Agents inhibiting tumor angiogenesis have been developed as a new class of anticancer agents. Several of these therapeutics target the vascular endothelial growth factor (VEGF) signaling pathway. VEGF comprises several isoforms which bind to different receptors, including FLT1, KDR, and NRP1, and promote angiogenesis through activation of a kinase cascade that includes RAS and MAPK. Drugs that are known to interfere with the normal VEGF signaling pathway include bevacizumab, a monoclonal antibody; sorafenib and sunitinib, small molecule kinase inhibitors; and experimental drugs aflibercept, brivanib, cilengitide, axitinib, motesanib, and vandetanib.
Bevacizumab, a monoclonal antibody targeting VEGFA, is indicated in combination with intravenous 5-fluoruracil-based chemotherapy for first-line or second-line treatment of patients with metastatic carcinoma of the colon or rectum, and in combination with carboplatin and paclitaxel for first-line treatment of patients with unresectable, locally advanced, recurrent, or metastatic nonsquamous, nonsmall cell lung cancer. Bevacizumab is also indicated in combination with paclitaxel for treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer and for glioblastoma, as a single agent for patients with progressive disease following prior therapy (Avastin (bevacizumab) drug label: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125085s0169lbl.pdf; retrieved 27 July 2009).
Sorafenib and sunitinib are small molecule kinase inhibitors. They have overlapping activity but differing potency for inhibition of VEGFR1 (FLT1) and VEGFR2 (KDR), and sorafenib has high potency inhibition of Raf-1 (RAF1) and p38 MAP kinase (MAPK). Sunitinib has higher potency inhibition for kinases not depicted here. Sorafenib is indicated for the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma (Nexavar (sorafenib) drug label: http://www.fda.gov/cder/foi/label/2007/021923s004s005s006s007lbl.pdf; retrieved 7 May 2009). Sunitinib is indicated for the treatment of gastrointestinal stromal tumor after disease progression or intolerance to imatinib mesylate and for advanced renal cell carcinoma (Sutent (sunitinib) drug label: http://www.fda.gov/cder/foi/label/2007/021968s002s003s004s005s006lbl.pdf; retrieved May 7, 2009). Brivanib, cilengitide, axitinib, motesanib, and vandetanib are experimental drugs influencing the angiogenesis pathway.
Recently, an association was found between VEGFA genotype and treatment outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab to treat metastatic breast cancer. The AA genotype of VEGF: 2578C > A (rs699947), a promoter polymorphism, was associated with superior median overall survival in patients receiving both paclitaxel and bevacizumab. Patients in the combination arm who carried the A allele of VEGF: 1154G > A (rs1570360) also showed superior median overall survival. These results will require confirmation to support a role for VEGFA polymorphisms in affecting clinical outcome following bevacizumab treatment for metastatic breast cancer.
Several studies have investigated variants in angiogenesis pathway genes for association with disease risk. Studies focusing on VEGFA have produced conflicting results: Schneider et al. reported that the A allele of VEGFA: -2578C > A (rs1547651) and the C allele of VEGFA: -1498T > C (rs833061) are associated with increased breast cancer risk. Lu et al. found that the 460C (rs833061) and +405G (rs2010963) VEGFA alleles were significantly associated with reduced overall survival after diagnosis of breast cancer, and that the -460T/+405C/+936C (rs3025039) haplotype was significantly associated with increased overall survival. A large-scale evaluation of single nucleotide polymorphisms (SNPs) identified four SNPs in the VEGFA promoter region the TT genotype of VEGFA:Ex1-73C > T ([rs25648) the AA genotype of VEGFA: -15648A > C (rs833052), the TT genotype of VEGFA: -9228G > T (rs1109324), and the TT genotype of VEGFA: -8339A > T (rs1547651)] that were associated with increased bladder cancer risk and one intronic SNP associated with reduced bladder cancer risk the CT genotype of VEGFA:IVS2+1378C > T ([rs3024994)]. The CC genotype of VEGFA: -1498T > C (rs833061) has been shown to be associated with decreased risk of bone metastases in breast cancer patients. Other research has shown no association between VEGFA variants and risk of developing breast cancer, colorectal cancer, prostate cancer, or non-small cell lung cancer.
Selected polymorphisms in other VEGF pathway genes, including KDR, FLT1, NOS3, and NRP1 were not associated with breast cancer risk. The same study also found that the NOS3: -786TT (rs2070744) genotype is significantly associated with greater likelihood of invasive breast cancer, and that the NOS3: 894GG (rs1799983) genotype is associated with increased likelihood of having metastatic disease. Further research is necessary to clarify the role of angiogenesis pathway gene variants in disease etiology and drug treatment outcome.
As a guide to future investigation of potential mechanisms of inter-individual variability of efficacy and toxicity, multiple signaling molecules and a simplified depiction of their interactions are diagrammed. While these signaling pathways are active in multiple cell types, the diagram and the supporting data are limited to the endothelial cell, as endothelial cells are thought to be the primary target of these agents in the treatment of cancer. Many more interactions and molecules have been described as important to angiogenesis and to VEGF signaling. This diagram, however, limits its scope to the molecules inhibited by the depicted agents and the immediately interacting signaling molecules shown primarily in mammals or mammalian cell lines.
As a guide to future investigation of potential mechanisms of interindividual variability of efficacy and toxicity, multiple signaling molecules and a simplified depiction of their interactions are diagrammed. While these signaling pathways are active in multiple cell types, as endothelial cells are thought to be the primary target of these agents in the treatment of cancer, the diagram and the supporting data are limited to the endothelial cell. Many more interactions and molecules have been described as important to angiogenesis and to VEGF signaling. This diagram however limits its scope to the molecules inhibited by the depicted agents and the immediately interacting signaling molecules demonstrated primarily in mammals or mammalian cell lines.
Maitland Michael L, Lou Xing Jian, Ramirez Jacqueline, Desai Apurva A, Berlin Dorit S, McLeod Howard L, Weichselbaum Ralph R, Ratain Mark J, Altman Russ B, Klein Teri E. "Vascular endothelial growth factor pathway" Pharmacogenetics and genomics (2010).
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