Article

Antiangiogenic therapies targeting the vascular endothelia growth factor signaling system.

Royal Melbourne Hospital, Western Hospital, and Ludwig Institute for Cancer Research, Parkville, Victoria, Australia.
Critical reviews in oncogenesis 01/2012; 17(1):51-67. DOI: 10.1615/CritRevOncog.v17.i1.50
Source: PubMed

ABSTRACT Angiogenesis is critical to the growth of human tumors and the development of metastasis. Amongst the many proangiogenic mechanisms identified, the vascular endothelial growth factor (VEGF) signaling pathway has been implicated as the key regulator of tumor neovascularisation. Various therapeutic agents targeting the VEGF pathway have been successfully developed, with many now approved and in routine clinical use. In general, VEGF-mediated angiogenesis can be inhibited by 2 approaches: antibodies directed against VEGF ligands or VEGF receptors (VEGFRs) and tyrosine kinase inhibitors targeting the VEGFRs. Thus far, clinical benefits achieved with VEGF-targeted agents are limited by their modest efficacy and the development of resistance. With no shortage of drugs in development, the lack of well-validated biomarkers to predict for response or resistance to VEGF-directed therapies is now becoming a key factor limiting the further rational development of this class of anticancer agent. This review discusses the biology of VEGF signaling, the clinical efficacy of VEGF-targeting therapies, potential mechanisms of resistance, and emerging predictive biomarkers.

4 Followers
 · 
95 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Angiogenic remodeling during embryonic development and in adult tissue homeostasis is orchestrated by cooperative signaling between several distinct molecular pathways, which are often exploited by tumors. Indeed, tumors upregulate pro-angiogenic molecules while simultaneously suppressing angiostatic pathways in order to recruit blood vessels for growth, survival, and metastatic spread. Understanding how cancers exploit pro- and anti-angiogenic signals is a key step in developing new, molecularly targeted anti-angiogenic therapies. While EphA2, a receptor tyrosine kinase (RTK), is required for vascular endothelial growth factor (VEGF)-induced angiogenesis, the mechanism through which these pathways intersect remains unclear. Slit2 expression is elevated in EphA2-deficient endothelium, and here it is reported that inhibiting Slit activity rescues VEGF-induced angiogenesis in cell culture and in vivo, as well as VEGFdependent tumor angiogenesis, in EphA2-deficient endothelial cells and animals.Moreover, blocking Slit activity or Slit2 expression in EphA2-deficient endothelial cells restores VEGF-induced activation of Src and Rac, both of which are required for VEGFmediated angiogenesis. These data suggest that EphA2 suppression of Slit2 expression and Slit angiostatic activity enables VEGF-induced angiogenesis in vitro and in vivo, providing a plausible mechanism for impaired endothelial responses to VEGF in the absence of EphA2 function. Implications: Modulation of angiostatic factor Slit2 by EphA2 receptor regulates endothelial responses to VEGF-mediated angiogenesis and tumor neovascularization. Copyright © 2014, American Association for Cancer Research.
    Molecular Cancer Research 12/2014; 13(3). DOI:10.1158/1541-7786.MCR-14-0142 · 4.50 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Pre-clinical studies suggest that anti-angiogenic agents may be toxic to the developing growth plate. The purpose of this study was to evaluate the incidence of growth plate abnormalities in children with refractory cancer undergoing anti-angiogenic therapy.ProcedureTargeted radiographic studies from 53 subjects enrolled on six separate Children's Oncology Group Phase 1 and Pilot Consortium clinical trials evaluating new anti-cancer agents interfering with angiogenesis were reviewed. Subjects received tyrosine kinase inhibitors with anti-angiogenic effects (n = 35), monoclonal antibodies targeting vascular endothelial growth factor (VEGF) (n = 13), or angiopoietin (n = 5). Radiographs of their distal femur/proximal tibia were obtained at baseline. Follow-up radiographs were obtained after odd-numbered treatment cycles in patients with open growth plates who did not experience disease progression prior to cycle 3.ResultsBaseline and follow-up growth plate radiographs were acquired in 48/53 (90%) of patients. Five patients (9.4%), all of whom received a specific VEGF/VEGFR blocking agent (sunitinib [n = 1] or pazopanib [n = 4]), had growth plate abnormalities. Four patients had growth plate widening that was apparent on at least two successive radiographs, but was not confirmed by MRI. The fifth patient had progressive growth plate widening and evidence of physeal cartilage hypertrophy on MRI. Subsequent off treatment radiographs showed that the growth plate changes were reversible.Conclusion Growth plate abnormalities occur in a small, but relevant number of patients undergoing anti-angiogenic therapy. These results support the need for growth plate monitoring in children with open growth plates who are receiving anti-angiogenic therapy, and for improved methods to assess toxicity of anti-angiogenic agents to the developing skeleton. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 09/2014; 62(1). DOI:10.1002/pbc.25229 · 2.56 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In the present study possible effects of black pomegranate peel extract (PPE) on the B16F10 melanoma cells proliferation and Human Umbilical Vein Endothelial Cells (HUVECs) angiogenesis were investigated. PPE was added into the cell lines (B16F10 and HUVECs) media with different concentrations (10–450 µg/ml). After 48 h, the cell survival was measured by 3-(Dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) assay. Angiogenesis was investigated by matrigel assay (PPE (200, 300, 400 µg/ml)); HUVECs, vascular endothelial growth factor (VEGF) mRNA expression was detected by quantitative reverse transcriptase–polymerase chain reaction (QRT-PCR) assay. VEGF concentration in culture medium of HUVECs was determined by enzyme-linked immunosorbent assay (ELISA). PPE had positive anti proliferative effect on melanoma cells in a dose-dependent manner, but not on HUVECs. The matrigel assay results indicated that PPE significantly inhibited length, size and junction of the tube like structures (P<0.05). VEGF mRNA expression and concentration levels in culture medium of PPE treated HUVECs reduced significantly in a concentration-dependent manner (P<0.05). Simultaneous inhibition of melanoma cell proliferation and angiogenesis proposed that, PPE can be a good candidate against melanoma development. Based on the results, PPE could effectively suppress angiogenesis potentially through a VEGF dependent mechanism. Further studies are needed to confirm these results.