Patient-derived xenografts and organoids model therapy response in prostate cancer

Area of Science:

• Oncology
• Cancer Biology
• Genitourinary Cancers

Background:

• Prostate cancer (PCa) progression and therapy resistance are poorly understood due to limited experimental models.
• Existing models often fail to recapitulate the heterogeneity of metastatic PCa.
• There is a critical need for preclinical models that accurately reflect diverse stages of PCa development.

Purpose of the Study:

• To establish and characterize a novel patient-derived xenograft (PDX) model of treatment-naïve metastatic prostate cancer (PNPCa).
• To investigate the genomic and transcriptomic features of the PNPCa model.
• To evaluate the utility of the PNPCa model and other metastatic PDX models in drug sensitivity screening.

Main Methods:

• Generation of an androgen-dependent PDX model from a soft tissue metastasis of prostate cancer.
• RNA and whole-exome sequencing of PDX tissue and derived organoids.
• Medium-throughput organoid screening of FDA-approved compounds against multiple metastatic PDX models.

Main Results:

• The PNPCa model demonstrated high transcriptomic and genomic similarity to the primary tumor.
• PNPCa harbors BRCA2 and CHD1 mutations, SPOP/FOXA1-like signature, and microsatellite instability, a combination not previously modeled in vivo.
• Multikinase inhibitors showed broad efficacy across various PDX and patient-derived organoids, including those resistant to standard therapies.

Conclusions:

• The developed PNPCa model provides a valuable preclinical tool for studying prostate cancer metastasis and therapy resistance.
• The study highlights the potential of multikinase inhibitors for treating advanced prostate cancer with acquired resistance.
• This platform can facilitate drug screening for both standard-of-care and repurposed compounds in diverse metastatic PCa contexts.