PDGFR-A is a therapeutic target in alveolar rhabdomyosarcoma

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Progression and metastasis of solid tumors is a principal cause of death for cancer patients. The childhood muscle cancer alveolar rhabdomyosarcoma is a classic example. A gap in understanding the disease-specific mechanisms of progression underlies the dismal outcome for patients with advanced alveolar rhabdomyosarcoma. Our initial studies of rhabdomyosarcoma gene expression amongst patients enrolled in a national clinical trial suggest that the platelet-derived growth factor receptor A (PDGFR-A) may be a mediator of disease progression and metastasis. In our studies PDGFR-A has been found to be a transcriptional target of Pax3:Fkhr, the translocation-mediated fusion gene found in the majority of alveolar rhabdomyosarcomas. We hypothesize that PDGFR-A signaling pathways play a prominent role in progression and metastasis of alveolar rhabdomyosarcoma. To test this hypothesis, we have generated conditional mouse tumor models that authentically recapitulate the primary mutations and the metastatic progression of alveolar rhabdomyosarcomas in humans. We found that PDGFR-A and its downstream effecters, MAPK and Akt, were highly activated in both primary and metastasized tumor. We also confirmed that PDGFR-A, MAPK and Akt were activated in mouse and human alveolar rhabdomyosarcoma cell cultures, and that cell proliferation was inhibited by PDGFR-A specific siRNA. To determine the pathophysiological impact of PDGFR-A blockade for rhabdomyosarcoma in vivo, we treated the receptor tyrosine kinase inhibitor, Imatinib, or PDGFR-A blocking antibody, which significantly inhibit tumor growth. These results establish proof-of-principal for PDGFR-A as a therapeutic target in childhood alveolar rhabdomyosarcomas.