Optimizing Sequential Targeted Therapies in Advanced Renal Cell Carcinoma Using Patient-Derived Orthotopic Xenograft...

Area of Science:

• Oncology
• Translational Research
• Xenograft Models

Background:

• Advanced renal cell carcinoma (aRCC) lacks optimal targeted therapy sequences due to heterogeneity and resistance.
• Patient-derived orthotopic xenograft (PDOX) models offer a platform to study individualized aRCC treatments.

Purpose of the Study:

• To develop and validate a luciferase-enabled PDOX platform for evaluating sequential targeted therapies in aRCC.
• To assess the efficacy of different sequential drug regimens in patient-specific aRCC models.

Main Methods:

• Two patient-derived renal cell carcinoma (RCC) xenografts (sarcomatoid and clear cell with sarcomatoid component) were established and orthotopically implanted in mice.
• Bioluminescence imaging (BLI) monitored tumor growth and metastasis, with mice randomized to sequential therapy arms (e.g., Everolimus→Sunitinib).
• Tumor burden, metastasis, proliferation (Ki67), angiogenesis (CD31), and PD-L1 expression were analyzed post-treatment.

Main Results:

• PDOX models accurately recapitulated patient tumor histology, proliferation, and clinical course (aggressive vs. indolent).
• The Pazopanib→Everolimus sequence showed the greatest reduction in tumor weight and lung metastases in the aggressive model.
• Sequential therapies (Sunitinib→Everolimus, Pazopanib→Everolimus) effectively reduced tumor burden and proliferation in the indolent model.

Conclusions:

• The RCC PDOX platform reliably preserves patient-specific tumor biology for evaluating sequential targeted therapies.
• This study provides proof-of-concept for personalized treatment strategies in advanced RCC.
• Further investigation into rational combinations with immune checkpoint blockade is warranted.