Obstacles to improving outcomes in the treatment of uveal melanoma

Tsai, Katy K.; Bollin, Kathryn; Patel, Sapna

doi:10.1002/cncr.31284

Cited by 18 publications

(13 citation statements)

References 80 publications

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“…While local control of UM by enucleation or local radiation is effective, approximately 50% of patients will develop metastasis, primarily to the liver. Patients with metastatic UM have an estimated survival of 6 months . There is a crucial need to better understand the mechanisms involved in tumor dissemination and develop new sustainable and effective adjuvant therapeutic options.…”

Section: Introductionmentioning

confidence: 99%

“…Patients with metastatic UM have an estimated survival of 6 months. 3,4 There is a crucial need to better understand the mechanisms involved in tumor dissemination and develop new sustainable and effective adjuvant therapeutic options. Drug repurposing studies are a cost-effective means to find new applications to approved drugs with good safety profiles.…”

Section: Introductionmentioning

confidence: 99%

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Beta‐blockers exert potent anti‐tumor effects in cutaneous and uveal melanoma

et al. 2019

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Background Melanoma is a life‐threatening group of cancers mainly affecting the skin (cutaneous melanoma, CM) and the eyes (uveal melanoma, UM). Nearly half of patients with UM develop liver metastases regardless of the primary treatment. For this reason, adjuvant therapy to prevent disease progression is essential to improve survival of patients with melanoma. Beta‐adrenoceptors (β‐AR) have emerged as novel targets to inhibit tumor growth and dissemination in CM, but have not been investigated in UM. Methods The aim of this study was to comprehensively evaluate the effects of a non‐selective β‐blocker in UM and CM. Propranolol was tested on four UM and two CM cell lines to determine the effects of this beta‐blocker. The expression of β‐AR in UM was assessed in enucleated eyes of 36 patients. Results The results showed that propranolol exerts potent anti‐proliferative effects, attenuates migration, reduces VEGF and induces cell cycle arrest and apoptosis in both UM and CM in a dose‐dependent manner. Furthermore, levels of cell‐free DNA released from the cells correlated to propranolol treatment and may be an indicator of treatment response. Finally, immunohistochemical analysis revealed the expression of β1 and β2 adrenoceptors in all UM patients, with higher expression seen in the more aggressive epithelioid versus less aggressive spindle cells. Conclusions Collectively our data suggest that a nonselective beta‐blocker may be effective against melanoma. For the first time, we show potent anti‐tumor effects in UM cells following propranolol administration and expression of β1 and β2 adrenoceptors in patient tissue.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Beta‐blockers exert potent anti‐tumor effects in cutaneous and uveal melanoma

et al. 2019

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“…Although overall survival (OS) of Uveal Melanoma (UM) patients is relatively high, reaching about 80% at 5 years, with high-risk UM patients frequently developing a metastatic disease, which has a severe prognosis. In about 90% of cases, metastases involve the liver, and untreated patients have a mean survival time of about 2 months, reaching about 6 months in treated patients [1,2,3]. While in metastatic cutaneous melanoma targeted therapies with B-Raf Proto-Oncogene, Serine/Threonine Kinase (B-RAF) and Mitogen-Activated Protein Kinase Kinase (MEK) inhibitors or immunotherapy with anti-Cytotoxic T-Lymphocyte Associated Protein (CTLA)-4 and/or anti- Programmed Cell Death (PD)-1/ Programmed Cell Death 1 Ligand (PDL)-1, treatments are highly effective [4], no effective standard treatment is available for metastatic UM so far.…”

Section: Introductionmentioning

confidence: 99%

Targeted Therapy of Uveal Melanoma: Recent Failures and New Perspectives

Croce

Ferrini

Pfeffer

et al. 2019

Cancers

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Among Uveal Melanoma (UM) driver mutations, those involving GNAQ or GNA11 genes are the most frequent, while a minor fraction of tumors bears mutations in the PLCB4 or CYSLTR2 genes. Direct inhibition of constitutively active oncoproteins deriving from these mutations is still in its infancy in UM, whereas BRAFV600E-targeted therapy has obtained relevant results in cutaneous melanoma. However, UM driver mutations converge on common downstream signaling pathways such as PKC/MAPK, PI3K/AKT, and YAP/TAZ, which are presently considered as actionable targets. In addition, BAP1 loss, which characterizes UM metastatic progression, affects chromatin structure via histone H2A deubiquitylation that may be counteracted by histone deacetylase inhibitors. Encouraging results of preclinical studies targeting signaling molecules such as MAPK and PKC were unfortunately not confirmed in early clinical studies. Indeed, a general survey of all clinical trials applying new targeted and immune therapy to UM displayed disappointing results. This paper summarizes the most recent studies of UM-targeted therapies, analyzing the possible origins of failures. We also focus on hyperexpressed molecules involved in UM aggressiveness as potential new targets for therapy.

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“…The prevention and therapy of uveal melanoma (UM) metastases remain as an unmet clinical need, which sadly leaves the patients an average survival time of less than six months following the diagnosis of such systemic lesions [ 1 , 2 ]. The metastases develop in approximately half of the UM patients mainly in the liver usually 5–10 years after the successful local control of the primary tumor, with a latency of up to 40 years [ 3 , 4 , 5 ]. This pattern suggests that the tumor cells have already started to disseminate at the time of initial diagnosis and could survive in the extraocular environment for many years possibly in a dormant state.…”

Section: Introductionmentioning

confidence: 99%

Metastasis of Uveal Melanoma with Monosomy-3 Is Associated with a Less Glycogenetic Gene Expression Profile and the Dysregulation of Glycogen Storage

Vardanyan

Brosig

Merz³

et al. 2020

Cancers

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The prolonged storage of glucose as glycogen can promote the quiescence of tumor cells, whereas the accumulation of an aberrant form of glycogen without the primer protein glycogenin can induce the metabolic switch towards a glycolytic phenotype. Here, we analyzed the expression of n = 67 genes involved in glycogen metabolism on the uveal melanoma (UM) cohort of the Cancer Genome Atlas (TCGA) study and validated the differentially expressed genes in an independent cohort. We also evaluated the glycogen levels with regard to the prognostic factors via a differential periodic acid-Schiff (PAS) staining. UMs with monosomy-3 exhibited a less glycogenetic and more insulin-resistant gene expression profile, together with the reduction of glycogen levels, which were associated with the metastases. Expression of glycogenin-1 (Locus: 3q24) was lower in the monosomy-3 tumors, whereas the complementary isoform glycogenin-2 (Locus: Xp22.33) was upregulated in females. Remarkably, glycogen was more abundant in the monosomy-3 tumors of male versus female patients. We therefore provide the first evidence to the dysregulation of glycogen metabolism as a novel factor that may be aggravating the course of UM particularly in males.

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Obstacles to improving outcomes in the treatment of uveal melanoma

Cited by 18 publications

References 80 publications

Beta‐blockers exert potent anti‐tumor effects in cutaneous and uveal melanoma

Beta‐blockers exert potent anti‐tumor effects in cutaneous and uveal melanoma

Targeted Therapy of Uveal Melanoma: Recent Failures and New Perspectives

Metastasis of Uveal Melanoma with Monosomy-3 Is Associated with a Less Glycogenetic Gene Expression Profile and the Dysregulation of Glycogen Storage

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