scholarly journals Increased Non-Homologous End Joining Makes DNA-PK a Promising Target for Therapeutic Intervention in Uveal Melanoma

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1278 ◽  
Author(s):  
Doherty ◽  
Bryant ◽  
Valluru ◽  
Rennie ◽  
Sisley
Keyword(s):  
Uveal Melanoma ◽  
Messenger Rna ◽  
Therapeutic Option ◽  
Survival Rates ◽  
The Cancer Genome Atlas ◽  
End Joining ◽  
Expression Of Genes ◽  
Effective Therapeutic Option ◽  
Non Homologous End Joining ◽  
Induced Apoptosis

Uveal melanoma (UM) is the most common primary intraocular tumour in adults, with a mean survival of six months following metastasis. The survival rates have not improved in over 30 years. This study has shown that sister chromatid exchange (SCE) is low in UM which is likely due to a reduced expression of FANCD2. As FANCD2 can function to suppress non-homologous end joining (NHEJ), this study therefore investigated NHEJ in UM. The activation of the catalytic subunit of the NHEJ pathway protein DNA-dependent protein kinase (DNA-PK) was measured by analysing the foci formation and the ligation efficiency by NHEJ determined using a plasmid-based end-joining assay. Using small-interfering RNA (siRNA) knock-down, and chemical inhibitors of DNA-PK, the survival of primary UM cultures and two cell lines were determined. To assess the homologous recombination capacity in response to the inhibition of DNA-PK, a SCE analysis was performed. In addition, to support the findings, the messenger RNA (mRNA) expression of genes associated with NHEJ was analysed using the Cancer Genome Atlas (TCGA)-UM RNAseq data (n = 79). The NHEJ activity and DNA-PKcs activation was upregulated in UM and the inhibition of DNA-PK selectively induced apoptosis and sensitized to ionising radiation and inter-strand cross-linking agents. The inhibition of the NHEJ protein DNA-PK is lethal to UM, indicating a potentially effective therapeutic option, either alone or as a sensitizer for other treatments.

scholarly journals Ischemia Is Related to Tumour Genetics in Uveal Melanoma

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1004 ◽  
Author(s):  
Niels J. Brouwer ◽  
Annemijn P. A. Wierenga ◽  
Gülçin Gezgin ◽  
Marina Marinkovic ◽  
Gregorius P. M. Luyten ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Messenger Rna ◽  
Tumour Size ◽  
Hypoxia Inducible Factor ◽  
The Cancer Genome Atlas ◽  
Basal Diameter ◽  
Von Hippel Lindau ◽  
The Status ◽  
Using Data ◽  
Tumour Genetics

Hypoxia-inducible factor 1-alpha (HIF1a) and its regulator von Hippel–Lindau protein (VHL) play an important role in tumour ischemia. Currently, drugs that target HIF1a are being developed to treat malignancies. Although HIF1a is known to be expressed in uveal melanoma (UM), it is as yet unknown which factors, such as tumour size or genetics, determine its expression. Therefore, we aimed to determine which tumour characteristics relate to HIF1a expression in UM. Data from 64 patients who were enucleated for UM were analysed. Messenger RNA (mRNA) expression was determined with the Illumina HT-12 v4 chip. In 54 cases, the status of chromosomes 3 and 8q, and BRCA1-associated protein 1 (BAP1) protein expression (immunohistochemistry) were determined. Findings were corroborated using data of 80 patients from the Cancer Genome Atlas (TCGA) study. A significantly increased expression of HIF1a, and a decreased expression of VHL were associated with monosomy 3/loss of BAP1 expression. The relationship between BAP1 loss and HIF1a expression was independent of chromosome 3. The largest basal diameter and tumour thickness showed no relationship with HIF1a. HIF1a expression related to an increased presence of infiltrating T cells and macrophages. From this study, we conclude that HIF1a is strongly related to tumour genetics in UM, especially to loss of BAP1 expression, and less to tumour size. Tumour ischemia is furthermore related to the presence of an inflammatory phenotype.

hsTRAIL/Apo2L Induces Apoptosis in Enteropathy-Associated T-Cell Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1665-1665
Author(s):  
Marijn Radersma ◽  
Laura R de Baaij ◽  
Nathalie J Hijmering ◽  
Gert Ossenkoppele ◽  
Chris JLM Meijer ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Therapeutic Option ◽  
Survival Rates ◽  
Death Receptor ◽  
Isolated Cells ◽  
Lymphoma Cells ◽  
Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway ◽  
Trail Receptors ◽  
Induced Apoptosis

Abstract Abstract 1665 EATL is an intestinal tumor of aberrant intraepithelial T-lymphocytes (IELs) and may be preceded by refractory celiac disease type II (RCD II). Current therapies include surgery, chemotherapy and autologous and/or allogeneic stem cell transplantation. Despite these therapies, the overall outcome of EATL is very poor with 1- and 5-year survival rates in the range of 31–39% and 8–20%, respectively. Therefore, new therapeutic options are needed. Human soluble tumor necrosis factor-related apoptosis-inducing ligand, hsTRAIL/Apo2L, a member of the TNF family, has proven to selectively kill tumor cells via an alternative, death-receptor mediated apoptosis pathway. In this present study we evaluated if hsTRAIL/Apo2L induces apoptosis in both isolated lymphoma cells of EATL biopsies and isolated cells of RCD II biopsies. hsTRAIL/Apo2L induced apoptosis in isolated EATL lymphoma cells. RCD II cells were less sensitive to hsTRAIL/Apo2L compared to EATL cells. hsTRAIL/Apo2L induced apoptosis in EATL cells was caspase-9 dependent, but unexpectedly active caspase-8 involvement could not be detected. RT-MLPA analysis on EATL samples confirmed this observation by showing increased levels of c-Flip in EATL cells, which suggests a blockage in the extrinsic apoptosis pathway. Both EATL and RCDII cells showed expression of TRAIL receptors R1 and R2 and almost no expression of R3 and R4. In conclusion, our study showed that hsTRAIL/Apo2L induces apoptosis in EATL cells through the intrinsic apoptosis pathway. Moreover, we showed that TRAIL receptor R1 and R2 are expressed in EATL cells. Based on these results, hsTRAIL/Apo2L may be a new therapeutic option for EATL patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Convalescent Plasma Therapy: An Effective Therapeutic Option to Treat COVID-19? A Narrative Review

2020 ◽  
Vol Volume 8 ◽  
pp. 7-21
Author(s):  
Ishita Ray ◽  
Diana Fiorela Sánchez ◽  
Chris Andrea Robert ◽  
Mary Phyllis Robert
Keyword(s):  
Therapeutic Option ◽  
Narrative Review ◽  
Plasma Therapy ◽  
Effective Therapeutic Option

scholarly journals Withanolide D Enhances Radiosensitivity of Human Cancer Cells by Inhibiting DNA Damage Non-homologous End Joining Repair Pathway

2020 ◽  
Vol 9 ◽  
Author(s):  
Jerome Lacombe ◽  
Titouan Cretignier ◽  
Laetitia Meli ◽  
E. M. Kithsiri Wijeratne ◽  
Jean-Luc Veuthey ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Human Cancer ◽  
Repair Pathway ◽  
End Joining ◽  
Human Cancer Cells ◽  
Non Homologous End Joining

scholarly journals Patient profiles as an aim to optimize selection in the second line setting: the role of aflibercept

2021 ◽  
Author(s):  
B. González Astorga ◽  
F. Salvà Ballabrera ◽  
E. Aranda Aguilar ◽  
E. Élez Fernández ◽  
P. García-Alfonso ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Therapeutic Option ◽  
Scientific Evidence ◽  
Treatment Options ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Effective Therapeutic Option ◽  
Line Setting ◽  
First Line Treatment

AbstractColorectal cancer is the second leading cause of cancer-related death worldwide. For metastatic colorectal cancer (mCRC) patients, it is recommended, as first-line treatment, chemotherapy (CT) based on doublet cytotoxic combinations of fluorouracil, leucovorin, and irinotecan (FOLFIRI) and fluorouracil, leucovorin, and oxaliplatin (FOLFOX). In addition to CT, biological (targeted agents) are indicated in the first-line treatment, unless contraindicated. In this context, most of mCRC patients are likely to progress and to change from first line to second line treatment when they develop resistance to first-line treatment options. It is in this second line setting where Aflibercept offers an alternative and effective therapeutic option, thought its specific mechanism of action for different patient’s profile: RAS mutant, RAS wild-type (wt), BRAF mutant, potentially resectable and elderly patients. In this paper, a panel of experienced oncologists specialized in the management of mCRC experts have reviewed and selected scientific evidence focused on Aflibercept as an alternative treatment.

scholarly journals Monosomy 3 Is Linked to Resistance to MEK Inhibitors in Uveal Melanoma

2021 ◽  
Vol 22 (13) ◽  
pp. 6727
Author(s):  
Svenja Mergener ◽  
Jens T. Siveke ◽  
Samuel Peña-Llopis
Keyword(s):  
Cell Lines ◽  
Uveal Melanoma ◽  
Survival Data ◽  
Translation Initiation Factor ◽  
The Cancer Genome Atlas ◽  
Initiation Factor ◽  
Chromosome 3 ◽  
Mek Inhibitors ◽  
Mek Inhibition ◽  
Insight Into

The use of MEK inhibitors in the therapy of uveal melanoma (UM) has been investigated widely but has failed to show benefits in clinical trials due to fast acquisition of resistance. In this study, we investigated a variety of therapeutic compounds in primary-derived uveal melanoma cell lines and found monosomy of chromosome 3 (M3) and mutations in BAP1 to be associated with higher resistance to MEK inhibition. However, reconstitution of BAP1 in a BAP1-deficient UM cell line was unable to restore sensitivity to MEK inhibition. We then compared UM tumors from The Cancer Genome Atlas (TCGA) with mutations in BAP1 with tumors with wild-type BAP1. Principal component analysis (PCA) clearly differentiated both groups of tumors, which displayed disparate overall and progression-free survival data. Further analysis provided insight into differential expression of genes involved in signaling pathways, suggesting that the downregulation of the eukaryotic translation initiation factor 2A (EIF2A) observed in UM tumors with BAP1 mutations and M3 UM cell lines might lead to a decrease in ribosome biogenesis while inducing an adaptive response to stress. Taken together, our study links loss of chromosome 3 with decreased sensitivity to MEK inhibition and gives insight into possible related mechanisms, whose understanding is fundamental to overcome resistance in this aggressive tumor.

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