Multitargeting strategy using lenvatinib and golvatinib: Maximizing anti‐angiogenesis activity in a preclinical cancer model

Nakazawa, Youya; Kawano, Satoshi; Matsui, Junji; Funahashi, Yasuhiro; Tohyama, Osamu; Muto, Hiroki; Nakagawa, Takayuki; Matsushima, Tomohiro

doi:10.1111/cas.12581

Cited by 38 publications

(31 citation statements)

References 23 publications

(31 reference statements)

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“…58 Golvatinib is an orally bioavailable dual RTKI with potential antiangiogenic activity. 162 It could inhibit the activities of both c-Met and VEGFR-2. Lenvatinib is a multitarget RTKI of VEGFR1-3, FGFR 1-4, PDGFR-, RET, and c-Kit.…”

Section: Multitarget Rtkis As Antiangiogenic Agentsmentioning

confidence: 98%

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New strategies in achieving antiangiogenic effect: Multiplex inhibitors suppressing compensatory activations of RTKs

Shan

Wang

Zhang

2018

Medicinal Research Reviews

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Pathological angiogenesis plays a crucial role in malignant neoplasia. Vascular normalization has been confirmed as a promising strategy to promote chemotherapy efficacy. However, compensatory activation of alternative angiogenic receptor tyrosine kinases (RTKs) reduces vascular normalization and induces resistance. Moreover, complexity and heterogeneity of angiogenesis make it difficult to treat with single-target agents. Accordingly, it has been proposed that multiplex inhibition of RTKs could enhance treatment efficacy and overcome resistance on the basis of the vascular normalization concept. Meanwhile, it is feasible to develop multiplex inhibitors against VEGFR-2/Tie-2/EphB4 because of their highly conserved ATP-binding pockets. These inhibitors possess the properties of not only stabilizing the vascular normalization "time window" but also preventing the occurrence of resistance. This novel strategy has yielded promising results in the discovery of antiangiogenic agents. This review highlights the recent progress on the development of such angiogenesis inhibitors.

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Section: Multitarget Rtkis As Antiangiogenic Agentsmentioning

confidence: 98%

“…In addition, it may suppress the activity of VEGFR‐3, c‐MET, and HGF . Golvatinib is an orally bioavailable dual RTKI with potential antiangiogenic activity . It could inhibit the activities of both c‐Met and VEGFR‐2.…”

Section: Recent Advances In Small‐molecule Antiangiogenic Agentsmentioning

confidence: 99%

New strategies in achieving antiangiogenic effect: Multiplex inhibitors suppressing compensatory activations of RTKs

Shan

Wang

Zhang

2018

Medicinal Research Reviews

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“…This resistance is overcome by golvatinib (a c-Met inhibitor). 57,58 It is also reported that HGF confers resistance to sunitinib, an inhibitor of multiple kinases, including VEGFR2, by compensating for inhibited angiogenesis. 59,60 Previous studies showed that activity of the c-HGF-Met/Gab1 signaling pathway leads to VEGF production in EGFR-mutant lung cancer cell lines.…”

Section: C-met and Vegfmentioning

confidence: 99%

The c-Met receptor: Implication for targeted therapies in colorectal cancer

et al. 2017

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c-Met (mesenchymal-epithelial transition factor) is a tyrosine kinase receptor activated by hepatocyte growth factor and regulates multiple biological processes, such as cell scattering, survival, and proliferation. Aberrant c-Met signaling has been implicated in a variety of cancer types, including colorectal cancer. c-Met is genetically altered through various mechanisms that is associated with colorectal cancer progression and metastasis. Especially, in colorectal cancer, preclinical evidence for the aberrant activation of the c-Met signaling exists. Accordingly, molecular targeting of c-Met receptor could be a promising strategy, in the treatment of colorectal cancer patients. Recently, it was also shown that crosstalk between c-Met and other cell surface receptors attributes to tumorigenesis and development of therapeutic resistance. Characterization of the molecular mechanisms through which c-Met crosstalks with other receptors in favor of tumor formation and progression remains to explore. This review will describe the mechanisms of aberrant c-Met signaling in colorectal cancer and discuss on additional roles for c-Met receptor through crosstalk with other tyrosine kinase receptors and cell surface proteins in colorectal cancer. Novel therapeutic approaches for c-Met pathway targeting will also be discussed.

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“…Tie-2 receptor and its ligands, angiopoietins, are also important for angiogenesis. Angiopoietin-2 has been demonstrated as a VEGF negative regulator in several cancers (11,12). In addition to their pro-angiogenic effect, FGF and HGF can also directly promote proliferation, migration and invasion of cancer cells (13,14).…”

Section: Introductionmentioning

confidence: 99%

Dual roles of protein tyrosine phosphatase kappa in coordinating angiogenesis induced by pro-angiogenic factors

Park

Chen

Mason

et al. 2017

International Journal of Oncology

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A potential role may be played by receptor-type protein tyrosine phosphatase kappa (PTPRK) in angiogenesis due to its critical function in coordinating intracellular signal transduction from various receptors reliant on tyrosine phosphorylation. In the present study, we investigated the involvement of PTPRK in the cellular functions of vascular endothelial cells (HECV) and its role in angiogenesis using in vitro assays and a PTPRK knockdown vascular endothelial cell model. PTPRK knockdown in HECV cells (HECVPTPRKkd) resulted in a decrease of cell proliferation and cell-matrix adhesion; however, increased cell spreading and motility were seen. Reduced focal adhesion kinase (FAK) and paxillin protein levels were seen in the PTPRK knockdown cells which may contribute to the inhibitory effect on adhesion. HECVPTPRKkd cells were more responsive to the treatment of fibroblast growth factor (FGF) in their migration compared with the untreated control and cells treated with VEGF. Moreover, elevated c-Src and Akt1 were seen in the PTPRK knockdown cells. The FGF-promoted cell migration was remarkably suppressed by an addition of PLCγ inhibitor compared with other small inhibitors. Knockdown of PTPRK suppressed the ability of HECV cells to form tubules and also impaired the tubule formation that was induced by FGF and conditioned medium of cancer cells. Taken together, it suggests that PTPRK plays dual roles in coordinating angiogenesis. It plays a positive role in cell proliferation, adhesion and tubule formation, but suppresses cell migration, in particular, the FGF-promoted migration. PTPRK bears potential to be targeted for the prevention of tumour associated angiogenesis.

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Multitargeting strategy using lenvatinib and golvatinib: Maximizing anti‐angiogenesis activity in a preclinical cancer model

Cited by 38 publications

References 23 publications

New strategies in achieving antiangiogenic effect: Multiplex inhibitors suppressing compensatory activations of RTKs

New strategies in achieving antiangiogenic effect: Multiplex inhibitors suppressing compensatory activations of RTKs

The c-Met receptor: Implication for targeted therapies in colorectal cancer

Dual roles of protein tyrosine phosphatase kappa in coordinating angiogenesis induced by pro-angiogenic factors

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