Despite the advances in osteosarcoma (OS) treatment and increased survival rates, at least one third of the patients still succumb to their disease. Ultra aggressive treatment often leads to acute and long term toxicity without added benefit to a group of patients who may get cured with less aggressive therapy. The aim of this study was to discover potential survival biomarkers for OS. Because of the limited amount of pre-treatment biopsied tissue available for research and the pre-operative combination chemotherapy used in the clinic, we chose to use OS xenografts for marker gene discovery. In a recent study we identified a number of genes that were associated with chemoresponse in ten OS xenografts in nude mice treated with ifosfamide, cisplatin or doxorubicin. One of the candidate genes was CDH11, which had been shown to be decreased in OS patients with metastatic disease and that restoration of CDH11 expression reversed the metastatic potential of OS. To further validate the relevance of the marker genes identified in our study, a quantitative qRT-PCR analysis was performed using total RNA transcripts isolated from 23 OS patient samples (10 untreated biopsies, three OS primary tumors obtained at surgery, and 11 metastasis). Kaplan-Meier survival analysis performed based on the median expression level of CDH11, showed that patients with high expression levels of CDH11 had a longer survival rate than patients with low of CDH11 levels (p=0.02 based on log-rank test with 95% confidence interval). This is consistent with the biological function of CDH11 as a critical cell-cell adhesion and cell signalling molecule. The study demonstrates the power of identifying potential clinically relevant targets and biomarkers using high throughput genomics approach with OS xenografts as a model. The results will be further validated using additional patient samples and OS tissue arrays.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]