Crizotinib, a c-Met Inhibitor, Prevents Metastasis in a Metastatic Uveal Melanoma Model

Surriga, Oliver; Rajasekhar, Vinagolu K.; Ambrosini, Grazia; Dogan, Yildirim; Huang, Ruimin; Schwartz, Gary K.

doi:10.1158/1535-7163.mct-13-0499

Cited by 94 publications

(77 citation statements)

References 35 publications

(41 reference statements)

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“…Given the predominant hepatic metastasis of UM cells, disruption of the interaction between UM cells and liver microenvironment was examined 3. For instance, based on the rationale of binding membrane receptor tyrosine kinase c-Met on UM cells by the secreted hepatocyte growth factor (HGF) from hepatocytes, a clinical trial of targeting c-Met is undergoing 9.…”

Section: Introductionmentioning

confidence: 99%

The antihelminthic drug niclosamide effectively inhibits the malignant phenotypes of uveal melanoma in vitro and in vivo

Zhou

Jin

et al. 2017

Theranostics

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Uveal melanoma (UM) is a lethal intraocular malignancy with an average survival of only 2~8 months in patients with hepatic metastasis. Currently, there is no effective therapy for metastatic UM. Here, we reported that niclosamide, an effective repellence of tapeworm that has been approved for use in patients for approximately 50 years, exhibited strong antitumor activity in UM cells in vitro and in vivo. We showed that niclosamide potently inhibited UM cell proliferation, induced apoptosis and reduced migration and invasion. p-Niclosamide, a water-soluble niclosamide, exerted potent in vivo antitumor activity in a UM xenograft mouse model. Mechanistically, niclosamide abrogated the activation of the NF-κB pathway induced by tumor necrosis factor α (TNFα) in UM cells, while niclosamide elevated the levels of intracellullar and mitochondrial reactive oxygen species (ROS) in UM cells. Quenching ROS by N-acetylcysteine (NAC) weakened the ability of niclosamide-mediated apoptosis. Matrix metalloproteinase 9 (MMP-9) knockdown by shRNA potentiated, while ectopic expression of MMP-9 rescued, the niclosamide-attenuated invasion, implying that MMP-9 is pivotal for invasion blockage by niclosamide in UM cells. Furthermore, our results showed that niclosamide eliminated cancer stem-like cells (CSCs) as reflected by a decrease in the Aldefluor+ percentage and serial re-plating melanosphere formation, and these phenotypes were associated with the suppressed Wnt/β-catenin pathway by niclosamide in UM. Niclosamide caused a dose- and time-dependent reduction of β-catenin and the key components [e.g., DVLs, phospho-GSK3β (S9), c-Myc and Cyclin D1] in the canonical Wnt/β-catenin pathway. Additionally, niclosamide treatment in UM cells reduced ATP and cAMP contents, and decreased PKA-dependent phosphorylation of β-catenin at S552 and S675 which determine the stability of β-catenin protein, suggesting that niclosamide may work as a mitochondrial un-coupler. Taken together, our results shed light on the mechanism of antitumor action of niclosamide and warrant clinical trial for treatment of UM patients.

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Section: Introductionmentioning

confidence: 99%

The antihelminthic drug niclosamide effectively inhibits the malignant phenotypes of uveal melanoma in vitro and in vivo

Zhou

Jin

et al. 2017

Theranostics

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“…For example, the UM cell line OMM1.3, bearing a GNAQ Q209P mutation, retro-orbitally injected into nu/nu mice developed liver metastases 9 weeks post injection. In this model, treatment with the c-Met/ALK tyrosine kinase inhibitor crizotinib prevented liver metastasis development without blocking ocular tumor growth [98]. These data point out to an important role of the HGF/c-Met axis in metastatic spreading of UM to the liver.…”

Section: Animal Modelsmentioning

confidence: 92%

The biology of uveal melanoma

Amaro

Gangemi

Piaggio

et al. 2017

Cancer Metastasis Rev

178

190

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Uveal melanoma (UM), a rare cancer of the eye, is distinct from cutaneous melanoma by its etiology, the mutation frequency and profile, and its clinical behavior including resistance to targeted therapy and immune checkpoint blockers. Primary disease is efficiently controlled by surgery or radiation therapy, but about half of UMs develop distant metastasis mostly to the liver. Survival of patients with metastasis is below 1 year and has not improved in decades. Recent years have brought a deep understanding of UM biology characterized by initiating mutations in the G proteins GNAQ and GNA11. Cytogenetic alterations, in particular monosomy of chromosome 3 and amplification of the long arm of chromosome 8, and mutation of the BRCA1-associated protein 1, BAP1, a tumor suppressor gene, or the splicing factor SF3B1 determine UM metastasis. Cytogenetic and molecular profiling allow for a very precise prognostication that is still not matched by efficacious adjuvant therapies. G protein signaling has been shown to activate the YAP/TAZ pathway independent of HIPPO, and conventional signaling via the mitogen-activated kinase pathway probably also contributes to UM development and progression. Several lines of evidence indicate that inflammation and macrophages play a pro-tumor role in UM and in its hepatic metastases. UM cells benefit from the immune privilege in the eye and may adopt several mechanisms involved in this privilege for tumor escape that act even after leaving the niche. Here, we review the current knowledge of the biology of UM and discuss recent approaches to UM treatment.

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“…Signaling‐mediated by MET activates several downstream pathways leading to oncogenic cell proliferation, survival, and motility, making it an attractive therapeutic target. Crizotinib is an example of a selective MET inhibitor that has demonstrated antimetastatic activity in UM models by inhibiting phosphorylation, and thus activation, of this tyrosine kinase receptor . PHA665752 is another selective MET inhibitor that inhibits the migration and invasion by blocking the PI3K/AKT pathway …”

Section: Preclinical Approachesmentioning

confidence: 99%

Recent advances in uveal melanoma treatment

Álvarez‐Rodríguez

Latorre

Posch

et al. 2017

Medicinal Research Reviews

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Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Recent advances in the understanding of molecular characteristics helped to determine which tumors are most likely to progress. About 50% of patients carrying genetic alterations such as chromosomal aberrations and mutations are at significant risk for metastatic disease of which the majority will succumb to UM within few months. Currently, there is no effective treatment for metastatic uveal melanoma, and we hope this review will encourage researchers and clinicians to work to find a better standard of care.In this article we provide a comprehensive overview of the molecular framework of UM, highlighting the most common mutations involved in this kind of cancer. It also covers the most recent treatments from basic research to clinical trials, including small molecules, nucleic acids or immunotherapy, among others. It is intended to serve as a key reference for clinicians and researchers working in this field.

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Crizotinib, a c-Met Inhibitor, Prevents Metastasis in a Metastatic Uveal Melanoma Model

Cited by 94 publications

References 35 publications

The antihelminthic drug niclosamide effectively inhibits the malignant phenotypes of uveal melanoma in vitro and in vivo

The antihelminthic drug niclosamide effectively inhibits the malignant phenotypes of uveal melanoma in vitro and in vivo

The biology of uveal melanoma

Recent advances in uveal melanoma treatment

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