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.
|Sokolowski, E; Turina, C B; Kikuchi, K et al. (2014) Proof-of-concept rare cancers in drug development: the case for rhabdomyosarcoma. Oncogene 33:1877-89|
|Abraham, Jinu; Nuñez-Álvarez, Yaiza; Hettmer, Simone et al. (2014) Lineage of origin in rhabdomyosarcoma informs pharmacological response. Genes Dev 28:1578-91|
|Aslam, M Imran; Abraham, Jinu; Mansoor, Atiya et al. (2014) PDGFR? reverses EphB4 signaling in alveolar rhabdomyosarcoma. Proc Natl Acad Sci U S A 111:6383-8|
|Kikuchi, Ken; Hettmer, Simone; Aslam, M Imran et al. (2014) Cell-cycle dependent expression of a translocation-mediated fusion oncogene mediates checkpoint adaptation in rhabdomyosarcoma. PLoS Genet 10:e1004107|
|Berlow, Noah; Haider, Saad; Wan, Qian et al. (2014) An Integrated Approach to Anti-Cancer Drug Sensitivity Prediction. IEEE/ACM Trans Comput Biol Bioinform 11:995-1008|
|Aslam, M Imran; Hettmer, Simone; Abraham, Jinu et al. (2013) Dynamic and nuclear expression of PDGFR? and IGF-1R in alveolar Rhabdomyosarcoma. Mol Cancer Res 11:1303-13|
|Li, Guangheng; Kikuchi, Ken; Radka, Megan et al. (2013) IL-4 receptor blockade abrogates satellite cell: rhabdomyosarcoma fusion and prevents tumor establishment. Stem Cells 31:2304-12|
|Alabran, Jennifer L; Hooper, Jody E; Hill, Melissa et al. (2013) Overcoming autopsy barriers in pediatric cancer research. Pediatr Blood Cancer 60:204-9|
|Kikuchi, K; Soundararajan, A; Zarzabal, L A et al. (2013) Protein kinase C iota as a therapeutic target in alveolar rhabdomyosarcoma. Oncogene 32:286-95|
|Berlow, Noah; Davis, Lara E; Cantor, Emma L et al. (2013) A new approach for prediction of tumor sensitivity to targeted drugs based on functional data. BMC Bioinformatics 14:239|
Showing the most recent 10 out of 27 publications