MMGZ01, an anti-DLL4 monoclonal antibody, promotes nonfunctional vessels and inhibits breast tumor growth

Xu, Zhuobin; Wang, Zegen; Jia, Xuelian; Wang, Luxuan; Chen, Zhiguo; Wang, Shijing; Wang, Min; Zhang, Juan; Wu, Min

doi:10.1016/j.canlet.2015.12.025

Cited by 35 publications

(23 citation statements)

References 47 publications

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“…These potentials were further investigated in the following sections. Together, our data supported that DAPT treatment led to EC hyper-sprouting, resulting in a “nonfunctional vasculature” exhibiting limited resemblance of normal vascular networks [6,8,15,24,27]. Even though Jagged1 treatment led to increased branching in the vessel network, such vascular architecture possessed a greater similarity to untreated control.…”

Section: Resultssupporting

confidence: 66%

“…Nonetheless, the most commonly accepted theory for Notch signaling in tumor angiogenesis is that inhibition of Notch signaling through down-regulation of Dll4 leads to overgrowth of tumor vasculatures, even though such increased vascularity is non-productive [9,13,21,23–25]. Given its importance in tumor angiogenesis and progression, a better understanding of Notch signaling in a suitable angiogenesis model will provide new insights for targeting tumors that are resistant to anti-angiogenesis therapy [9,26,27]. …”

Section: Introductionmentioning

confidence: 99%

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Notch signaling in regulating angiogenesis in a 3D biomimetic environment

et al. 2017

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Angiogenesis is a complex cellular process involving highly orchestrated invasion and organization of endothelial cells (ECs) in a three-dimensional (3D) environment. Recent evidence indicates that Notch signaling is critically involved in regulating specialized functions and distinct fates of ECs in newly formed vasculatures during angiogenesis. Here we demonstrated, for the first time, the application of a microengineered biomimetic system to quantitatively investigate the role of Notch signaling in regulating early angiogenic sprouting and vasculature formation of ECs in 3D extracellular matrix. Morphological features of angiogenesis including invasion distance, invasion area, and tip cell number were quantified and compared under pharmacological perturbations of Notch signaling. In addition, influences of Notch signaling on EC proliferation in angiogenic vasculatures and directional invasion of tip cells were also investigated. Moreover, leveraging a novel nanobiosensor system, mRNA expression of Dll4, a Notch ligand, was monitored in invading tip cells using live cell imaging during dynamic angiogenic process. Our data showed that inhibition of Notch signaling resulted in hyper-sprouting endothelial structures, while activation of Notch signaling led to opposite effects. Our results also supported the role of Notch signaling in regulating EC proliferation and dynamic invasion of tip cells during angiogenesis.

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Section: Resultssupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Notch signaling in regulating angiogenesis in a 3D biomimetic environment

et al. 2017

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“…74 Preventing DLL4 activation in BC using antibodybased drugs represents another potential DLL4-targeting strategy, exhibiting potent anti-tumor activity in preclinical studies. 79,80 In addition, a combination of anti-DLL4 and anti-VEGF treatment in BC using bispecific antibodies not only induces tumor cell apoptosis, but also interferes with tumor angiogenesis, thus inhibiting BC progression in vivo. 81,82…”

Section: Delta-like Ligands In Breast Cancermentioning

confidence: 99%

<p>The Role of DLLs in Cancer: A Novel Therapeutic Target</p>

Xiu

Liu

Kuang

2020

OTT

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Delta-like ligands (DLLs) control Notch signaling. DLL1, DLL3 and DLL4 are frequently deregulated in cancer and influence tumor growth, the tumor vasculature and tumor immunity, which play different roles in cancer progression. DLLs have attracted intense research interest as anti-cancer therapeutics. In this review, we discuss the role of DLLs in cancer and summarize the emerging DLL-relevant targeting methods to aid future studies.

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“…In relevant in vitro and in vivo cancer models, DLL4 has also been implicated in chemoresistance [16], tumour angiogenesis [17] and CSC activity [18]. Therefore, all of these studies suggest that DLL4 and Notch 4 are viable therapeutic targets for both triple negative and ER+ breast cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4

et al. 2019

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Background: Optimising breast cancer treatment remains a challenge. Resistance to therapy is a major problem in both ER-and ER+ breast cancer. Tumour recurrence after chemotherapy and/or targeted therapy leads to more aggressive tumours with enhanced metastatic ability. Self-renewing cancer stem cells (CSCs) have been implicated in treatment resistance, recurrence and the development of metastatic disease. Methods: In this study, we utilised in vitro, in vivo and ex vivo breast cancer models using ER+ MCF-7 and ER-MDA-MB-231 cells, as well as solid and metastatic breast cancer patient samples, to interrogate the effects of FKBPL and its peptide therapeutics on metastasis, endocrine therapy resistant CSCs and DLL4 and Notch4 expression. The effects of FKBPL overexpression or peptide treatment were assessed using a t-test or one-way ANOVA with Dunnett's multiple comparison test. Results: We demonstrated that FKBPL overexpression or treatment with FKBPL-based therapeutics (AD-01, preclinical peptide /ALM201, clinical peptide) inhibit i) CSCs in both ER+ and ER-breast cancer, ii) cancer metastasis in a triple negative breast cancer metastasis model and iii) endocrine therapy resistant CSCs in ER+ breast cancer, via modulation of the DLL4 and Notch4 protein and/or mRNA expression. AD-01 was effective at reducing triple negative MDA-MB-231 breast cancer cell migration (n ≥ 3, p < 0.05) and invasion (n ≥ 3, p < 0.001) and this was translated in vivo where AD-01 inhibited breast cancer metastasis in MDA-MB-231-lucD3H1 in vivo model (p < 0.05). In ER+ MCF-7 cells and primary breast tumour samples, we demonstrated that ALM201 inhibits endocrine therapy resistant mammospheres, representative of CSC content (n ≥ 3, p < 0.05). Whilst an in vivo limiting dilution assay, using SCID mice, demonstrated that ALM201 alone or in combination with tamoxifen was very effective at delaying tumour recurrence by 12 (p < 0.05) or 21 days (p < 0.001), respectively, by reducing the number of CSCs. The potential mechanism of action, in addition to CD44, involves downregulation of DLL4 and Notch4. Conclusion: This study demonstrates, for the first time, the pre-clinical activity of novel systemic anti-cancer therapeutic peptides, ALM201 and AD-01, in the metastatic setting, and highlights their impact on endocrine therapy resistant CSCs; both areas of unmet clinical need.

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MMGZ01, an anti-DLL4 monoclonal antibody, promotes nonfunctional vessels and inhibits breast tumor growth

Cited by 35 publications

References 47 publications

Notch signaling in regulating angiogenesis in a 3D biomimetic environment

Notch signaling in regulating angiogenesis in a 3D biomimetic environment

<p>The Role of DLLs in Cancer: A Novel Therapeutic Target</p>

FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4

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