence.
- EC exhibits four distinct molecular subtypes, each with unique characteristics affecting prognosis and treatment response.
- Accurate preclinical models are crucial for developing targeted therapies for specific EC subtypes.
Purpose of the Study:
- To develop and characterize novel patient-derived xenograft (PDX) models of endometrial cancer.
- To ensure these PDX models accurately represent the molecular diversity of EC.
- To assess the utility of these models in evaluating targeted therapies, specifically PARP inhibitors (PARPi).
Main Methods:
- Whole exome or whole genome sequencing of 11 EC PDX models and matched primary tumors.
- Analysis of tumor heterogeneity across different PDX lineages and passages.
- Assessment of homologous recombination (HR) deficiency and in vivo response to talazoparib (PARPi) in selected PDX models.
Main Results:
- Successful generation of PDX models from grade 2/3 EC tumors, including carcinosarcomas, representing all four molecular subtypes.
- PDX models largely recapitulated the molecular landscape of primary tumors with manageable genomic drift.
- Four copy-number-high PDX models demonstrated in vivo sensitivity to talazoparib, indicating potential for PARPi efficacy.
Conclusions:
- Developed EC PDX models effectively represent the four molecular subtypes and capture intra-tumor heterogeneity.
- Copy-number-high EC PDX models show sensitivity to PARP inhibitors.
- Combination therapies involving PARPi may be necessary for deeper and more durable responses in endometrial cancer.
