Skip to main content

ZD6474, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor, inhibits tumor growth of multiple nervous system tumors.

Publication ,  Journal Article
Rich, JN; Sathornsumetee, S; Keir, ST; Kieran, MW; Laforme, A; Kaipainen, A; McLendon, RE; Graner, MW; Rasheed, BKA; Wang, L; Reardon, DA ...
Published in: Clin Cancer Res
November 15, 2005

PURPOSE: Primary central nervous system (CNS) tumors represent a diverse group of tumor types with heterogeneous molecular mechanisms that underlie their formation and maintenance. CNS tumors depend on angiogenesis and often display increased activity of ErbB-associated pathways. Current nonspecific therapies frequently have poor efficacy in many of these tumor types, so there is a pressing need for the development of novel targeted therapies. EXPERIMENTAL DESIGN: ZD6474 is a novel, orally available low molecular weight inhibitor of the kinase activities associated with vascular endothelial growth factor receptor-2 and epidermal growth factor receptor. We hypothesized that ZD6474 may provide benefit in the treatment of several CNS tumor types. RESULTS: In mice bearing established s.c. tumor xenografts of CNS tumors (malignant glioma and ependymoma) or rhabdomyosarcoma, a limited course of ZD6474 treatment produced significant tumor growth delays and a high rate of partial tumor regression in most models examined. Mice with i.c. malignant glioma xenografts treated with ZD6474 experienced a significant prolongation of survival. Tumors from mice treated with ZD6474 displayed a lower proliferative index and disrupted tumor vascularity. Notably, some of these models are insensitive to low molecular weight kinase inhibitors targeting only vascular endothelial growth factor receptor-2 or epidermal growth factor receptor functions, suggesting that the combined disruption of both epidermal growth factor receptor and vascular endothelial growth factor receptor-2 activities may significantly increase tumor control. CONCLUSIONS: In conclusion, ZD6474 shows significant activity against xenograft models of several primary human CNS tumor types. Consideration for clinical development in this disease setting seems warranted.

Duke Scholars

Published In

Clin Cancer Res

DOI

ISSN

1078-0432

Publication Date

November 15, 2005

Volume

11

Issue

22

Start / End Page

8145 / 8157

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Receptors, Vascular Endothelial Growth Factor
  • Quinazolines
  • Piperidines
  • Phosphorylation
  • Oncology & Carcinogenesis
  • Neovascularization, Pathologic
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase 1
  • Mice, Nude
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Rich, J. N., Sathornsumetee, S., Keir, S. T., Kieran, M. W., Laforme, A., Kaipainen, A., … Friedman, H. S. (2005). ZD6474, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor, inhibits tumor growth of multiple nervous system tumors. Clin Cancer Res, 11(22), 8145–8157. https://doi.org/10.1158/1078-0432.CCR-05-0319
Rich, Jeremy N., Sith Sathornsumetee, Stephen T. Keir, Mark W. Kieran, Andrea Laforme, Arja Kaipainen, Roger E. McLendon, et al. “ZD6474, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor, inhibits tumor growth of multiple nervous system tumors.Clin Cancer Res 11, no. 22 (November 15, 2005): 8145–57. https://doi.org/10.1158/1078-0432.CCR-05-0319.
Rich JN, Sathornsumetee S, Keir ST, Kieran MW, Laforme A, Kaipainen A, et al. ZD6474, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor, inhibits tumor growth of multiple nervous system tumors. Clin Cancer Res. 2005 Nov 15;11(22):8145–57.
Rich, Jeremy N., et al. “ZD6474, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor, inhibits tumor growth of multiple nervous system tumors.Clin Cancer Res, vol. 11, no. 22, Nov. 2005, pp. 8145–57. Pubmed, doi:10.1158/1078-0432.CCR-05-0319.
Rich JN, Sathornsumetee S, Keir ST, Kieran MW, Laforme A, Kaipainen A, McLendon RE, Graner MW, Rasheed BKA, Wang L, Reardon DA, Ryan AJ, Wheeler C, Dimery I, Bigner DD, Friedman HS. ZD6474, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor, inhibits tumor growth of multiple nervous system tumors. Clin Cancer Res. 2005 Nov 15;11(22):8145–8157.

Published In

Clin Cancer Res

DOI

ISSN

1078-0432

Publication Date

November 15, 2005

Volume

11

Issue

22

Start / End Page

8145 / 8157

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Receptors, Vascular Endothelial Growth Factor
  • Quinazolines
  • Piperidines
  • Phosphorylation
  • Oncology & Carcinogenesis
  • Neovascularization, Pathologic
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase 1
  • Mice, Nude