The vascular endothelial growth factor (VEGF receptor) signaling pathways include 3 membrane-bound receptors (VEGF receptors -1, -2, and -3). These receptors are selectively bound and activated by 7 different ligands
(VEGF-A, B, C, D, and E and placenta growth factor-1).
- VEGF receptor-1 is implicated in immune modulation and participates in a number of processes,
including:
- Angiogenesis
- Tumor cell survival
- Monocyte migration
- VEGF receptor-2 is the predominant mediator of angiogenesis
- VEGF receptor-3 signaling has a primary role in metastatic tumor colonization, mainly through lymphangiogenesis
VEGF receptor activation through kinase phosphorylation triggers a downstream cascade of reactions. This signal
transduction results in specific cellular responses that may play a role in tumor progression. Therefore, the
VEGF receptor pathways present an interesting target for clinical investigation.
All 3 VEGF receptors can be expressed in certain cancer cell lines, where they are thought to stimulate
cell proliferation and survival when their respective ligands activate autocrine mechanisms.
- Emerging preclinical evidence suggests that VEGF receptors -1, -2, and -3 are important for tumor cell proliferation
- Preclinical evidence has shown that blocking VEGF receptor-1 may lead to tumor cell apoptosis and
directly inhibit tumor growth
- In animal studies, blocking VEGF receptor-2 signaling decreased tumor growth and prolonged survival
- In preclinical studies, when VEGF receptor-3 was blocked, the viability of malignant cells was
compromised. Therefore, in addition to its known role in lymphangiogenesis, VEGF receptor-3 is thought to play a role in
tumor cell survival
- Preclinical studies have shown that blocking VEGF receptor-2 signaling disrupts the formation of tumor
vasculature
- More recent preclinical evidence suggests that VEGF receptor-3 signaling may also play an important role
in vascular angiogenesis by supporting the formation of new tumor vasculature. In preclinical studies, blocking
VEGF receptor-3 decreased the size and density of tumor blood vessels
- Interactions have also been observed between VEGF receptor-3 and VEGF receptor-2. Research has shown that VEGF receptor-2 can activate the VEGF receptor-3 pathway, leading to synergistic angiogenic effects
- In a preclinical study, blocking VEGF receptor-3 leads to normalization of lymphatic vessels and suppressed lymph node and distant metastases
- In addition to VEGF receptor-3, VEGF receptors-1 and -2 are involved in tumor metastasis. Blockade of both VEGF receptor-1 and VEGF receptor-3 signaling, in a preclinical study, reduced the functionality of lymphatic vessels and metastasis of tumor cells. VEGF receptor-2 has also been observed in lymphatic vessels and capillaries that are undergoing lymphangiogenesis.
- In a preclinical study, blockade of both VEGF receptor-1 and VEGF receptor-2 signaling reduced the
functionality of lymphatic vessels and metastasis of tumor cells
VEGF receptor signaling pathways may be blocked extracellularly by monoclonal antibody binding of a circulating ligand. These pathways may also be blocked intracellularly by binding the receptor tyrosine kinase.
Preclinical evidence suggests that blocking all 3 VEGF receptor signaling pathways may more efficiently disrupt tumor cell proliferation, angiogenesis, and metastatic tumor colonization than blocking an individual pathway.
Information in the Oncology Investigational Pipeline relates to therapies currently
being researched.
References: 1. Rugo HS, Herbst RS, Liu G, et al. Phase I trial of the oral
antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic
and clinical results. J Clin Oncol. 2005;23:5474-5483. 2. Spano JP,
Moore M, Kim S, et al. A phase I study of axitinib (AG-013736), a potent inhibitor
of VEGFRs, in combination with gemcitabine (GEM) in patients (pts) with advanced
pancreatic cancer. J Clin Oncol. 2006;24(suppl):Abstract 13092. 3.
Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in
tumor growth and angiogenesis. J Clin Oncol. 2005;23:1011-1027. 4.
Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med.
2003;9:669-676. 5. Zeng H, Dvorak HF, Mukhopadhyay D. Vascular permeability
factor (VPF)/vascular endothelial growth factor (VEGF) receptor-1 down-modulates
VPF/VEGF receptor-2-mediated endothelial cell proliferation, but not migration,
through phosphatidylinositol 3-kinase-dependent pathways. J Biol Chem.
2001;276:26969-26979.
6. Stacker SA, Caesar C, Baldwin ME, et al. VEGF-D promotes the metastatic
spread of tumor cells via the lymphatics. Nat Med. 2001;7:186-191. 7.
Data on file. Pfizer Inc, New York, NY.
|
|