Evidence for activation of KIT, PDGFRα, and PDGFRβ receptors in the Ewing sarcoma family of tumors

Abstract

BACKGROUND. The Ewing sarcoma family of tumors (ESFT) is one of the most common malignant neoplasms of children and adolescents, characterized by nonrandom translocations involving the Ewing sarcoma (EWS) gene. Over the years the adoption of intensive multimodality treatment approaches has led to a gradual improvement in the survival of patients with ESFT. The prognosis is still unsatisfactory for high‐risk patients, however, and novel therapeutic approaches are desirable. The aim of the study was to investigate the expression/activation of KIT, PDGFRα, and PDGFRβ receptor tyrosine kinases (RTKs) as potential therapeutic targets in ESFT. METHODS. RNA and proteins were extracted from 20 frozen ESFT specimens to ascertain the state activation of KIT, PDGFRα, and PDGFRβ. RESULTS. No mutations were found, whereas the cognate ligands were detected in all cases by polymerase chain reaction (PCR). The expression and activation of KIT, PDGFRα, and PDGFRβ were confirmed by quantitative PCR, immunohistochemistry, and immunoprecipitation and/or Western blot analysis. In particular, when compared with a protein pool obtained from normal adult tissues, PDGFRβ showed a greater protein expression and/or a stronger phosphorylation signal. CONCLUSIONS. The results are consistent with an autocrine/paracrine loop activation of the KIT, PDGFRα, and PDGFRβ receptors and suggest a rationale for the use of RTK inhibitors, either alone or in combination with chemotherapy. Cancer 2007. © 2007 American Cancer Society.

Array comparative genomic hybridization reveals frequent alterations of G1/S checkpoint genes in undifferentiated pleomorphic sarcoma of bone

“…Expression of VEGFA, the ligand of KDR, has been shown to associate with poor prognosis in sarcomas, including osteosarcoma and Ewing sarcoma [ (Lee et al, 1999;Kaya et al, 2000;Fuchs et al, 2004), reviewed in (DuBois and Demetri, 2007)], and in one study on nonmetastatic osteosarcoma, the expression of KDR was found in 67% of the patients (Lee et al, 1999). Expression of the normal KIT receptor has been reported in many neoplasms, including osteosarcoma and Ewing sarcoma (Sulzbacher et al, 2003;Tamborini et al, 2004;Burger et al, 2005;Entz-Werle et al, 2005;McIntyre et al, 2005;Bozzi et al, 2007).…”

“…Frequent gains at the 4q12 region, including high level amplifications, have been reported in osteosarcoma, too Man et al, 2004). Involvement of PDGF receptors and their ligands have been suggested in sarcomas, as in osteosarcoma and Ewing sarcoma [ (Sulzbacher et al, 2003;Bozzi et al, 2007), reviewed in (DuBois and Demetri, 2007)], and the expression of PDGF-AA homodimer has been reported to associate with tumor progression in osteosarcoma (Sulzbacher et al, 2003). Expression of VEGFA, the ligand of KDR, has been shown to associate with poor prognosis in sarcomas, including osteosarcoma and Ewing sarcoma [ (Lee et al, 1999;Kaya et al, 2000;Fuchs et al, 2004), reviewed in (DuBois and Demetri, 2007)], and in one study on nonmetastatic osteosarcoma, the expression of KDR was found in 67% of the patients (Lee et al, 1999).…”

Olaratumab Exerts Antitumor Activity in Preclinical Models of Pediatric Bone and Soft Tissue Tumors through Inhibition of Platelet-Derived Growth Factor Receptor α

“…Although the prevalence of PDGFRA genetic aberrations in pediatric cancer is reported to be only about 2% (19), members of the PDGF pathway are highly expressed in several subtypes of pediatric bone and soft tissue tumors, including rhabdomyosarcoma (20,21), synovial sarcoma (22), osteogenic sarcoma (23), Ewing sarcoma (24), and MRT (25). In addition, PDGFRa expression is linked to adverse outcomes in pediatric patients with rhabdomyosarcoma (26).…”

Targets for cancer therapy in childhood sarcomas

“…PDGFR is expressed in all three types of childhood sarcomas discussed here (33)(34)(35) and c-kit expression has been found in Ewing's sarcoma and osteosarcoma (36)(37)(38). Mutations were only found in the case of c-kit and in a small fraction of Ewing's sarcomas (39).…”

“…Mutations were only found in the case of c-kit and in a small fraction of Ewing's sarcomas (39). However, both PDGFR and c-kit are activated in these childhood sarcomas (37,40) and PDGF was found to act as mitogen for osteosarcoma cells (41). Furthermore, expression of PDGF-AA was found to be associated with tumor progression in osteosarcoma (42).…”