PhD program N090/N094

Vascular BiologyJune 2008

Inhibition of angiogenesis

VEGF / VEGFR inhibitors

Erhard Hofer

Department of Vascular Biology and Thrombosis ResearchCenter for Biomolecular Medicine and PharmacologyMedical University of Vienna

Figure 13.49 The Biology of Cancer (© Garland Science 2007)

Heterotypic interactions as targets for therapeutic intervention

Inhibition of tumor angiogenesis

1-Bevacizumab 2-VEGF-trap

3-Pegaptinib

(Combination with 5-fluorouracil forcolorectal cancer)

(Macular degeneration)

4

5- SU11248 Bay43-9006

6- downstream Signals ?

Inhibition of angiogenesis

inhibition of VEGF and VEGF signalingmAb-based

Anti-VEGF- Avastinanti-VEGFR

VEGF traptyrosine kinase inhibitors

Tumor:normalization of tumor vesselscombination therapy

Macular degeneration

Prospects for vascular tumor targetingand gene therapy

Avastin

(Bevacizumab)

Genentech Inc.

Effects on ATCC

tumor cell lines

rhabdomyosarcoma

glioblastoma leiommyosarcoma

Renal cell cancerPhase II trialSingle agent

Based on this phase IIIStudiesIFN-a + BevacizumabIs conductedIn renal cancer

Side effects:FeverHypertensionproteinurea

BevacizumabColorectal cancerPhase IIICombination therapy

Hurwitz et al. 2004Mass et al. 2004

IFL: Irinotecan5-fluorouracilleucovorin

Kabbinavar et al., 2005

5-fluorouracilleucovorin

DC101 - VEGFR2 mAb

AZD21771 - Astra Zeneca - preclinical

ATP-competitiveVEGFR2 kinase inhibitor,Mimics binding ofATP adenine ring

SU11248 - Sunitinib - Pfitzer

GIST (gastrointestinal stromal tumorsKidney cancerApproved 2006

Vascular tumor targeting

Gentherapien:

rAdenovirenrRetroviren

Targeting of viruses to tumors, tumor endothelium

Targeting of liposomes to tumors, tumor endothelium

Oncolytic viruses

BM progenitor cells home to tumor vasculature