Assessing a Novel 3D Assay System for Drug Screening against OS Metastasis

Area of Science:

• Oncology
• Drug Discovery
• Translational Medicine

Background:

• Osteosarcoma (OS) is an aggressive bone cancer with poor prognosis, often leading to fatal pulmonary metastasis despite current treatments.
• Conventional drug discovery for OS focuses on cytotoxicity against proliferating cells, potentially missing agents that target dormant disseminated tumor cells (DTCs) responsible for metastasis.

Purpose of the Study:

• To develop and validate a phenotypic drug screening assay targeting OS DTCs and their metastatic potential.
• To assess the translational relevance of the assay using drugs with known clinical activity in OS.
• To explore oclacitinib, a veterinary drug, as a potential anti-metastatic agent for OS.

Main Methods:

• Utilized a 3D reconstituted basement membrane extract (3D BME) model with high and low metastatic OS cell lines to study tumor dormancy and outgrowth.
• Validated the assay by comparing drug activity with existing human OS clinical trial data (regorafenib, saracatinib).
• Tested oclacitinib, a Janus kinase-1 inhibitor, for anti-metastatic effects in the OS model.

Main Results:

• The 3D BME assay demonstrated concordance with human clinical trial outcomes for OS drugs.
• Oclacitinib showed no evidence of anti-metastatic activity in the osteosarcoma model, despite a theoretical rationale.
• The validated 3D BME assay proved efficient for evaluating drugs targeting OS DTCs.

Conclusions:

• The developed 3D BME assay is a robust and efficient platform for identifying drugs that inhibit osteosarcoma metastasis.
• This model system holds significant potential for advancing drug discovery for osteosarcoma by focusing on disseminated tumor cells.
• Further research is needed to identify effective anti-metastatic agents for osteosarcoma, as oclacitinib was not found to be effective.