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Address for correspondence: John V. Heymach, MD, PhD, Dept. of Thoracic/Head and Neck Medical Oncology, M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 432, Houston, TX 77030-4009
Department of Cancer Biology, University of Texas, M. D. Anderson Cancer Center, Houston, TXDepartment of Thoracic/Head and Neck Medical Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, TX
The search for tumor-derived factors that stimulate angiogenesis led to the identification of vascular endothelial growth factor (VEGF, also known as VEGF-A) as an endothelial mitogen.
The VEGF gene undergoes alternative splicing to yield at least five different isoforms, ranging in size from 121 to 206 amino acids, of which VEGF165 is the predominant form.
THE VEGF FAMILY
VEGF is now known to be the prototypic member of a family of structurally related dimeric proteins including VEGF-B, VEGF-C, VEGF-D, and VEGF-E, as well as placental-growth factor (PlGF) -1 and -2.
Indeed, VEGF family members are important in physiological angiogenic processes in the adult including wound healing, ovulation, and pregnancy, as well as pathological conditions such as cancer.
VEGF ligands activate angiogenic programs through binding of several receptors. VEGFR-1 (Flt-1) binds VEGF, VEGF-B, and PlGF -1,2 and promotes recruitment of endothelial progenitors and monocyte migration. VEGFR-2 (Flk-1/KDR) is expressed on nearly all endothelial cells and binds VEGF, VEGF-C, VEGF-D, and VEGF-E. Signal transduction through VEGFR2 has been shown to regulate endothelial cell proliferation, migration, and survival.
although VEGFR-3 may also be expressed on tumor-associated blood vessels. Through binding to VEGF-C and VEGF-D, VEGFR-3 is thought to facilitate the outgrowth of lymphatic vessels. Neuropilin (NRP)-1,2 have been demonstrated to be coreceptors for VEGF. NRP-1 binds VEGF165 and PlGF, and NRP-2 binds VEGF165 and VEGF-C.
Unlike other VEGFRs, NRP-1,2 lack intracellular signaling domains. Although the specific role of NRP-1,2 in angiogenesis is not fully known, NRP-1,2 bind VEGF ligands and enhance their affinity to other VEGFRs.
Although VEGF-A binds VEGFR1 with a higher affinity than VEGFR-2, the biological effects of VEGF-A are thought to be mediated through VEGFR-2. On ligand binding, VEGFR-2 dimerizes, resulting in kinase activation and autophosphorylation of tyrosine residues including Tyr951, Tyr996, Tyr1054, Tyr1175, and Tyr1214.
Phosphorylation of these residues leads to the activation of signal-transduction molecules phospholipase C-γ (PLC-γ), PI3K, Akt, Ras, Src, and MAPK (Figure 1). Phosphorylation of Tyr1175 results in the binding and phosphorylation of PLC-γ, which subsequently stimulates the release of Ca2+ from internal stores and activation of protein kinase C (PKC). Activation of PKC stimulates the Raf/MEK/ERK pathway, which promotes cell proliferation. Ca2+ mobilization and PKC activation are thought to be key signaling events in VEGF-A–induced vascular permeability via activation of endothelial nitric oxide synthase activity.
FIGURE 1Signal transduction via the VEGF family. VEGF family members, VEGF, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and PlGF bind three VEGFR tyrosine kinases, resulting in dimerization, receptor autophosphorylation, and activation of downstream signal-transduction pathways. Signal transduction through VEGFR2 is shown. Ligand binding to VEGFR2 activates signal-transduction molecules phospholipase C-γ(PLC-γ), PI3K, Akt, Ras, Src, and MAPK and regulates cell proliferation, migration, survival, and vascular permeability.
PI3K is a heterodimer composed of a p85 regulatory subunit and a p110 catalytic subunit and is critical in the regulation of cell proliferation, migration, and survival. VEGF-A has been shown to stimulate phosphorylation of p85 and enhance PI3K enzymatic activity. The mechanism by which VEGF-A results in activation of PI3K remains unclear, although studies have implicated a role for Src kinases, β-catenin, and VE-cadherin.
VEGFR-2–induced activation of PI3K results in accumulation of phosphatidylinositol-3,4,5-triphosphate, which induces phosphorylation of Akt/PKB. Once activated, Akt/PKB phosphorylates and thus inhibits proapoptotic proteins, BAD, and caspase-9.
Members of the Src family kinases, Src, Fyn, and Yes, are expressed in endothelial cells. After VEGFR-2 autophosphorylation, T-cell–specific adapter binds Tyr951 and then associates with Src. Src kinases regulate actin stress fiber organization and may mediate VEGF-A–induced PI3K activation. Ligand binding to VEGFR-2 also triggers activation of the Ras pathway, initiating signaling through the Raf-1–MEK–ERK signal cascade
known to be important in growth factor–induced cell proliferation. This activation may occur through multiple routes. The adaptor protein Grb2 is thought to bind pTyr1214 on VEGFR-2, leading to stimulation of the guanine-nucleotide–exchange protein Sos and activation of Ras.
Several different types of agents have been developed to target the VEGF pathway. These include monoclonal antibodies against VEGF (i.e., bevacizumab) and proteins that bind VEGF such as VEGF Trap, a molecule generated as a fusion protein of the VEGFR extracellular domain and the Fc portion of immunoglobulin G1. Other strategies to target the VEGF pathway include antibodies that block the receptor (IMC-1121b) as well as small-molecule inhibitors of the receptor tyrosine kinase such as sunitinib, sorafenib, and ZD6474 (Table 1). Receptor tyrosine kinase inhibitors are typically administered orally, and because of the structural similarity of the different receptor tyrosine kinases, they generally inhibit multiple kinases in addition to the VEGF receptors. Representative agents targeting the VEGF pathway that are currently in clinical testing are listed in Table 1. The clinical activity of other therapeutic agents such as COX-2 inhibitors, thalidomide, and EGFR inhibitors may also be attributable, at least in part, to reduced expression of VEGF and other proangiogenic factors.
TABLE 1Examples of Agents in Clinical Development Targeting the VEGF Pathway
The VEGF pathway has now been validated as a therapeutic target by phase III randomized clinical trials for patients with several different tumor types. In patients with previously untreated non-small cell lung cancer, the addition of bevacizumab to carboplatin and paclitaxel prolonged survival by approximately 2 months compared with treatment with carboplatin and paclitaxel alone.
Randomized phase II/III Trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC # 704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) Trial - E4599 (Abstract).
Patients with squamous cell histology were excluded from this trial because of a high rate of life-theatening hemoptysis observed in phase II testing of the same regimen. The addition of bevacizumab to chemotherapy has provided benefit in other tumor types as well, including colorectal, breast, and renal-cell cancer.
Randomized phase II/III Trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC # 704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) Trial - E4599 (Abstract).
Randomized Phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC) (Abstract).
Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma.
Currently, there are ongoing trials using VEGF pathway inhibitors for virtually every type of tumor, and it seems likely that they will become a standard component of treatment for a broad range of tumor types. But despite this progress, major challenges remain. These include developing biomarkers to predict which patients are most likely to respond to treatment; improving management of toxicities, particularly hemoptysis and cardiovascular/thromboembolic complications; and understanding mechanisms of therapeutic resistance so that combinations of VEGF inhibitors with other types of therapy can be more rationally designed.
Randomized phase II/III Trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC # 704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) Trial - E4599 (Abstract).
Randomized Phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC) (Abstract).
Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma.
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