Combined biological therapy of breast cancer using monoclonal antibodies directed against HER2/neu protein and vascular endothelial growth factor.
Vascular endothelial growth factor (VEGF) is one of the most important endothelial mitogens involved in the development and differentiation of the vascular system. Vascular endothelial growth factor is a highly conserved, homodimeric glycoprotein with multiple isoforms. The most abundant isoform, VEGF165, binds to vascular endothelial growth factor receptors-1 (Flt-1) and 2 (KDR/Flk-1) with picomolar affinity. Recently, correlation between microvessel density and engineered expression of VEGF in human breast xenografts was observed. A role of VEGF in breast cancer progression is evident from clinical studies showing elevated serum VEGF in invasive breast cancers. Vascular endothelial growth factor in breast tumor cytosols is correlated with microvessel density, and VEGF165 content correlates with disease-free and overall survival in primary breast cancers. Preliminary data indicate a transcriptional upregulation of VEGF in HER2-overexpressing breast cancer cells. We hypothesize that the upregulation of VEGF in HER2-overexpressing breast cancers contributes to the aggressive phenotype observed in HER2-positive cases and that the "angiogenic switch" associated with HER2 can be attenuated by trastuzumab. Although tumor angiogenesis in breast cancer is complex, the VEGF/vascular endothelial growth factor receptor (VEGFR) system provides a useful model for testing new angiogenesis inhibitors that target this pathway. The VEGF/VEGFR system provides a number of opportunities for therapeutic intervention in breast cancer. Understanding the biology of this system is paramount to fully exploiting VEGF as a therapeutic target in breast cancer. We hypothesize that new therapeutic molecules targeting VEGF and/or its receptors, such as recombinant humanized monoclonal anti-VEGF antibody (rhuMAb VEGF), may have unique activity against HER2-overexpressing breast cancers.
Division of Hematology-Oncology and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA.
Mark D
MD
Pegram
David M
DM
Reese
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008222:Lymphokines / Q000037:antagonists & inhibitors*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D016228:Endothelial Growth Factors; D008222:Lymphokines; D018719:Erb-b2 Receptor Tyrosine Kinases; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C467484:VEGFA protein, human