Conjunctival Melanoma and BRAF Inhibitor Therapy

Pahlitzsch, Milena; Bertelmann, Eckart; Maï, C.

doi:10.4172/2155-9570.1000322

Cited by 29 publications

(15 citation statements)

References 17 publications

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“…44 It has been used to target metastases and a primary CM. 45 Vemurafenib was previously shown to have a selective effect on CM cell lines in vitro 46 and we used that information to validate the usability of the zebrafish CM model. In our experiments, the effects of the vemurafenib in the treatment of engrafted embryos were the same as those observed in vitro showing that the zebrafish embryo model can be used in drug screens against human CM.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of (fli:GFP) Casper Zebrafish Embryos as a Model for Human Conjunctival Melanoma

Pontes

Groenewoud

Cao

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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Citation: Pontes KCS, Groenewoud A, Cao J, Ataide LMS, Snaar-Jagalska E, Jager MJ. Evaluation of (fli:GFP) Casper zebrafish embryos as a model for human conjunctival melanoma. Invest Ophthalmol Vis Sci. 2017;58:6065-6071. DOI:10.1167/iovs.17-22023 PURPOSE. Conjunctival melanoma (CM) is a rare malignant disease that can lead to recurrences and metastases. There is a lack of effective treatments for the metastases, and we set out to develop a new animal model to test potential therapies. Zebrafish are being used as a model for many diseases, and our goal was to test whether this animal could be used to study CM. METHODS.Three human CM cell lines (CRMM-1 and CM2005.1, which both harbor a B-RAF mutation, and CRMM-2, which has an N-RAS mutation) were injected into the yolk sac, around the eye, and into the duct of Cuvier of transgenic (fli:GFP) Casper zebrafish embryos. Fluorescent and confocal images were taken to assess the phenotype and the behavior of engrafted cells and to test the effect of Vemurafenib as a treatment against CM.RESULTS. While the cells that had been injected inside the yolk sac died and those injected around the eye sporadically went into the circulation, the cells that had been injected into the duct of Cuvier colonized the zebrafish: cells from all three cell lines proliferated and disseminated to the eyes, where they formed clusters, and to the tail, where we noticed extravasation and micrometastases. Vemurafenib, a potent agent for treatment of B-RAF V600E-positive melanoma, inhibited outgrowth of CRMM-1 and CM2005.1 cells in a mutation-dependent way.CONCLUSIONS. The (fli:GFP) Casper zebrafish embryo can be used as an efficient animal model to study metastatic behavior of human CM cells and warrants further testing of drug efficacy to aid care of CM patients.

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Section: Discussionmentioning

confidence: 99%

Evaluation of (fli:GFP) Casper Zebrafish Embryos as a Model for Human Conjunctival Melanoma

Pontes

Groenewoud

Cao

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…Apart from BRAF inhibitors being potentially useful for the treatment of advanced CM, BRAF inhibition was found to be efficient as an adjuvant treatment in a case of extensive CM without metastasis (Pahlitzsch et al. ; Riechardt et al. ).…”

Section: Discussionmentioning

confidence: 99%

Conjunctival malignant melanoma in Denmark: epidemiology, treatment and prognosis with special emphasis on tumorigenesis and genetic profile

Larsen

2016

Acta Ophthalmologica

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Conjunctival malignant melanoma is a rare disease associated with considerable mortality. Most published data have been based on case reports or series of referred patients. In addition, very little is known about the genetic and epigenetic profile of conjunctival melanoma and the resemblance to uveal, cutaneous and mucosal melanoma. The aim was to determine the incidence rate of conjunctival melanoma, and to relate clinicopathological features and treatment to prognosis. A further aim was to determine the prevalence of BRAF mutations in conjunctival melanoma, to determine whether BRAF mutations are early events in pathogenesis, and relate clinicopathological features and prognosis to BRAF‐mutation status. Finally, we wanted to identify tumour‐specific and prognostic microRNAs in conjunctival melanoma, and to compare these with the microRNA expression of other melanoma subtypes. In order to investigate these rare tumours, we studied all the conjunctival melanomas that had been surgically removed in Denmark over a period of 52 years (1960–2012). Tissue samples, clinical files, pathology reports and follow‐up data were collected and re‐evaluated. Using droplet digital polymerase chain reaction and immunohistochemistry, we investigated BRAF mutations; and using microRNA expression profiling, we investigated differentially expressed microRNAs. The overall incidence of conjunctival melanoma was 0.5/1 000 000/year, and it increased in Denmark over 52 years. The increase was mainly caused by an increase in older patients (>65 years) and bulbar lesions. Clinicopathological features significantly associated with a poor prognosis were extrabulbar location, involvement of adjacent tissue structures, tumour thickness exceeding 2 mm and local tumour recurrence. Patients undergoing incisional biopsy and/or treatment involving excision without adjuvant therapy fared worse than patients treated with excision and any type of adjuvant treatment. We found that 35% (39/110) of conjunctival melanomas were BRAF‐mutated, and the incidence of BRAF mutations was constant over time. BRAF‐mutation status corresponded in conjunctival melanoma and paired premalignant lesions. BRAF mutations were more frequent in males, in young patients, and in tumours with a sun‐exposed tumour location (bulbar conjunctiva or caruncle), with a mixed or non‐pigmented colour, with absence of primary acquired melanosis, and with origin in a nevus. Immunohistochemistry was able to accurately detect BRAF V600E mutations. In univariate analysis, distant metastatic disease was associated with BRAF mutations. No prognostic associations with BRAF mutations were identified in multivariate analyses. MicroRNA expression analysis revealed 25 tumour‐specific microRNAs in conjunctival melanoma. Five possibly oncogenic miRNAs (miR‐20b‐5p, miR‐146b‐5p, miR‐146a‐5p, miR‐506‐3p and miR‐509‐3p) were up‐regulated. Seven microRNAs (miR‐30d‐5p, miR‐138‐5p, miR‐146a‐5p, miR‐500a‐5p, miR‐501‐3p, miR‐501‐5p and miR‐502‐3p) were significantly and simultaneously up‐regulated i...

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“…BRAF inhibitors (BRAFi), including Vemurafenib and Dabrafenib, can prolong survival of metastatic cutaneous melanoma patients [ 22 , 23 ]. In CM, Vemurafenib has been used to target metastases and a primary melanoma with opposite outcomes: the metastatic tumor progressed after 2 months of treatment while the primary tumor was controlled for 16 months [ 24 , 25 ]. MEK inhibitor (MEKi) treatment is being tested in phase II and III clinical trials of metastatic cutaneous melanoma.…”

Section: Introductionmentioning

confidence: 99%

Targeting of the MAPK and AKT pathways in conjunctival melanoma shows potential synergy

et al. 2016

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PurposeConjunctival melanoma (CM) is a rare but lethal form of cancer. Similar to cutaneous melanoma, CM frequently carries activating mutations in BRAF and NRAS. We studied whether CM as well as conjunctival benign and premalignant melanocytic lesions express targets in the mitogen-activated protein kinase (MAPK) and AKT pathways, and whether specific inhibitors can suppress CM growth in vitro.Methods131 conjunctival lesions obtained from 129 patients were collected. The presence of BRAF V600E mutation and expression of phosphorylated (p)-ERK and p-AKT were assessed by immunohistochemistry. We studied cell proliferation, phosphorylation, cell cycling and apoptosis in three CM cell lines using two BRAF inhibitors (Vemurafenib and Dabrafenib), a MEK inhibitor (MEK162) and an AKT inhibitor (MK2206).ResultsThe BRAF V600E mutation was present in 19% of nevi and 26% of melanomas, but not in primary acquired melanosis (PAM). Nuclear and cytoplasmic p-ERK and p-AKT were expressed in all conjunctival lesions. Both BRAF inhibitors suppressed growth of both BRAF mutant CM cell lines, but only one induced cell death. MEK162 and MK2206 inhibited proliferation of CM cells in a dose-dependent manner, and the combination of these two drugs led to synergistic growth inhibition and cell death in all CM cell lines.ConclusionERK and AKT are constitutively activated in conjunctival nevi, PAM and melanoma. While BRAF inhibitors prohibited cell growth, they were not always cytotoxic. Combining MEK and AKT inhibitors led to more growth inhibition and cell death in CM cells. The combination may benefit patients suffering from metastatic conjunctival melanoma.

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Conjunctival Melanoma and BRAF Inhibitor Therapy

Cited by 29 publications

References 17 publications

Evaluation of (fli:GFP) Casper Zebrafish Embryos as a Model for Human Conjunctival Melanoma

Evaluation of (fli:GFP) Casper Zebrafish Embryos as a Model for Human Conjunctival Melanoma

Conjunctival malignant melanoma in Denmark: epidemiology, treatment and prognosis with special emphasis on tumorigenesis and genetic profile

Targeting of the MAPK and AKT pathways in conjunctival melanoma shows potential synergy

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