Abstract
For metastases in the central nervous system, angiogenesis enhances metastatic potential and promotes progression. Primary factors which drive vessel growth are vascular endothelial growth factor (VEGF) and angiopoietin-2. Preclinical models show inhibition of either factor reduces metastases spread and inhibits growth. This work sets out to answer two questions in a preclinical mouse model. First, whether the combined inhibition of VEGF and angiopoietin-2, reduces passive permeability and limits drug uptake into brain metastases; and second, whether this inhibition reduces metastases burden in brain. We observed combinatorial inhibition of VEGF and angiopoietin-2, decreased (p < 0.05) angiogenesis and vascular branching in an aortic ring assay and decreased (p < 0.05) endothelial wound closure times. Using a brain metastases of breast cancer model (induced by intracardiac injections of brain seeking MDA-MB-231Br cells or 4T1Br cells), we observed, similar to VEGF, angiopoetin-2 expression correlates to increased angiogenesis (p < 0.05) and increased lesion permeability. To determine efficacy, animals were administered bevacizumab plus L1-10 (angiopoietin inhibitor) twice per week until neurological symptoms developed. Lesion permeability significantly decreased by ∼50% (p < 0.05) compared to untreated lesions, but remained ∼25% greater (p < 0.0%) than brain. In subsequent experiments, animals were administered similar regimens but sacrificed on day 32. The number of metastatic lesions developed was significantly (p < 0.001) reduced in the bevacizumab group (56%) and combination group (86%). Lesions’ size was reduced in bevacizumab treated lesions (∼67%) and bevacizumab and L1-10 treated lesions (∼78%) developing area < 0.5 mm2. In summary, combinatorial inhibition of VEGF and angiopoietin reduces lesion permeability and brain metastatic burden.
Highlights
Current treatment options of brain and CNS metastases are modest and only expand survival approximately 4 months (Labidi et al, 2009; Pestalozzi, 2009; Goldfarb et al, 2011)
We evaluated the effects of bevacizumab and L1-10 on metastases formation and permeability of experimental brain metastases
To confirm that vascular endothelial growth factor (VEGF) and Ang-2 synergistically induced angiogenesis in vitro, which could be inhibited with bevacizumab and L1-10, we used aortic ring and wound healing assays
Summary
Current treatment options of brain and CNS metastases are modest and only expand survival approximately 4 months (Labidi et al, 2009; Pestalozzi, 2009; Goldfarb et al, 2011). A secondary driver of angiogenesis is angiopoietin-2 (Ang-2), which activates in response to hypoxia and induces vessel destabilization upon binding the Tie receptor (LaManna et al, 2004; Chae et al, 2010). Both VEGF and Ang-2 have been shown to independently induce angiogenesis (Blacher et al, 2001; Teichert-Kuliszewska et al, 2001). We observed a reduction in the number of metastatic lesions in bevacizumab and bevacizumab + L1-10 treated groups These data suggest that combinatorial therapy of VEGF blockade and Ang-2 inhibition may be an effective strategy to reduce brain metastases formation. This dual target approach reduced permeability and drug uptake in established brain metastases, which warrants caution in the therapeutic use of VEGF and Ang-2 inhibition
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
