A Comparative Oncology Drug Discovery Pipeline to Identify and Validate New Treatments for Osteosarcoma

Area of Science:

• Oncology
• Drug Discovery
• Comparative Medicine

Background:

• Osteosarcoma is a rare, aggressive bone cancer primarily affecting children.
• Treatment advancements for osteosarcoma have stagnated due to genomic heterogeneity and limited patient samples.
• Developing new therapies is crucial for improving survival rates.

Purpose of the Study:

• To identify novel therapeutic vulnerabilities in osteosarcoma.
• To establish an effective drug discovery pipeline for rare cancers.
• To overcome barriers in osteosarcoma research.

Main Methods:

• Utilized comparative oncology and patient-derived cancer models.
• Employed high-throughput chemical screens in a cross-species drug discovery pipeline.
• Conducted in vitro drug screens and in vivo validation using patient-derived xenografts.

Main Results:

• Identified the proteasome pathway as a therapeutic sensitivity in osteosarcoma.
• Identified the CRM1 nuclear export pathway as a therapeutic sensitivity in osteosarcoma.
• Demonstrated that dual inhibition of these pathways induces synergistic cytotoxicity.

Conclusions:

• The study provides a framework for identifying and studying therapeutic vulnerabilities in osteosarcoma and other rare cancers.
• New tools and experimental approaches have been developed for rare cancer research.
• Dual inhibition of proteasome and CRM1 pathways represents a promising therapeutic strategy.