EphB4 mediates resistance to antiangiogenic therapy in experimental glioma

Uhl, Christian; Markel, Moritz; Broggini, Thomas; Nieminen, M.; Kremenetskaia, Irina; Vajkoczy, Peter; Czabanka, Marcus

doi:10.1007/s10456-018-9633-6

Cited by 22 publications

(20 citation statements)

References 20 publications

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“…This may be driven, at least in part, by increases in MET signaling, but other mechanisms such as increased Eph signaling may also play a role. Indeed, upregulation of EphA2 or ephrin-A1 may be involved in resistance to VEGF-targeted therapies [44], and recent evidence suggests that EphB4 overexpression can confer resistance to sunitinib treatment [45]. Our present studies demonstrate EphA2 or EphA3 can be upregulated or activated following resistance, but this effect can be variable amongst several cell lines.…”

Section: Discussionmentioning

confidence: 45%

Enhanced efficacy of sitravatinib in metastatic models of antiangiogenic therapy resistance

et al. 2019

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Tyrosine kinase inhibitors (TKIs) that primarily target angiogenesis are approved to treat several cancers in the metastatic setting; however, resistance is common. Sequential treatment or ‘switching’ from one TKI to another following failure can be effective, but predicting which drugs will have cross-over sensitivity remains a challenge. Here we examined sitravatinib (MGCD516), a spectrum-selective TKI able to block MET, TAM (TYRO3, AXL, MerTK) and multiple receptor families (including PDGFRs, VEGFRs, and Ephs). Transcriptomic analysis of several mouse and human cell lines revealed diverse molecular changes after resistance to two TKIs (sunitinib and axitinib) with multiple sitravatinib targets found to be upregulated. Sitravatinib treatment in vitro resulted in enhanced anti-proliferative effects in resistant cells and was improved compared to TKIs with similar target profiles. In vivo , primary tumor growth inhibition after sitravatinib treatment in mice was enhanced in resistant tumors and metastasis suppression improved when tumors were surgically removed. Together, these results suggest that the diverse and often inconsistent compensatory signaling mechanisms found to contribute to TKI resistance may paradoxically improve the tumor-inhibiting effects of broad-spectrum TKIs such as sitravatinib that are able to block multiple signaling pathways. Sitravatinib in the second-line setting following antiangiogenic TKI treatment may have enhanced inhibitory effects in local and disseminated disease, and improve outcomes in patients with refractory disease.

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Section: Discussionmentioning

confidence: 45%

Enhanced efficacy of sitravatinib in metastatic models of antiangiogenic therapy resistance

et al. 2019

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“…EphB4-ephrinB2 signalling was also associated with increased tumor angiogenesis and tumor progression [166] as well as with resistance to anti-angiogenic therapy [167]. Indeed, in this preclinical study of glioma, EphB4 overexpression was associated with alterations in vascular morphogenesis, pericyte coverage, cellular proliferation and apoptosis, inducing a vascular phenotype resistant to therapy.…”

Section: Eph/ephrin Signallingmentioning

confidence: 77%

Tumor angiogenesis: causes, consequences, challenges and opportunities

Lugano

Ramachandran

Dimberg

2019

Cell. Mol. Life Sci.

1,157

834

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Tumor vascularization occurs through several distinct biological processes, which not only vary between tumor type and anatomic location, but also occur simultaneously within the same cancer tissue. These processes are orchestrated by a range of secreted factors and signaling pathways and can involve participation of non-endothelial cells, such as progenitors or cancer stem cells. Anti-angiogenic therapies using either antibodies or tyrosine kinase inhibitors have been approved to treat several types of cancer. However, the benefit of treatment has so far been modest, some patients not responding at all and others acquiring resistance. It is becoming increasingly clear that blocking tumors from accessing the circulation is not an easy task to accomplish. Tumor vessel functionality and gene expression often differ vastly when comparing different cancer subtypes, and vessel phenotype can be markedly heterogeneous within a single tumor. Here, we summarize the current understanding of cellular and molecular mechanisms involved in tumor angiogenesis and discuss challenges and opportunities associated with vascular targeting.

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“…Both forward and reverse signaling by the EphB4/ephrinB2 interaction is context-dependent and can vary from one cancer type to another ( 37 ). EphB4 is upregulated in GBM and EphB4/ephrinB2 pathway is involved in the neo-angiogenesis ( 38 ), tumors progression, prognosis of GBM ( 32 , 33 , 39 ), and in the resistance to anti-angiogenesis therapy ( 39 ). These data underscore the oncogenic function of EphB4 in GBM, and suggest EphB4 as a promising therapeutic target ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

PDCD10-Deficiency Promotes Malignant Behaviors and Tumor Growth via Triggering EphB4 Kinase Activity in Glioblastoma

et al. 2020

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We previously reported an angiogenic and tumor-suppressor-like function of programmed cell death 10 (PDCD10) in glioblastoma (GBM). However, the underlying mechanism remains to be elucidated. We hypothesized that loss of PDCD10 activates GBM cells and tumor progression via EphB4. To this end, PDCD10 was knocked down in U87 and T98g by lentiviral mediated shRNA transduction (shPDCD10). GBM cell phenotype in vitro and tumor growth in a mouse xenograft model were investigated in presence or absence of the treatment with a specific EphB4 kinase inhibitor NVP-BHG712 (NVP). We demonstrated that knockdown of PDCD10 in GBM cells significantly upregulated the mRNA and protein expression of EphB4 accompanied by the activation of Erk1/2. EphB4 kinase activity, reflected by phospho-EphB4, significantly increased in shPDCD10 GBM cells, and in tumors derived from shPDCD10 GBM xenografts, which was abolished by the treatment with NVP. Furthermore, NVP treatment significantly suppressed PDCD10-knockdown mediated aggressive GBM cell phenotype in vitro and extensive tumor cell proliferation, the tumor neo-angiogenesis, and a quick progression of tumor formation in vivo. In summary, loss of PDCD10 activates GBM cells and promotes tumor growth via triggering EphB4. Targeting EphB4 might be an effective strategy particularly for the personalized therapy in GBM patients with PDCD10-deficiency.

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EphB4 mediates resistance to antiangiogenic therapy in experimental glioma

Cited by 22 publications

References 20 publications

Enhanced efficacy of sitravatinib in metastatic models of antiangiogenic therapy resistance

Enhanced efficacy of sitravatinib in metastatic models of antiangiogenic therapy resistance

Tumor angiogenesis: causes, consequences, challenges and opportunities

PDCD10-Deficiency Promotes Malignant Behaviors and Tumor Growth via Triggering EphB4 Kinase Activity in Glioblastoma

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