Grotzer
Fakultäten » Medizinische Fakultät » Kinderspital Zürich: Medizinische Klinik » Onkologie, Abteilung » Prof. Dr. Felix Niggli » Grotzer
Completed research project
| Title / Titel | Novel Therapeutic Approaches for Central Nervous System Primitive Neuroectodermal Tumors of Childhood | ||||||
|---|---|---|---|---|---|---|---|
| Abstract (PDF, 14 KB) | |||||||
| Summary / Zusammenfassung | Primitive neuroectodermal brain tumors (PNET) including medulloblastoma (PNET/MB) are the most common malignant childhood brain tumors. To evaluate whether oncogene MYC, Trk receptors, and neurotrophins can be defined as potential molecular prognostic markers of use for routine disease risk stratification of children with PNET/MB, we will analyze prospectively the expression of MYC, Trk receptors, and neurotrophins by quantitative RT-PCR in a multi-institution group effort (Aim 1). We anticipate that a single PNET might express different Trks at different expression levels. The following goals are directed to understand the role(s) of Trk receptor function and MYC in PNET. We will analyze the effects of neurotrophin addition and withdrawal on primary cultures of PNET and human PNET cell lines expressing different levels of TrkC (Aim 2). PNET expressing functional TrkC may be susceptible to programmed cell death or terminal neuronal differentiation through autocrine/paracrine secreted NT-3. Alternatively, functional TrkC may down-regulate angiogenesis in PNET similarly to TrkA in neuroblastoma another common childhood solid tumor with important biological similarities to PNET. Or, functional TrkC may regulate pathways previously not related to TrkC signaling. To understand the role(s) of MYC function in PNET, we will analyze primary cultures of PNET and human PNET cell lines expressing different levels of MYC (Aim 3). To determine whether TrkC receptor or MYC modulate treatment responsiveness in PNET, we will examine radio-sensitivity and sensitivity to anti-tumor drugs in primary PNET cultures and PNET cells expressing different levels of functional TrkC (Aim 4) and different levels of MYC (Aim 5). To identify novel therapeutic strategies for high-risk patients, we will downregulate MYC by treatment with phosphorothioate oligodeoxy-nucleotides and a small drug MYC inhibitor in primary PNET cultures, PNET cell lines, and PNET xenografts (Aim 6). Also to identify novel therapeutic strategies, we will restore caspase-dependent apoptosis pathways in primary PNET cultures, PNET cell lines, and PNET xenografts (Aim 7). | ||||||
| Publications / Publikationen | Grotzer MA, Janss AJ, Fung K-M, Biegel JA, Sutton LN, Rorke LB, Zhao H, Cnaan A, Phillips PC, Lee VMY, Trojanowski JQ. TrkC expression predicts good clinical outcome in primitive neuroectodermal brain tumors. Journal of Clinical Oncology 2000;18:1027-35Grotzer MA, Eggert A, Zuzak TJ, Marwaha S, Wiewrodt BR, Ikegaki N, Brodeur GM, Phillips PC. Resistance to TRAIL-induced apoptosis in PNET cells correlates with a loss of caspase-8. Oncogene 2000;19: 4604-4610Grotzer MA, Hogarty MD, Janss AJ, Liu X, Zhao H, Eggert A, Sutton LN, Rorke LB, Brodeur GM, Phillips PC. MYC messenger RNA expression predicts survival outcome in childhood primitive neuroectodermal tumor/medulloblastoma. Clinical Cancer Research 2001;7:2425-33Zuzak TJ, Steinhoff DF, Sutton LN, Phillips PC, Eggert A, Grotzer MA. Loss of caspase-8 gene expression is common in childhood primitive neuroectodermal braintumor/medulloblastoma. Eur J Cancer 2002;38: 83-91Pingoud-Meier C, Lang D, Janss AJ, Rorke LB, Phillips PC, Shalaby T, Grotzer MA. Loss of caspase-8 protein expression correlates with unfavorable survival outcome in childhood medulloblastoma. Clin Cancer Res 2003;9: 6401-6409 | ||||||
| Keywords / Suchbegriffe | brain tumor, medulloblastoma, prognosis, experimental therapies | ||||||
| Project leadership and contacts / Projektleitung und Kontakte |
|
||||||
| Funding source(s) / Unterstützt durch |
SNF (Personen- und Projektförderung) Forschungsstiftung Kind und Krebs |
||||||
| Duration of Project / Projektdauer | Apr 2004 to Mar 2008 |