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 ligand-dependent or constitutive 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. Tumors in this model have dramatic responses to the receptor tyrosine kinase inhibitor, Imatinib, which significantly inhibits PDGFR-A signaling.
Our first aim i s to delineate the PDGFR-A signaling pathway in rhabdomyosarcoma by functional testing in vitro. For these experiments, mouse and human alveolar rhabdomyosarcoma cell cultures will be examined for alterations of the Akt, MAPK, and PKC signaling pathways in the presence or absence of PDGFR-A inhibitors or siRNA. The functional ability to metastasize under PDGFR-A inhibitory conditions will be assayed in ovo.
Our second aim i s to determine the pathophysiological impact of PDGFR-A blockade for rhabdomyosarcoma in vivo. To achieve this aim, we will use a conditional allele of PDGFR-A to abrogate PDGFR-A signaling in our mouse model of alveolar rhabdomyosarcoma, and we will measure the differences in onset, frequency, and progression with and without PDGFR-A signaling. This study establishes proof-of-principal for a systematic, rational genetic approach to molecular therapeutics in childhood alveolar rhabdomyosarcomas and other tumors.
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. This study of platelet-derived growth factors in cancer progression establishes proof-of- principal for a systematic, rational genetic approach to molecular therapeutics in childhood alveolar rhabdomyosarcomas and other tumors.
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