Neuroblastomas are neural crest derived tumors that express tyrosine kinase receptors encoded by TrkA, TrkB, and TrkC during development. These receptors bind to the neurotrophins NGF, BDNF, and NT-3, respectively. We have shown that favorable neuroblastoma express TrkA and TrkC, while unfavorable, N-myc amplified neuroblastomas express TrkB. In medulloblastomas, high expression of TrkC is associated with more favorable outcome. These studies have lead to our hypothesis that activation of TrkA and/or TrkC induces differentiation leading to a favorable outcome, while activation of TrkB is critical to the survival or growth of unfavorable tumors. Supporting this concept are studies in neuroblastoma that show a distinct difference in response to neurotrophin addition--favorable primary tumors respond to NGF by differentiation while BDNF promotes growth/ survival in cell lines. An important question raise by our hypothesis is how do different members of the Trk family promote the opposite fates of differentiation and growth. The goals of this proposal are to understand the roles of TrkB and TrkC in neuroblastoma and medulloblastoma pathogenesis and to elucidate the mechanism by which similar receptors promote different outcomes. Specifically, we will determine the role of TrkB receptors in unfavorable neuroblastomas by examining the signal transduction pathways in cell lines expressing endogenous TrkB. We will determine the activation patterns of the signaling intermediates, SHC, PI3 kinase, and PLC-gamma1, and determine if pathways involved in differentiation in PC12 cells--prolonged activation of ERK and phosphorylation of SNT--are induced by BDNF. We will determine whether the overexpression of TrkB or TrkC (expressed primarily in favorable tumors), mediates differentiation or cell growth. We will examine the role of TrkC receptors in favorable neuroblastomas by determining the effect of neurotrophin addition and withdrawal on primary cultures of favorable neuroblastomas. Signal transduction pathways will be examined when sufficient tissue is available. We plan to conduct parallel studies in medulloblastoma cell lines. We will determine the effect of BDNF and NT-3 and we will develop monoclonal antibodies that can specifically recognize TrkA, TrkB and TrkC by immunohistochemistry. The successful completion of these studies may provide important insights into the selective effects of activating the different Trk family receptors. Furthermore, our results should provide important information about the role of TrkB and TrkC in different subsets of neuroblastomas and medulloblastomas and medulloblastomas by their pattern of Trk expression may help predict outcome and guide therapy for these patients.

Project Start
1998-05-01
Project End
1999-04-30
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ho, Ruth; Eggert, Angelika; Hishiki, Tomoro et al. (2002) Resistance to chemotherapy mediated by TrkB in neuroblastomas. Cancer Res 62:6462-6
Eggert, A; Grotzer, M A; Zuzak, T J et al. (2002) Expression of Apo-3 and Apo-3L in primitive neuroectodermal tumours of the central and peripheral nervous system. Eur J Cancer 38:92-8
Tang, X X; Evans, A E; Zhao, H et al. (2001) Association among EPHB2, TrkA, and MYCN expression in low-stage neuroblastomas. Med Pediatr Oncol 36:80-2
Eggert, A; Grotzer, M A; Zuzak, T J et al. (2001) Resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in neuroblastoma cells correlates with a loss of caspase-8 expression. Cancer Res 61:1314-9
Grotzer, M A; Wiewrodt, R; Janss, A J et al. (2001) High microvessel density in primitive neuroectodermal brain tumors of childhood. Neuropediatrics 32:75-9
Grotzer, M A; Janss, A J; Fung, K M et al. (2001) Abundance of apoptotic neoplastic cells in diagnostic biopsy samples is not a prognostic factor in childhood primitive neuroectodermal tumors of the central nervous system. J Pediatr Hematol Oncol 23:25-9
Grotzer, M A; Geoerger, B; Janss, A J et al. (2001) Prognostic significance of Ki-67 (MIB-1) proliferation index in childhood primitive neuroectodermal tumors of the central nervous system. Med Pediatr Oncol 36:268-73
Geoerger, B; Kerr, K; Tang, C B et al. (2001) Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy. Cancer Res 61:1527-32
Evans, A E; Kisselbach, K D; Liu, X et al. (2001) Effect of CEP-751 (KT-6587) on neuroblastoma xenografts expressing TrkB. Med Pediatr Oncol 36:181-4
Eggert, A; Grotzer, M A; Ikegaki, N et al. (2001) Expression of the neurotrophin receptor TrkB is associated with unfavorable outcome in Wilms' tumor. J Clin Oncol 19:689-96

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