RESUMO
Alveolar rhabdomyosarcoma is an aggressive skeletal muscle cancer of childhood. Our initial studies of rhabdomyosarcoma gene expression for patients enrolled in a national clinical trial suggested that platelet-derived growth factor receptor A (PDGFR-A) may be a mediator of disease progression and metastasis. Using our conditional mouse tumor models that authentically recapitulate the primary mutations and metastatic progression of alveolar rhabdomyosarcomas in humans, we found by immunoblotting and immunokinase assays that PDGFR-A and its downstream effectors, mitogen-activated protein kinase and Akt, were highly activated in both primary and metastatic tumors. Inhibition of PDGFR-A by RNA interference, small molecule inhibitor or neutralizing antibody had a dramatic effect on tumor cell growth both in vitro and in vivo, although resistance evolved in one-third of tumors. These results establish proof-of-principal for PDGFR-A as a therapeutic target in alveolar rhabdomyosarcoma.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Musculares/tratamento farmacológico , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/fisiologia , Rabdomiossarcoma Alveolar/tratamento farmacológico , Animais , Benzamidas , Linhagem Celular Tumoral , Células Cultivadas , Genes p16 , Humanos , Mesilato de Imatinib , Camundongos , Camundongos Knockout , Neoplasias Musculares/etiologia , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Rabdomiossarcoma Alveolar/etiologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We report the seventh case of angiosarcoma of the heart in a child. The patient was a 23-month-old female who presented for lower extremity limping and underwent open surgical biopsy of the femur. Immediately postoperatively, she developed pericardial tamponade, and a bulky intracardiac mass was discovered as the underlying cause. The mass was composed of highly pleomorphic tumor cells reactive for the endothelial markers CD31, CD34, and factor VIII-related antigen (FVIII-RA). Staging evaluation revealed widespread metastases involving the brain, ovaries, and bone marrow. She died of complications of metastatic disease 8 months following initial presentation. Unusual features of this case include the young age of the patient, left-sided nature of the cardiac tumor, presentation secondary to metastatic disease, and the pattern of metastases. The literature on cardiac angiosarcoma, which is limited to six case reports in the pediatric population, is also reviewed.