Expression of Therapeutically Relevant Molecules in Ewing's Sarcoma Family Tumors.
Atif Ahmed, Joan Whiting, Bruce Pawel. Children's Mercy Hospital, Kansas City, MO; Children's Hospital of Philadelphia, PA
Background: Ewing sarcoma family tumor (EFT) is an aggressive malignant tumor of bone and soft tissue in children and adolescents. Modern treatment regimens are effective in localized disease. Metastasis occurs in 20-25% of cases and results in mortality in 80% of patients. New insight has led to identification of mTOR, AKt, VEGF and NF-kappa B as important kinases and transcription factors that regulate the proliferation of EFT tumor cells in vitro. BRAF is another kinase molecule that is over-expressed in numerous cancers and has not been previously studied in EFT.
Design: 72 cases with established diagnosis of EFT were selected. Survival data was available in 50 cases, classified as as no evidence of disease (NED), alive with disease (AED) or died of disease (DOD). Formalin-fixed tumor sections were stained with antibodies against phosphorylated mTOR, AKT, BRAF, VEGF and NF-kappa B proteins. Stained sections were analyzed and graded for extent (percentage of stained cells) and strength of staining (negative , weak  or strong ). A composite score (from 0 to 200) was calculated by multiplying percentage of stained cells by strength of staining. The results were statistically correlated with patients' survival outcome.
Results: 1-4 cases were excluded because of insufficient viable tumor. The remaining cases (≥68) showed variable positive staining for the selected markers. Significant staining (score ≥100) was identified in 86% of cases stained for Akt, 55% of cases stained for NF-Kappa B, 37% of cases stained for m-TOR and only 12% of cases stained for VEGF. BRAF showed negative or weak staining (score <100) in 97% of cases.
Decreased VEGF expression (score <100) was significantly associated with NED, i.e. better prognosis (p<0.05). No significant association was demonstrated between the expression of the remaining proteins and the prognosis.
Conclusions: The majority of EFT cases express mTOR, AKT, VEGF and NF-kappa B proteins and do not express BRAF. EFT tumors may be amenable to treatment that targets the expressed proteins. High Akt expression suggests potential universal response to Akt-targeted therapy. BRAF kinase inhibitors are unlikely to be effective in the treatment of Ewing's sarcoma family tumors. VEGF expression is related to prognosis and larger studies may be needed to correlate VEGF over-expression to patients' prognosis and document the effectiveness of VEGF inhibitors in the treatment of these patients.
Category: Bone & Soft Tissue
Tuesday, March 1, 2011 9:30 AM
Poster Session III # 8, Tuesday Morning