Medulloblastoma is the most common malignant brain tumor in children. To approach the problem of effective therapy, the progression of human medulloblastoma must first be understood. We hypothesize that platelet-derived growth factor (PDGFR)-mediated signal transduction enhances tumor cell responses that promote the growth and metastatic spread of medulloblastoma, and have shown that (i) PDGFR is significantly overexpressed by metastatic medulloblastomas, (ii) inhibitors of medulloblastoma cell PDGFR activity decrease phosphorylation of the downstream signaling target, MAPK, alter gene expression, and decrease cell migration and survival and (iii) in silico analysis of 135 known pro-metastatic genes within independent datasets of microarray gene expression of medulloblastomas, only three genes, including DDGFR, demonstrated detectable mRNA expression in at least one third of all tumors analyzed and significant overexpression by metastatic tumors in each dataset. These data, combined with the preliminary data showing that both alpha (PDGFRA) and beta (PDGFRB) subtypes of the receptor are 1) expressed on the RNA and protein level by medulloblastoma tumors and cells, 2) sparsely expressed by normal brain, 3) activated in an autocrine and paracrine fashion in medulloblastoma cells, and 4) capable of inducing apoptosis of medulloblastoma cells in a dose-dependent manner following treatment with a selective inhibitor of PDGFR tyrosine kinase activity, suggest a mechanism by which PDGFR may be vital for medulloblastoma growth and progression. Thus, PDGFR is a potential novel target for therapeutic intervention. To test this hypothesis we will employ human medulloblastoma cell lines. We will (i) conduct comprehensive in vitro studies to determine the PDGFR signaling cascade and its effects on survival, proliferation, adhesion, migration and invasion, (ii) determine the key gene expression changes induced by PDGFR signaling in these cells, (iii) develop medulloblastoma cells with deficient PDGFR expression by inducible siRNA transfection specific for each PDGFR and determine the effect of inhibited expression and activity on survival, proliferation and migration in vitro and growth and metastasis in vivo, and (iv) determine the expression pattern of phosphorylated PDGFR protein and its correlation with metastasis and outcome in human medulloblastomas as a way to assess the potential clinical utility of PDGFR inhibitors for this disease ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA111835-02
Application #
7227904
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Jhappan, Chamelli
Project Start
2006-05-01
Project End
2011-03-31
Budget Start
2007-05-01
Budget End
2008-03-31
Support Year
2
Fiscal Year
2007
Total Cost
$257,494
Indirect Cost
Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010
McKinney, Nicole; Yuan, Liangping; Zhang, Hongying et al. (2015) EphrinB1 expression is dysregulated and promotes oncogenic signaling in medulloblastoma. J Neurooncol 121:109-18
Petersen, William; Liu, Jingbo; Yuan, Liangping et al. (2014) Dasatinib suppression of medulloblastoma survival and migration is markedly enhanced by combining treatment with the aurora kinase inhibitor AT9283. Cancer Lett 354:68-76
Yuan, Liangping; Zhang, Hongying; Liu, Jingbo et al. (2013) Growth factor receptor-Src-mediated suppression of GRK6 dysregulates CXCR4 signaling and promotes medulloblastoma migration. Mol Cancer 12:18
Abouantoun, Thamara J; Castellino, Robert C; MacDonald, Tobey J (2011) Sunitinib induces PTEN expression and inhibits PDGFR signaling and migration of medulloblastoma cells. J Neurooncol 101:215-26
Smith, Courtney; Santi, Mariarita; Rushing, Elisabeth J et al. (2011) Characterization of signaling function and expression of HLA class I molecules in medulloblastoma. J Neurooncol 103:197-206
Yuan, Liangping; Santi, Mariarita; Rushing, Elisabeth J et al. (2010) ERK activation of p21 activated kinase-1 (Pak1) is critical for medulloblastoma cell migration. Clin Exp Metastasis 27:481-91
Abouantoun, Thamara J; MacDonald, Tobey J (2009) Imatinib blocks migration and invasion of medulloblastoma cells by concurrently inhibiting activation of platelet-derived growth factor receptor and transactivation of epidermal growth factor receptor. Mol Cancer Ther 8:1137-47
Smith, Courtney; Santi, Mariarita; Rajan, Bhargavi et al. (2009) A novel role of HLA class I in the pathology of medulloblastoma. J Transl Med 7:59
Thorarinsdottir, Halldora K; Santi, Mariarita; McCarter, Robert et al. (2008) Protein expression of platelet-derived growth factor receptor correlates with malignant histology and PTEN with survival in childhood gliomas. Clin Cancer Res 14:3386-94