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

Abstract

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.

Synergistic Antitumor Activity of ZD6474, An Inhibitor of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor Signaling, with Gemcitabine and Ionizing Radiation against Pancreatic Cancer

“…Tumor growth was also inhibited by ZD6474 in vivo; according to previous studies on solid tumor xenografts (13,29,44,45), chronic administration of ZD6474 is well tolerated in athymic mice and produces significant inhibition of tumor growth, which may result from inhibition of both EGFR and VEGFR-2 activity. Furthermore, preclinical studies with cetuximab, gefitinib, and, more recently, ZD6474 showed that these agents potentiated the antitumor activity of standard cytotoxics and radiotherapy (17,30,44,46).…”

Combined therapy of temozolomide and ZD6474 (vandetanib) effectively reduces glioblastoma tumor volume through anti-angiogenic and anti-proliferative mechanisms

“…Some of the factors known to be involved in angiogenesis include vascular endothelial growth factor (VEGF), epithelium growth factor (EGF), transforming growth factor (TGF), cathespin D, angiostatin, angiostatin-binding proteins, interleukin-4, VCAM-1 and cadherin, and the representative therapeutics in the clinic include thalidomide and ZD6474 (vandetanib) (16)(17)(18). For suppressing angiogenesis, therapeutics targeting EGFR have been developed since the receptor was shown to be involved in tumor growth, migration, infiltration and metastasis (19). ZD6474 is an orally administrable 4-anilinoquinazoline that specifically targets VEGFR2 and EGFR, and published reports indicate that its combination with radiotherapy leads to effective tumor control (8,19).…”

“…For suppressing angiogenesis, therapeutics targeting EGFR have been developed since the receptor was shown to be involved in tumor growth, migration, infiltration and metastasis (19). ZD6474 is an orally administrable 4-anilinoquinazoline that specifically targets VEGFR2 and EGFR, and published reports indicate that its combination with radiotherapy leads to effective tumor control (8,19). Based on these findings, we hypothesized that a combination of anti-angiogenic ZD6474 with TMZ would lead to a synergistic effect.…”

Angiogenesis: An update and potential drug approaches (Review)

“…In human tumor xenograft models of diverse tissue (lung, breast, prostate, colorectal, vulval) origin, chronic (once daily) administration of ZD6474 led to dose-dependent inhibition of tumor growth (71,74). It was also reported in the xenograft model that ZD6474 has high activity against several central nervous system tumors including gliomas (75). While there have been some recent drawbacks in the development of tyrosine kinase inhibitors (e.g., PTK/ZK; Schering/Novartis), a number of novel members of the same class have shown promising effects in clinical trials and some have been approved for clinical use.…”