Inhibition of angiogenesis

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Presentation transcript:

Inhibition of angiogenesis PhD program N090/N094 Vascular Biology June 2008 Inhibition of angiogenesis VEGF / VEGFR inhibitors Erhard Hofer Department of Vascular Biology and Thrombosis Research Center for Biomolecular Medicine and Pharmacology Medical University of Vienna

Heterotypic interactions as targets for therapeutic intervention Figure 13.49 The Biology of Cancer (© Garland Science 2007)

Inhibition of tumor angiogenesis (Combination with 5-fluorouracil for colorectal cancer) 1-Bevacizumab 2-VEGF-trap 3-Pegaptinib (Macular degeneration) 4 6- downstream Signals ? 5- SU11248 Bay43-9006

Inhibition of angiogenesis inhibition of VEGF and VEGF signaling mAb-based Anti-VEGF- Avastin anti-VEGFR VEGF trap tyrosine kinase inhibitors Tumor: normalization of tumor vessels combination therapy Macular degeneration Prospects for vascular tumor targeting and gene therapy

Avastin (Bevacizumab) Genentech Inc. Effects on ATCC tumor cell lines rhabdomyosarcoma Avastin (Bevacizumab) Genentech Inc. Effects on ATCC tumor cell lines glioblastoma leiommyosarcoma

Renal cell cancer Phase II trial Single agent Based on this phase III Studies IFN-a + Bevacizumab Is conducted In renal cancer Side effects: Fever Hypertension proteinurea

Bevacizumab Colorectal cancer Phase III Combination therapy Hurwitz et al. 2004 Mass et al. 2004 IFL: Irinotecan 5-fluorouracil leucovorin

Kabbinavar et al., 2005 5-fluorouracil leucovorin

DC101 - VEGFR2 mAb

AZD21771 - Astra Zeneca - preclinical ATP-competitive VEGFR2 kinase inhibitor, Mimics binding of ATP adenine ring AZD21771 - Astra Zeneca - preclinical

SU11248 - Sunitinib - Pfitzer GIST (gastrointestinal stromal tumors Kidney cancer Approved 2006

Vascular tumor targeting

Gentherapien: rAdenoviren rRetroviren Targeting of viruses to tumors, tumor endothelium Targeting of liposomes to tumors, tumor endothelium Oncolytic viruses BM progenitor cells home to tumor vasculature