Decitabine limits escape from MEK inhibition in uveal melanoma

Gonçalves, Jessica E.S.; Emmons, Michael F.; Faião-Flores, Fernanda; Aplin, Andrew E.; Harbour, J. William; Licht, Jonathan D.; Wink, Márcia Rosângela; Smalley, Keiran S.M.

doi:10.1111/pcmr.12849

Cited by 23 publications

(19 citation statements)

References 23 publications

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“…Goncalves et al 8 also reported the effects of another MEK inhibitor, trametinib, in 3D spheroids of UM cell lines placed in a collagen matrix. They observed an increase in the number of dead cells at the edge of the spheroid following treatment with a single concentration of trametinib, as measured by propidium iodide staining.…”

Section: Discussionmentioning

confidence: 99%

“… 5 – 7 The lack of effective tumor treatments in metastatic UM creates an urgent unmet need for improved cellular systems, not only to enhance our understanding of this disease but also to more accurately translate drug efficacy to patients. Recent studies have profiled more complex UM culture systems, including 3D spheroids created from UM cell lines embedded in either collagen or Matrigel (Corning Inc., Corning, NY) 8 , 9 ; however, the methods used by these groups and the technical challenges, such as spheroid uniformity, are not described in great detail. Method optimization for 3D spheroid culture and an improved understanding of the advantages and challenges that each of these methods offers are key to bridging the gap between 2D-cultured monolayers, animal models, and patient clinical trials.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of Uveal Melanoma Cell Lines and Primary Tumor Samples in 3D Culture

Aughton

Shahidipour

Djirackor

et al. 2020

Trans. Vis. Sci. Tech.

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Uveal melanoma (UM) typically spreads to the liver, where it is incurable, as there are limited therapeutic interventions available. This study aimed to standardize laboratory methods for generating three-dimensional (3D) spheroids using UM cell lines and primary UM (PUM) samples for use in drug screening. Methods: Six UM cell lines and nine PUM, of differing genetic characteristics were cultured in two dimensions (2D) and three dimensions. 3D spheroid formation and growth were time monitored, and ImageJ software was used to calculate crosssectional areas. PUM spheroids underwent immunohistochemistry for melanoma markers, nuclear BAP1, and cell proliferation. Chromosomal alterations in patient UM biopsies were compared with the corresponding 3D spheroid. In vitro drug assays testing doxorubicin and selumetinib assessed drug penetration and toxicity after 48 hours using imaging and the CellTiter-Glo 3D Cell Viability Assay. Results: All six UM cell lines formed spheroids of varying sizes and compactness; six of the nine PUM samples (67%) also formed spheroids, composed of MelanA+ proliferating melanocytes and admixed macrophages. PUM spheroids were genetically identical to the original sampled tumor. In vitro drug assays showed varying penetrations into UM cell line spheroids, with doxorubicin passing into the spheroid core and selumetinib having an effect largely on peripheral cells. Both drugs caused a dose-dependent reduction in viability of 3D spheroid cells. Conclusions: UM cell lines and PUM samples can successfully generate uniform 3D spheroids. PUM spheroids retain histological and genetic characteristics of the primary tumor. 3D spheroids are an important system for use in future high-throughput drug testing. Translational Relevance: The use of 3D spheroids allows early-phase drug screening and is an important first step toward treatment personalization for UM patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characterization of Uveal Melanoma Cell Lines and Primary Tumor Samples in 3D Culture

Aughton

Shahidipour

Djirackor

et al. 2020

Trans. Vis. Sci. Tech.

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“…While large-scale epigenetic changes have been documented in UM tumors, and these changes have been significantly related to prognosis, there are currently no approved treatments using these agents in UM. In vitro, treatment with epigenetic modifying drugs has been shown to reduce growth and invasiveness in UM cell lines, and decitabine (a DNMT inhibitor) in combination with MEK inhibition has been shown to suppress growth in UM cells [ 39 , 40 ]. Additionally, decitabine has been used safely in clinical trials via hepatic arterial infusion in patients with unresectable liver metastases (NCT02316028), which is promising in the context of high risk UM patients [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Novel Methylation Patterns Predict Outcome in Uveal Melanoma

Ferrier

Burnier

2020

Life

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Uveal melanoma (UM) is the most common intraocular tumor in adults. Despite effective local treatments, 50% of patients develop metastasis. Better ways to determine prognosis are needed as well as new therapeutic targets. Epigenetic changes are important events driving cancer progression; however, few studies exist on methylation changes in UM. Our aim was to identify methylation events associated with UM prognosis. Matched clinical, genetic, and methylation data for 80 UM cases were obtained from The Cancer Genome Atlas (TCGA). Top differentially methylated loci were sorted through hierarchical clustering based on methylation patterns, and these patterns were compared to tumor characteristics, genomic aberrations, and patient outcome. Hierarchical clustering revealed two distinct groups. These classifications effectively separated high and low-risk cases, with significant differences between groups in patient survival (p < 0.0001) and correlation with known prognostic factors. Major differences in methylation of specific genes, notably NFIA, HDAC4, and IL12RB2, were also seen. The methylation patterns identified in this study indicate potential novel prognostic indicators of UM and highlight the power of methylation changes in predicting outcome. The methylation events enriched in the high-risk group suggest that epigenetic modulating drugs may be useful in reducing metastatic potential, and that specific differentially methylated loci could act as biomarkers of therapeutic response.

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“…MEK inhibitors (MEKis) appear to have anti-proliferative activity in metastatic UM patients, though responses are short-lived. Gonçalves and colleagues recently evaluated a group of epigenetic inhibitors, including Disruptor of telomeric silencing 1-like inhibitors (DOT1Lis), EZH2is, lysine-specific demethylase 1 inhibitors (LSD1is), DNMTis, and histone acetyltransferase inhibitors (HATis) as a strategy to diminish escape from MEKi therapy in vitro [ 99 ]. The authors proved that decitabine dramatically enhanced the anti-proliferative activity of trametinib in cell viability, 3D organoid, and colony formation assays.…”

Section: Potential Of Epigenetic Therapies In Ummentioning

confidence: 99%

“…Likewise, the DNMTi-MEKi combination more efficiently suppressed the growth of MP41 cells in UM xenografts than monotherapy. Thus, DNMTi may improve the activity of MEKi in UM [ 99 ].…”

Section: Potential Of Epigenetic Therapies In Ummentioning

confidence: 99%

Targeting Epigenetic Modifications in Uveal Melanoma

Baradaran

Kozovská

Furdová

et al. 2020

IJMS

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Uveal melanoma (UM), the most common intraocular malignancy in adults, is a rare subset of melanoma. Despite effective primary therapy, around 50% of patients will develop the metastatic disease. Several clinical trials have been evaluated for patients with advanced UM, though outcomes remain dismal due to the lack of efficient therapies. Epigenetic dysregulation consisting of aberrant DNA methylation, histone modifications, and small non-coding RNA expression, silencing tumor suppressor genes, or activating oncogenes, have been shown to play a significant role in UM initiation and progression. Given that there is no evidence any approach improves results so far, adopting combination therapies, incorporating a new generation of epigenetic drugs targeting these alterations, may pave the way for novel promising therapeutic options. Furthermore, the fusion of effector enzymes with nuclease-deficient Cas9 (dCas9) in clustered regularly interspaced short palindromic repeats (CRISPR) associated protein 9 (Cas9) system equips a potent tool for locus-specific erasure or establishment of DNA methylation as well as histone modifications and, therefore, transcriptional regulation of specific genes. Both, CRISPR-dCas9 potential for driver epigenetic alterations discovery, and possibilities for their targeting in UM are highlighted in this review.

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Decitabine limits escape from MEK inhibition in uveal melanoma

Cited by 23 publications

References 23 publications

Characterization of Uveal Melanoma Cell Lines and Primary Tumor Samples in 3D Culture

Characterization of Uveal Melanoma Cell Lines and Primary Tumor Samples in 3D Culture

Novel Methylation Patterns Predict Outcome in Uveal Melanoma

Targeting Epigenetic Modifications in Uveal Melanoma

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