Expression of therapeutic targets in Ewing sarcoma family tumors

Department of Pathology, Children's Mercy Hospital, Kansas City, MO 64108, USA.
Human pathology (Impact Factor: 2.77). 12/2011; 43(7):1077-83. DOI: 10.1016/j.humpath.2011.09.001
Source: PubMed


Ewing sarcoma family tumor is an aggressive malignant tumor of bone and soft tissue in children and adolescents. Despite advances in modern therapy, metastasis occurs in 20% to 25% of cases and results in mortality in 80% of patients. Intracellular molecules mammalian target of rapamycin, Akt, vascular endothelial growth factor, nuclear factor κB, and BRAF are important kinases and transcription factors that regulate the proliferation of tumor cells. We studied the expression of these proteins in 72 Ewing sarcoma family tumors. Patients' survival data were available in 55 cases. Formalin-fixed, paraffin-embedded tumor sections were stained with antibodies against phosphorylated mammalian target of rapamycin, Akt, BRAF, vascular endothelial growth factor, and nuclear factor κB proteins. Stained sections were analyzed for percentage and strength of staining, and a composite score (0-200) was subsequently generated. Although most tumors expressed mammalian target of rapamycin, Akt, nuclear factor κB, and vascular endothelial growth factor, only 37%, 86%, 55%, and 12%, respectively, showed high expression (staining score ≥ 100). There was no significant correlation between mammalian target of rapamycin and Akt expression and clinical outcome. High nuclear factor κB expression was significantly associated with tumors in pelvic locations. Decreased vascular endothelial growth factor expression (score <100) was significantly associated with better prognosis (P < .05). BRAF was not expressed in most cases and showed negative or weak staining (score <100) in 97% of cases. Thus, except for BRAF, Ewing sarcoma family 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 sarcoma family tumors.

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    • "A few studies have also been done in sarcomas. Ahmed et al. found no expression of BRAF in 72 Ewing family tumors [4] , and Cipriani et al. [5] evaluated 104 tumors, including 90 sarcomas, with no BRAF mutation identified in the sarcoma group. On the other hand, Shukla et al. [6] identified BRAF mutations in 1.3% of Ewing sarcomas and 1.7% of embryonal rhabdomyosarcomas. "

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    ABSTRACT: Ewing’s sarcoma family of tumors (ESFT) is a malignant tumor of bone and soft tissue in children and adolescents that is characterized by molecular alterations that most commonly involve the EWS gene on chromosome 22. It is an aggressive tumor, with metastases present at diagnosis in 20–25% of cases. Modern treatment regimens for localized disease have resulted in significant improvement in survival. However, the pre­sence of metastasis is associated with morta­lity in 70–80% of patients. New insights into the pathogenesis and prolife­rative mechanisms of human cancers have led to the identification of a number of proteins acting as messenger molecules and modulators of tumor growth. Targeting these molecules in ESFT has the potential effect of controlling tumor growth. This chapter summarizes the current research on molecular pathogenesis, proliferation pathways and new investigational pharmacologic agents that are under development in the race for the cure of this malignancy.
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    ABSTRACT: Background Hypoxia inducible factor-1 α (HIF-1α) has been identified as an important novel target in apoptosis resistance of pediatric tumors such as Rhabdomyosarcoma (RMS) and Ewing’s sarcoma (ES). Evidence suggests that PI3K/Akt signaling plays a role in regulation of HIF-1α activation as well as apoptosis resistance in various adult tumors. However the relevance of PI3K/Akt signaling in HIF-1bα activation and apoptosis resistance in childhood tumors has not been addressed yet. Thus, this study was to investigate whether PI3K/Akt signaling is involved in hypoxia induced activation of HIF-1α as well as in resistance to hypoxia-induced apoptosis in childhood tumors such as RMS and ES. Methods Constitutive activation of PI3K/Akt signaling was analyzed by Western blotting. Hypoxic activation of HIF-1α was determined by Western Blot analysis and electrophoretic mobility shift assay. Apoptosis was determined by flow cytometric analysis of the propidium iodine stained nuclei of cells treated with PI3K inhibitor LY294002 in combination with either TNF-related apoptosis-inducing ligand (TRAIL) or doxorubicin. Results This study demonstrated that PI3K/Akt signaling was constitutively activated in RMS and ES cell lines, A204 and A673, respectively. Targeting PI3K/Akt signaling by the inhibitor LY294002 (30 μM) significantly decreased the protein expression as well as DNA binding activity of HIF-1α and restored the apoptosis-inducing ability of cells in hypoxia Additionally, pretreatment with LY294002 sensitized A204 and A673 cells to TRAIL or doxorubicin induced apoptosis under hypoxia. Conclusion These results suggest that the constitutively active PI3K/Akt signaling contributes to hypoxic activation of HIF-1α as well as HIF1α-mediated apoptosis resistance in RMS and ES cells under hypoxia.
    Full-text · Article · Apr 2013 · Cancer Cell International
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