Metastatic disease from uveal melanoma: treatment options and future prospects

Carvajal, Richard D.; Schwartz, Gary K.; Tezel, Tongalp H.; Marr, Brian P.; Francis, Jasmine H.; Nathan, Paul

doi:10.1136/bjophthalmol-2016-309034

Cited by 332 publications

(352 citation statements)

References 102 publications

(67 reference statements)

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“…However, probably due to vitally distinct molecular genetics of UM from that of cutaneous melanoma 5, the clinical activity of ipilimumab in patients with metastatic UM is limited and the clinical efficacy of pembrolizumab remains to be evaluated 8. Therefore, novel therapeutic drugs for effective treatment of patients with UM, especially for the patients with metastatic UM, are urgently needed.…”

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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“…At present, ClinicalTrials.gov lists 69 trials for metastatic UM (for recent reviews, see [65, 66]). Targeted therapies based on the activation of the mitogen-activated protein (MAP) kinase pathway by mutated G protein GNAQ or GNA11 have been tested in several clinical trials.…”

Section: Clinical Features Of Uveal Melanomamentioning

confidence: 99%

The biology of uveal melanoma

Amaro

Gangemi

Piaggio

et al. 2017

Cancer Metastasis Rev

189

193

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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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“…Multiple factors are involved in determining the risk for metastasis which include tumor location, size and genetic profile. High risk patients can also be determined by genotypic profiling using multiplex ligation-dependent probe amplification method [3]. Ocular melanoma metastasis to the liver has well defined gene expression pattern that is remarkably different from other tumors.…”

Section: Case Discussionmentioning

confidence: 99%

“…Choroid is involved in almost 85% -90% of cases, iris and ciliary body are involved in remaining cases. Despite the development of most effective therapeutic methods, 50 % of patients still develop metastatic disease [3]. Incidence of melanoma is increasing rapidly in both men and women.…”

Section: Introductionmentioning

confidence: 99%

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Late Metastatic Presentation of Ocular Melanoma

Malik¹,

Hussain²,

Naqvi³

2017

AJMCR

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Choroidal melanoma is the most common primary intraocular malignant tumor and the second most common type of primary malignant melanoma in the body. The liver is main site of metastasis in more than 80% cases. There is no consensus regarding follow up with patient having ocular melanoma to see any metastatic disease. We present a case admitted with right upper quadrant pain and diagnosed with metastatic melanoma due to right ocular lesion treated 20 years ago. After the diagnosis was made patient survived only for two weeks. That further signifies the unpredictable course of the disease. BackgroundChoroidal melanoma represents 85 %, of all ocular melanomas and up to 50 % of patients develop metastatic disease [3]. Liver is the most common site of metastasis and its associated with a very poor prognosis. Uveal melanoma originates from melanocytes located anywhere in uveal tract. Choroid is involved in almost 85% -90% of cases, iris and ciliary body are involved in remaining cases. Despite the development of most effective therapeutic methods, 50 % of patients still develop metastatic disease [3]. Incidence of melanoma is increasing rapidly in both men and women. Cutaneous melanoma and ocular melanoma are considered different entities in both metastatic latency and metastatic diffusion. Liver is the principal target organ of ocular metastasis. While cutaneous melanoma spreads to lymph nodes and soft tissues with a minor incidence of hepatic diffusion [5]. Case Presentation61-year-old female was admitted with abdominal pain mainly in right upper quadrant of abdomen for last 4 weeks. Pain was constant, moderate and radiating to right upper flank with no known aggravating and relieving factors. Pain was associated with night sweats. According to patient she was trying to pull a chair and noticed pain. She did not seek medical attention thinking about muscle spasm but it did not get better. She has a history of right eye choroidal melanoma treated with enucleation in 7/1997. Since then patient was having regular follow up with an ophthalmologist and was negative for metastatic diffusion or recurrence. Her past medical history was significant for basal cell carcinoma of forehead, squamous cell carcinoma of nose and diabetes mellitus. She was on oral hypoglycemic. Patient denied nausea, vomiting black color stools any recent changes in weight or appetite. Patient was feeling depressed due to recent death of her husband but denied any homicidal or suicidal thoughts. After initial treatment with analgesic she had CT of abdomen and pelvis that showed multiple lesion in liver suggestive of metastatic disease. Interventional radiologist consult was requested and patient has CT guided biopsy that came positive for malignant melanoma and there was no other lesion identified on physical examination suggestive of malignant melanoma. Patient has elevated AST and ALT but normal bilirubin level. Patient was discharged home to follow up with oncology.CT scan showing multiple lesions in liver

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Metastatic disease from uveal melanoma: treatment options and future prospects

Cited by 332 publications

References 102 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

Late Metastatic Presentation of Ocular Melanoma

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