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Integrated Patient-Derived Xenograft and Patient-Derived Cell Models Reveal Therapeutic Vulnerabilities Beyond
Abstract:
Endometrial cancer (EC), the most common gynecologic malignancy in the USA, has seen limited improvement in patient outcomes over recent decades, underscoring the need for relevant preclinical models. To address EC heterogeneity, we established an integrated platform of patient-derived xenografts (PDXs) and matched patient-derived primary cancer cells (PDCs) for disease modeling and systematic drug sensitivity testing. Fresh tumor specimens (n=103) were collected from EC patients to generate PDXs in immunodeficient mice and corresponding PDCs. Fifty-three PDX models were successfully established (52% engraftment rate), with higher success observed in high-grade, recurrent, metastatic tumors (70%), compared with their low-grade counterparts (56%). Histopathologic and immunohistochemical analyses confirmed that PDX tumors faithfully preserved morphology, hormone receptor status, and intertumoral heterogeneity across multiple passages. Using 13 PDC models, we performed an unbiased screening of 179 FDA-approved oncology drugs, revealing marked intertumoral variability in drug response. Almost all PDC models exhibited limited sensitivity to NCCN-recommended therapies, highlighting the need for alternative treatment strategies. In contrast, multiple FDA-approved agents including epigenetic modulators, dual PI3-kinase/HDAC inhibitors, topoisomerase II inhibitors, and proteasome inhibitors demonstrated potent antitumor activity. Importantly, a low-dose combination of the DNA methyltransferase inhibitor 5-azacytidine and the histone deacetylase inhibitor romidepsin significantly suppressed tumor growth across six independent PDX models. Together, these findings establish a comprehensive PDX and PDC platform as a robust translational resource. By capturing the histopathologic and molecular diversity of EC and identifying clinically actionable therapeutic advantages, including an epigenetic combination regimen, this study offers a translational resource for preclinical drug evaluation.
Insights
Researchers developed patient-derived xenografts and cells to model endometrial cancer (EC) heterogeneity. This platform identified novel drug sensitivities, including an effective epigenetic combination therapy, offering a new preclinical resource for EC treatment.
Area of Science:
- Oncology
- Translational Research
- Cancer Modeling
Background:
- Endometrial cancer (EC) is the most common gynecologic malignancy in the USA.
- Limited progress in patient outcomes necessitates improved preclinical models that capture EC heterogeneity.
- Existing models often fail to represent the diverse nature of EC.
Purpose of the Study:
- To establish an integrated platform of patient-derived xenografts (PDXs) and patient-derived primary cancer cells (PDCs) for endometrial cancer.
- To perform systematic drug sensitivity testing using this platform.
- To identify novel therapeutic strategies for endometrial cancer.
Main Methods:
- Collected 103 fresh endometrial cancer tumor specimens.
- Generated 53 PDX models in immunodeficient mice and matched PDCs.
- Performed histopathologic and immunohistochemical analyses to validate PDX fidelity.
- Conducted unbiased screening of 179 FDA-approved oncology drugs on 13 PDC models.
- Tested a combination regimen of 5-azacytidine and romidepsin on six PDX models.
Main Results:
- Achieved a 52% PDX engraftment rate, with higher success in high-grade, recurrent, or metastatic tumors (70%).
- Confirmed PDX models preserved EC morphology, hormone receptor status, and heterogeneity across passages.
- Observed significant intertumoral variability in drug response, with limited sensitivity to NCCN-recommended therapies.
- Identified potent antitumor activity with epigenetic modulators, dual PI3-kinase/HDAC inhibitors, topoisomerase II inhibitors, and proteasome inhibitors.
- Demonstrated significant tumor growth suppression using a low-dose combination of 5-azacytidine and romidepsin in PDX models.
Conclusions:
- The established PDX and PDC platform serves as a robust translational resource for endometrial cancer research.
- The platform captures the histopathologic and molecular diversity of EC.
- Identified clinically actionable therapeutic advantages, including an epigenetic combination regimen, for preclinical drug evaluation.
