- Universität Zürich > Medizinische Fakultät > Kinderspital Zürich > Onkologie, Abteilung > Prof. Dr. Felix Niggli
- Grotzer
Completed Research Project
- Title / Titel
- Inhibition of Insulin-like Growth Factor I Receptor Signaling in Pediatric Teratoid/Rhabdoid CNS Tumors
- Summary / Zusammenfassung
- Central nervous system (CNS) atypical teratoid/rhabdoid tumors (ATT/RhT) are among the pediatric malignant tumors with the worst prognosis and fatal outcome. To date there are no explanations for their remarkable resistance to cytostatic drugs and radiotherapy. Insulin-like growth factor I receptor (IGF-IR) plays a critical role in cell survival, proliferation, transformation and regulation of apoptosis. IGF-IR protects cancer cells from apoptosis induced by a variety of anticancer drugs and radiation, but when impaired by inhibitors such as antisense strategies, dominant negative mutants, or triple-helix formation, tumor cells undergo massive apoptosis, resulting in an inhibition of tumorigenesis and metastases in experimental animal models. Our preliminary studies using MIB-1 immunohistochemistry and terminal deoxytransferase-mediated dUTP nick-end labeling (TUNEL) showed that primary CNS ATT/RhT have marked tumor cell proliferation while they have relatively little tumor cell apoptosis. IGF-IR was found to be clearly over-expressed in ATT/RhT compared to near normal brain samples and to other pediatric CNS neoplasms as confirmed by Western blotting and immunohistochemistry. Moreover, we found IGF-I and IGF-II mRNA in an ATT/RhT cell line. Taken together, our preliminary results suggest the presence of an autocrine/paracrine IGF-I/II/IGF-IR loop in ATT/RhT that may be responsible for the low susceptibility of ATT/RhT cells to undergo apoptosis. The aims of the proposed study are to assess the biological consequences of inhibiting IGF-IR activity in ATT/RhT cell lines as well as in ATT/RhT xenograft models by an antisense strategy. We expect that our efforts to modulate the function of IGF-IR in ATT/RhT will form the basis of a better understanding of ATT/RhT biology and lead to novel therapeutic strategies.
- Publications / Publikationen
- Patti R, Reddy CD, Geoerger B, Grotzer MA, Manchala R, Sutton LN, Phillips PC. Autocrine secreted insulin-like growth factor-I stimulates MAP kinase-dependent mitogenic effects in human primitive neuroectodermal tumor/medulloblastoma. International Journal of Oncology 2000;16:577-84
- Keywords / Suchbegriffe
- brain tumor; apoptosis; targeted therapies
- Project Leadership and Contacts /
Projektleitung und Kontakte PD Dr. M. Grotzer (Project Leader) michael.grotzer@kispi.uzh.ch Dr. Tarek Shalaby tarek.shalaby@kispi.uzh.ch
- Funding Source(s) /
Unterstützt durch - Foundation
Krebsliga des Kantons Zürich
- In Collaboration with /
In Zusammenarbeit mit Dr. Ratnakar Patti, The Children's Hospital of Philadelphia, PA 19104, USA United States
- Duration of Project / Projektdauer
- Dec 2002 to Nov 2003