Drug sensitivity testing of patient-derived bone sarcomas identifies selective kinase inhibitors for patients with...

Area of Science:

• Oncology
• Cancer Biology
• Pharmacology

Background:

• Bone sarcomas, including osteosarcoma (OS) and Ewing sarcoma (ES), present significant treatment challenges, particularly in refractory cases.
• Genomic-based assays for these genetically complex tumors can be difficult to implement.
• Identifying effective therapeutic agents for refractory bone sarcomas is crucial.

Purpose of the Study:

• To assess the feasibility and predictive value of ex vivo drug sensitivity testing on bone sarcoma patient-derived cells (PDCs).
• To identify potential therapeutic agents for patients with refractory bone sarcomas.
• To correlate drug responses with molecular characteristics and patient outcomes.

Main Methods:

• Screening of 7 osteosarcoma (OS) and 4 Ewing sarcoma (ES) PDCs against a library of oncological drugs.
• Utilizing gene panel sequencing and mRNA expression arrays for molecular characterization.
• Correlating drug responses with tumor histology, genotype, and patient response to therapy.

Main Results:

• OS PDCs exhibited heterogeneous drug sensitivity, with responses to mTOR, PKC, MAPK, and CDK inhibitors correlating with tumor subtype and genotype.
• ES PDCs showed morphological dichotomy and differential sensitivity to specific drug classes (e.g., rapalogs, SMAC-mimetics).
• Drug sensitivity of PDCs correlated with patient response to chemotherapy in both OS and ES.

Conclusions:

• Ex vivo drug sensitivity testing of bone sarcoma PDCs is a valuable tool for rapid treatment identification.
• This method is particularly useful for genetically complex tumors where genome-based assays are challenging.
• PDC cultures can reveal phenotypic clones, potentially indicating clonal evolution and tumor recurrence mechanisms.