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The Establishment and Utilization of Patient Derived Xenograft Models of Central Nervous System Metastasis
Published on: May 7, 2021
Application of Drug Testing Platforms in Circulating Tumor Cells and Validation of a Patient-Derived Xenograft Mouse
Muh-Lii Liang1,2, Ting-Chi Yeh2,3, Man-Hsu Huang4
1Department of Neurosurgery, MacKay Memorial Hospital, Taipei 104, Taiwan.
Abstract:
Primary intracranial ependymoma is a challenging tumor to treat despite the availability of multidisciplinary therapeutic modalities, including surgical resection, radiotherapy, and adjuvant chemotherapy. After the completion of initial treatment, when resistant tumor cells recur, salvage therapy needs to be carried out with a more precise strategy. Circulating tumor cells (CTCs) have specifically been detected and validated for patients with primary or recurrent diffused glioma. The CTC drug screening platform can be used to perform a mini-invasive liquid biopsy for potential drug selection. The validation of potential drugs in a patient-derived xenograft (PDX) mouse model based on the same patient can serve as a preclinical testing platform. Here, we present the application of a drug testing model in a six-year-old girl with primary ependymoma on the posterior fossa, type A (EPN-PFA). She suffered from tumor recurrence with intracranial and spinal seeding at 2 years after her first operation and extraneural metastases in the pleura, lung, mediastinum, and distant femoral bone at 4 years after initial treatment. The CTC screening platform results showed that everolimus and entrectinib could be used to decrease CTC viability. The therapeutic efficacy of these two therapeutic agents has also been validated in a PDX mouse model from the same patient, and the results showed that these two therapeutic agents significantly decreased tumor growth. After precise drug screening and the combination of focal radiation on the femoral bone with everolimus chemotherapy, the whole-body bone scan showed significant shrinkage of the metastatic tumor on the right femoral bone. This novel approach can combine liquid biopsy, CTC drug testing platforms, and PDX model validation to achieve precision medicine in rare and challenging tumors with extraneural metastases.
Insights
This study introduces a precision medicine approach for treating recurrent ependymoma using circulating tumor cells (CTCs) and patient-derived xenograft (PDX) models. The method identified effective drugs, leading to significant tumor shrinkage in a pediatric patient with advanced disease.
Area of Science:
- Oncology
- Precision Medicine
- Pediatric Cancer Research
Background:
- Primary intracranial ependymoma is difficult to treat, with salvage therapy needed for recurrent or resistant disease.
- Extraneural metastases and recurrence pose significant challenges in ependymoma management.
- Circulating tumor cells (CTCs) offer a potential biomarker for monitoring and guiding treatment in glioma patients.
Purpose of the Study:
- To present a novel drug testing model combining liquid biopsy and patient-derived xenograft (PDX) models for precision medicine in pediatric ependymoma.
- To identify effective therapeutic agents for a patient with recurrent ependymoma and extraneural metastases.
- To validate the efficacy of identified drugs through preclinical testing in a patient-specific PDX mouse model.
Main Methods:
- Utilized a circulating tumor cell (CTC) drug screening platform for mini-invasive liquid biopsy and potential drug selection.
- Validated drug efficacy using a patient-derived xenograft (PDX) mouse model established from the same patient.
- Combined focal radiation with targeted chemotherapy (everolimus) based on drug screening and PDX model results.
Main Results:
- CTC screening identified everolimus and entrectinib as agents capable of decreasing CTC viability.
- Therapeutic efficacy was confirmed in the PDX model, showing significant reduction in tumor growth with these agents.
- A pediatric patient with recurrent ependymoma and extensive metastases showed significant metastatic tumor shrinkage after treatment.
Conclusions:
- A novel precision medicine approach integrating liquid biopsy, CTC drug testing, and PDX model validation is effective for rare, challenging tumors.
- This strategy enables precise drug selection and treatment planning for patients with recurrent ependymoma and extraneural metastases.
- The combined approach demonstrated significant therapeutic success, offering a promising avenue for personalized cancer therapy.
