For the past several years, our laboratory has been involved in the design and preclinical development of specifically targeted chemotherapeutic approaches to neuroblastoma. In the course of this work and recent work of other laboratories, it has become clear that resistance of neuroblastoma to chemotherapy correlates with the expression of tumor cell receptors for neurotrophins like nerve growth factor (NGF). Specifically, NGF can protect neuroblastoma cells from apoptosis induced by a variety of mechanically distinct chemotherapeutic agents. Two cell surface receptors have been identified for NGF. TrkA binds NGF with high affinity, while p75 binds this peptide with low affinity. Recent circumstantial evidence from several laboratories, including our own, has led to the hypothesis that the role of each of the receptors in the anti-apoptotic (and therefore chemoresistive) effect of NGF is critically dependent on the ratio of p75 to TrkA on the neuroblastoma cell surface. Preliminary data from other laboratories indicates that the p75/TrkA ratio correlates with clinical failure of chemotherapy. Using human neuroblastoma cells genetically engineered to differ only in their p75/TrkA ratio, and a series of novel highly selective p75 and TrkA ligands designed and synthesized by our co-investigator, we propose to definitively test this hypothesis both in vitro and in a nude mouse xenograft model of neuroblastoma. We will also define the downstream mechanistic changes in signal transduction that result from changes in the p75/TrkA ratio. These studies will identify therapeutic targets linked to the p75/TrkA ratio of neuroblastoma cells, and will begin to develop NGF analogues as potential therapeutic agents for overcoming NGF-mediated resistance of neuroblastoma to chemotherapeutic agent-induced apoptosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS038569-01A1
Application #
6040903
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Jacobs, Tom P
Project Start
1999-12-24
Project End
2003-11-30
Budget Start
1999-12-24
Budget End
2000-11-30
Support Year
1
Fiscal Year
2000
Total Cost
$228,874
Indirect Cost
Name
Children's Hosp Pittsburgh/Upmc Health Sys
Department
Type
DUNS #
044304145
City
Pittsburgh
State
PA
Country
United States
Zip Code
15224
Schor, Nina F (2018) A Life at the Interface: The 2017 Hower Award Lecture. Pediatr Neurol 80:3-7
Ratner, Nancy; Brodeur, Garrett M; Dale, Russell C et al. (2016) The ""neuro"" of neuroblastoma: Neuroblastoma as a neurodevelopmental disorder. Ann Neurol 80:13-23
Ganeshan, Veena R; Schor, Nina F (2014) p75 neurotrophin receptor and fenretinide-induced signaling in neuroblastoma. Cancer Chemother Pharmacol 73:271-9
Schor, Nina F (2013) Why our patients (and we) need basic science research. Neurology 80:2070-5
Ganeshan, Veena; Ashton, John; Schor, Nina F (2013) p75NTR: an enhancer of fenretinide toxicity in neuroblastoma. Cancer Chemother Pharmacol 71:777-87
Rogers, Danny A; Schor, Nina F (2013) Kidins220/ARMS is expressed in neuroblastoma tumors and stabilizes neurotrophic signaling in a human neuroblastoma cell line. Pediatr Res 74:517-24
Schor, Nina F (2013) Aiming at neuroblastoma and hitting other worthy targets. J Child Neurol 28:768-73
Ingraham, Christopher A; Wertalik, Larissa; Schor, Nina F (2011) Necdin and neurotrophin receptors: interactors of relevance for neuronal resistance to oxidant stress. Pediatr Res 69:279-84
Ganeshan, Veena R; Schor, Nina F (2011) Pharmacologic management of high-risk neuroblastoma in children. Paediatr Drugs 13:245-55
Rogers, Danny; Schor, Nina F (2010) The child is father to the man: developmental roles for proteins of importance for neurodegenerative disease. Ann Neurol 67:151-8

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