Vascular RhoJ Is an Effective and Selective Target for Tumor Angiogenesis and Vascular Disruption

Kim, Chan; Yang, Hanseul; Fukushima, Yoko; Saw, Phei Er; Lee, Junyeop; Park, Jin-Sung; Park, Intae; Jung, Jin‐Myung; Kataoka, Hiroshi; Lee, Doheon; Heo, Won Do; Kim, Injune; Jon, Sangyong; Adams, Ralf H.; Nishikawa, Shin‐Ichi; Uemura, Akiyoshi; Koh, Gou Young

doi:10.1016/j.ccr.2013.12.010

Cited by 117 publications

(133 citation statements)

References 42 publications

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“…The binding affinity of G3 to PlGF, which is critical for TAM recruitments, was comparable with that of anti-PlGF antibody (14), resulting in the decreased macrophage infiltration in G3-treated tumor compared with those treated with VT. Considering that the LLC tumor model is known to be relatively resistant to anti-VEGF therapy (28,31), these findings suggest the possibility of overcoming resistance to anti-VEGF therapy by concurrent blockade of PlGF with VEGF-Grab. Third, G3 demonstrated improvements in toxicity profile as compared with the parental VEGFR1-Fc.…”

Section: Discussionmentioning

confidence: 99%

Novel Glycosylated VEGF Decoy Receptor Fusion Protein, VEGF-Grab, Efficiently Suppresses Tumor Angiogenesis and Progression

Lee

Kim

Yang

et al. 2015

Molecular Cancer Therapeutics

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Antiangiogenic therapies targeting VEGFA have been commonly used in clinics to treat cancers over the past decade. However, their clinical efficacy has been limited, with drawbacks including acquisition of resistance and activation of compensatory pathways resulting from elevated circulating VEGFB and placental growth factor (PlGF). To bypass these disadvantages, we developed a novel glycosylated soluble decoy receptor fusion protein, VEGF-Grab, that can neutralize VEGFA, VEGFB, and PlGF. VEGF-Grab has the second and third immunoglobulin (Ig)-like domains of VEGF receptor 1 (VEGFR1) fused to IgG1 Fc, with three potential glycosylation sites introduced into the third Ig-like domain of VEGF-Grab by mutagenesis. Compared with VEGF-Trap, VEGF-Grab showed more potent decoy activity against VEGF and PlGF, mainly attributed to the VEGFR1 backbone. Most importantly, the negatively charged O-glycans attached to the third Ig-like domain of VEGFR1 counterbalanced the originally positively charged VEGFR1 backbone, minimizing nonspecific binding of VEGF-Grab to the extracellular matrix, and resulting in greatly improved pharmacokinetic profile. These advancements led to stronger and more durable antiangiogenic, antitumor, and antimetastatic efficacy in both implanted and spontaneous tumor models as compared with VEGF-Trap, while toxicity profiles were comparable with VEGF-Trap. Collectively, our results highlight VEGF-Grab as a promising therapeutic candidate for further clinical drug development. Mol Cancer Ther; 14(2); 470–9. ©2014 AACR.

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Section: Discussionmentioning

confidence: 99%

Novel Glycosylated VEGF Decoy Receptor Fusion Protein, VEGF-Grab, Efficiently Suppresses Tumor Angiogenesis and Progression

Lee

Kim

Yang

et al. 2015

Molecular Cancer Therapeutics

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“…PECAM-1 and JAM2 are adhesive proteins that accumulate in adherens junctions and maintain the restrictiveness of the endothelial barrier. RhoJ, an endothelial-enriched Rho GTPase, regulates angiogenesis and vessel integrity (41). GNG11 is a member of the g subunit family of heteromeric G-protein, which regulates cellular senescence in response to environmental stimuli (42).…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Signatures Predictive of Bevacizumab/Erlotinib Therapeutic Benefit in Advanced Nonsquamous Non–Small Cell Lung Cancer Patients (SAKK 19/05 trial)

Franzini

Baty

Macovei

et al. 2015

Clinical Cancer Research

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Purpose: We aimed to identify gene expression signatures associated with angiogenesis and hypoxia pathways with predictive value for treatment response to bevacizumab/erlotinib (BE) of nonsquamous advanced non-small cell lung cancer (NSCLC) patients.Experimental Design: Whole-genome gene expression profiling was performed on 42 biopsy samples (from SAKK 19/05 trial) using Affymetrix exon arrays, and associations with the following endpoints: time-to-progression (TTP) under therapy, tumorshrinkage (TS), and overall survival (OS) were investigated. Next, we performed gene set enrichment analyses using genes associated with the angiogenic process and hypoxia response to evaluate their predictive value for patients' outcome.Results: Our analysis revealed that both the angiogenic and hypoxia response signatures were enriched within the genes predictive of BE response, TS, and OS. Higher gene expression levels (GEL) of the 10-gene angiogenesis-associated signature and lower levels of the 10-gene hypoxia response signature predicted improved TTP under BE, 7.1 months versus 2.1 months for low versus high-risk patients (P ¼ 0.005), and median TTP 6.9 months versus 2.9 months (P ¼ 0.016), respectively. The hypoxia response signature associated with higher TS at 12 weeks and improved OS (17.8 months vs. 9.9 months for low vs. high-risk patients, P ¼ 0.001).Conclusions: We were able to identify gene expression signatures derived from the angiogenesis and hypoxia response pathways with predictive value for clinical outcome in advanced nonsquamous NSCLC patients. This could lead to the identification of clinically relevant biomarkers, which will allow for selecting the subset of patients who benefit from the treatment and predict drug response.

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“…12 Importantly, aberrant Rho signaling is associated with many pathologies, including cancer and vascular diseases, and is thought to be a promising target for novel therapies. [14][15][16][17][18] However, the RhoGTPases, unlike the Ras superfamily counterparts, are rarely mutated in cancers. 15,18 Instead, RhoGTPases are aberrantly activated by other mechanisms, including constitutively active splice variants of RhoGTPases, altered localization mediated by GDIs, and altered expression and function of the regulatory GEF and GAP proteins.…”

Section: Introductionmentioning

confidence: 99%

ARHGAP18: an endogenous inhibitor of angiogenesis, limiting tip formation and stabilizing junctions

et al. 2014

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The formation of the vascular network requires a tightly controlled balance of pro-angiogenic and stabilizing signals. Perturbation of this balance can result in dysregulated blood vessel morphogenesis and drive pathologies including cancer. Here, we have identified a novel gene, ARHGAP18, as an endogenous negative regulator of angiogenesis, limiting pro-angiogenic signaling and promoting vascular stability. Loss of ARHGAP18 promotes EC hypersprouting during zebrafish and murine retinal vessel development and enhances tumor vascularization and growth. Endogenous ARHGAP18 acts specifically on RhoC and relocalizes to the angiogenic and destabilized EC junctions in a ROCK dependent manner, where it is important in reaffirming stable EC junctions and suppressing tip cell behavior, at least partially through regulation of tip cell genes, Dll4, Flk-1 and Flt-4. These findings highlight ARHGAP18 as a specific RhoGAP to fine tune vascular morphogenesis, limiting tip cell formation and promoting junctional integrity to stabilize the angiogenic architecture.

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Vascular RhoJ Is an Effective and Selective Target for Tumor Angiogenesis and Vascular Disruption

Cited by 117 publications

References 42 publications

Novel Glycosylated VEGF Decoy Receptor Fusion Protein, VEGF-Grab, Efficiently Suppresses Tumor Angiogenesis and Progression

Novel Glycosylated VEGF Decoy Receptor Fusion Protein, VEGF-Grab, Efficiently Suppresses Tumor Angiogenesis and Progression

Gene Expression Signatures Predictive of Bevacizumab/Erlotinib Therapeutic Benefit in Advanced Nonsquamous Non–Small Cell Lung Cancer Patients (SAKK 19/05 trial)

ARHGAP18: an endogenous inhibitor of angiogenesis, limiting tip formation and stabilizing junctions

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