This Project pursues laboratory studies which address the need for effective new treatment strategies for medulloblastoma (MB) and related primitive neuroectodermal tumors (PNET). These studies emphasize the role of tyrosine kinase growth factors as targets for therapeutic intervention in PNET and establish a basis for extending new insights about the neurobiology of PNET into the clinical setting. Our primary focus will be new treatments for leptomeningeal (LM) dissemination of PNETs. This serious clinical problem has a profound negative effect on treatment outcome and survival. Moreover, the most effective current treatment for LM- PNET is craniospinal radiation therapy (RT), which causes severe cognitive impairment in many long-term survivors. Identification of effective alternatives which permit dose reduction or elimination of craniospinal RT is likely to improve the duration and quality of survival for these children. Our studies indicate that intrathecal (i.t.) administration of cytotoxic drugs, monoclonal antibodies, immunotoxins, and recombinant toxins has specific therapeutic advantages over systemic administration. Accordingly, this project will study the efficacy and toxicity of new agents administered regionally for the treatment of LM-PNET.
In Aim 1, we will extend our studies of topoisomerase 1 (Topo 1) inhibitors to evaluate the neurotoxicity and therapeutic efficacy of i.t. treatment with camptothecin, a Topo 1 inhibitor, in a nude rat model of leptomeningeal MB. We will expand these studies by exploring potential synergistic interactions, identified by our in vitro cytotoxicity studies, between Topo 1 inhibitors and 4- hydroperoxy-cyclophosphamide.
In Aim 2, we will investigate the neurotoxicity and efficacy of recombinant Pseudomonas exotoxin (PE) fused with acidic fibroblast growth factor, alone or in combination with transforming growth factor alpha-PE, for i.t. treatment in a nude rat model of leptomeningeal MB.
In Aim 3, we will evaluate the neurotoxicity and efficacy of i.t. rapamycin, an inhibitor of insulin-like growth factor signal transduction, in a model of leptomeningeal MB. We will extend these studies in Aim 4 to identify factors which predict rapamycin sensitivity or resistance in MB. We anticipate that these studies will broaden the scope of PNET therapeutic strategies and will be applicable to other childhood and adult brain tumors.

Project Start
1997-06-01
Project End
1998-04-30
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
2
Fiscal Year
1997
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
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
Huber, H; Eggert, A; Janss, A J et al. (2001) Angiogenic profile of childhood primitive neuroectodermal brain tumours/medulloblastomas. Eur J Cancer 37:2064-72
Eggert, A; Ikegaki, N; Liu, X G et al. (2001) TrkA signal transduction pathways in neuroblastoma. Med Pediatr Oncol 36:108-10
Damodar Reddy, C; Marwaha, S; Patti, R et al. (2001) Role of MAP kinase pathways in primitive neuroectodermal tumors. Anticancer Res 21:2733-8

Showing the most recent 10 out of 41 publications