Combinatorial screening using orthotopic patient derived xenograft-expanded early phase cultures of osteosarcoma...

Area of Science:

• Oncology
• Pharmacology
• Genitourinary Oncology

Background:

• Osteosarcoma drug discovery faces challenges due to limited clinical samples and inadequate preclinical models.
• Accurate preclinical models are crucial for identifying novel therapeutic agents for osteosarcoma.

Purpose of the Study:

• To develop and utilize patient-derived xenografts (PDXs) for high-throughput drug screening in osteosarcoma.
• To identify novel and repurposed drugs with potential efficacy against osteosarcoma.

Main Methods:

• Orthotopic patient-derived xenografts (PDXs) were established to model osteosarcoma.
• PDX-expanded short-term cultures and commercial cell lines were screened against focused drug libraries.
• Sensitivity to various inhibitors (HDAC, proteasome, PI3K/MEK, PI3K/mTOR, PARP, RAF, ERK, MEK) was assessed.

Main Results:

• Osteosarcoma cells exhibited highest sensitivity to HDAC, proteasome, and combination PI3K/MEK and PI3K/mTOR inhibitors.
• Cells were least sensitive to PARP, RAF, ERK, and MEK inhibitors.
• HDAC inhibitors demonstrated additive effects when combined with gemcitabine and doxorubicin.

Conclusions:

• The developed PDX model enables effective high-throughput drug screening for osteosarcoma.
• HDAC, proteasome, and PI3K pathway inhibitors represent promising therapeutic strategies for osteosarcoma.
• Combination therapies, particularly with HDAC inhibitors, warrant further investigation.