scholarly journals Targeting CK2 in cancer: a valuable strategy or a waste of time?

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Mauro Salvi ◽  
Christian Borgo ◽  
Lorenzo A. Pinna ◽  
Maria Ruzzene
Keyword(s):  
Drug Target ◽  
Clinical Grade ◽  
Anticancer Efficacy ◽  
Depth Analysis ◽  
Cancer Types ◽  
Pharmacological Target ◽  
Anticancer Target ◽  
Ck2 Inhibitors ◽  
Ck2 Inhibitor ◽  
Target Effects

AbstractCK2 is a protein kinase involved in several human diseases (ranging from neurological and cardiovascular diseases to autoimmune disorders, diabetes, and infections, including COVID-19), but its best-known implications are in cancer, where it is considered a pharmacological target. Several CK2 inhibitors are available and clinical trials are underway in different cancer types. Recently, the suitability of CK2 as a broad anticancer target has been questioned by the finding that a newly developed compound, named SGC-CK2-1, which is more selective than any other known CK2 inhibitor, is poorly effective in reducing cell growth in different cancer lines, prompting the conclusion that the anticancer efficacy of CX-4945, the commonly used clinical-grade CK2 inhibitor, is to be attributed to its off-target effects. Here we perform a detailed scrutiny of published studies on CK2 targeting and a more in-depth analysis of the available data on SGC-CK2-1 vs. CX-4945 efficacy, providing a different perspective about the actual reliance of cancer cells on CK2. Collectively taken, our arguments would indicate that the pretended dispensability of CK2 in cancer is far from having been proved and warn against premature conclusions, which could discourage ongoing investigations on a potentially valuable drug target.

scholarly journals In-Depth Analysis of the Impact of Different Serum-Free Media on the Production of Clinical Grade Dendritic Cells for Cancer Immunotherapy

2021 ◽  
Vol 11 ◽  
Author(s):  
João Calmeiro ◽  
Luís Mendes ◽  
Iola F. Duarte ◽  
Catarina Leitão ◽  
Adriana R. Tavares ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Ex Vivo ◽  
Culture Conditions ◽  
Clinical Grade ◽  
Serum Free ◽  
Depth Analysis ◽  
Free Media ◽  
The Impact

Dendritic cell (DC)-based antitumor vaccines have proven to be a safe approach, but often fail to generate robust results between trials. Translation to the clinic has been hindered in part by the lack of standard operation procedures for vaccines production, namely the definition of optimal culture conditions during ex-vivo DC differentiation. Here we sought to compare the ability of three clinical grade serum-free media, DendriMACS, AIM-V, and X-VIVO 15, alongside with fetal bovine serum-supplemented Roswell Park Memorial Institute Medium (RPMI), to support the differentiation of monocyte-derived DCs (Mo-DCs). Under these different culture conditions, phenotype, cell metabolomic profiles, response to maturation stimuli, cytokines production, allogenic T cell stimulatory capacity, as well as priming of antigen-specific CD8+ T cells and activation of autologous natural killer (NK) cells were analyzed. Immature Mo-DCs differentiated in AIM-V or X-VIVO 15 presented lower levels of CD1c, CD1a, and higher expression of CD11c, when compared to cells obtained with DendriMACS. Upon stimulation, only AIM-V or X-VIVO 15 DCs acquired a full mature phenotype, which supports their enhanced capacity to polarize T helper cell type 1 subset, to prime antigen-specific CD8+ T cells and to activate NK cells. CD8+ T cells and NK cells resulting from co-culture with AIM-V or X-VIVO 15 DCs also showed superior cytolytic activity. 1H nuclear magnetic resonance-based metabolomic analysis revealed that superior DC immunostimulatory capacities correlate with an enhanced catabolism of amino acids and glucose. Overall, our data highlight the impact of critically defining the culture medium used in the production of DCs for clinical application in cancer immunotherapy. Moreover, the manipulation of metabolic state during differentiation could be envisaged as a strategy to enhance desired cell characteristics.

scholarly journals Phosphorylation of Liver X Receptor α Selectively Regulates Target Gene Expression in Macrophages

2008 ◽  
Vol 28 (8) ◽  
pp. 2626-2636 ◽  
Author(s):  
Inés Pineda Torra ◽  
Naima Ismaili ◽  
Jonathan E. Feig ◽  
Chong-Feng Xu ◽  
Claudio Cavasotto ◽  
...  
Keyword(s):  
Target Gene ◽  
Target Genes ◽  
Metabolic Diseases ◽  
Liver X Receptor ◽  
Raw 264.7 Cells ◽  
Raw 264.7 ◽  
Deficient Mutant ◽  
Liver X Receptor Α ◽  
Ck2 Inhibitors ◽  
Ck2 Inhibitor

ABSTRACT Dysregulation of liver X receptor α (LXRα) activity has been linked to cardiovascular and metabolic diseases. Here, we show that LXRα target gene selectivity is achieved by modulation of LXRα phosphorylation. Under basal conditions, LXRα is phosphorylated at S198; phosphorylation is enhanced by LXR ligands and reduced both by casein kinase 2 (CK2) inhibitors and by activation of its heterodimeric partner RXR with 9-cis-retinoic acid (9cRA). Expression of some (AIM and LPL), but not other (ABCA1 or SREBPc1) established LXR target genes is increased in RAW 264.7 cells expressing the LXRα S198A phosphorylation-deficient mutant compared to those with WT receptors. Surprisingly, a gene normally not expressed in macrophages, the chemokine CCL24, is activated specifically in cells expressing LXRα S198A. Furthermore, inhibition of S198 phosphorylation by 9cRA or by a CK2 inhibitor similarly promotes CCL24 expression, thereby phenocopying the S198A mutation. Thus, our findings reveal a previously unrecognized role for phosphorylation in restricting the repertoire of LXRα-responsive genes.

scholarly journals QSAR Model of Indeno[1,2-b]indole Derivatives and Identification of N-isopentyl-2-methyl-4,9-dioxo-4,9-Dihydronaphtho[2,3-b]furan-3-carboxamide as a Potent CK2 Inhibitor

Molecules ◽  
2019 ◽  
Vol 25 (1) ◽  
pp. 97 ◽  
Author(s):  
Samer Haidar ◽  
Christelle Marminon ◽  
Dagmar Aichele ◽  
Abdelhamid Nacereddine ◽  
Wael Zeinyeh ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Qsar Model ◽  
Biological Evaluation ◽  
Indole Derivatives ◽  
Ic50 Value ◽  
Ic50 Values ◽  
Synthesis And Biological Evaluation ◽  
Ck2 Inhibitors ◽  
Ck2 Inhibitor

Casein kinase II (CK2) is an intensively studied enzyme, involved in different diseases, cancer in particular. Different scaffolds were used to develop inhibitors of this enzyme. Here, we report on the synthesis and biological evaluation of twenty phenolic, ketonic, and para-quinonic indeno[1,2-b]indole derivatives as CK2 inhibitors. The most active compounds were 5-isopropyl-1-methyl-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione 4h and 1,3-dibromo-5-isopropyl-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione 4w with identical IC50 values of 0.11 µM. Furthermore, the development of a QSAR model based on the structure of indeno[1,2-b]indoles was performed. This model was used to predict the activity of 25 compounds with naphtho[2,3-b]furan-4,9-dione derivatives, which were previously predicted as CK2 inhibitors via a molecular modeling approach. The activities of four naphtho[2,3-b]furan-4,9-dione derivatives were determined in vitro and one of them (N-isopentyl-2-methyl-4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-3-carboxamide) turned out to inhibit CK2 with an IC50 value of 2.33 µM. All four candidates were able to reduce the cell viability by more than 60% after 24 h of incubation using 10 µM.

scholarly journals UCHL1 as a novel target in breast cancer: emerging insights from cell and chemical biology

2021 ◽  
Author(s):  
Milon Mondal ◽  
Daniel Conole ◽  
Jaya Nautiyal ◽  
Edward W. Tate
Keyword(s):  
Breast Cancer ◽  
Drug Target ◽  
Chemical Biology ◽  
Treatment Options ◽  
Survival Rates ◽  
Cancer Types ◽  
Carboxyl Terminal ◽  
Novel Target ◽  
Substrate Proteins ◽  
Estrogen Receptor Negative

AbstractBreast cancer has the highest incidence and death rate among cancers in women worldwide. In particular, metastatic estrogen receptor negative (ER–) breast cancer and triple-negative breast cancer (TNBC) subtypes have very limited treatment options, with low survival rates. Ubiquitin carboxyl terminal hydrolase L1 (UCHL1), a ubiquitin C-terminal hydrolase belonging to the deubiquitinase (DUB) family of enzymes, is highly expressed in these cancer types, and several key reports have revealed emerging and important roles for UCHL1 in breast cancer. However, selective and potent small-molecule UCHL1 inhibitors have been disclosed only very recently, alongside chemical biology approaches to detect regulated UHCL1 activity in cancer cells. These tools will enable novel insights into oncogenic mechanisms driven by UCHL1, and identification of substrate proteins deubiquitinated by UCHL1, with the ultimate goal of realising the potential of UCHL1 as a drug target in breast cancer.

Artificial intelligence-based pathology for gastrointestinal and hepatobiliary cancers

Gut ◽  
2020 ◽  
pp. gutjnl-2020-322880 ◽  
Author(s):  
Julien Calderaro ◽  
Jakob Nikolas Kather
Keyword(s):  
Artificial Intelligence ◽  
Liver Cancer ◽  
Genetic Alterations ◽  
Clinical Implications ◽  
Complex Information ◽  
Wide Range ◽  
Depth Analysis ◽  
Cancer Types ◽  
Cancer Tissues ◽  
Very High

Artificial intelligence (AI) can extract complex information from visual data. Histopathology images of gastrointestinal (GI) and liver cancer contain a very high amount of information which human observers can only partially make sense of. Complementing human observers, AI allows an in-depth analysis of digitised histological slides of GI and liver cancer and offers a wide range of clinically relevant applications. First, AI can automatically detect tumour tissue, easing the exponentially increasing workload on pathologists. In addition, and possibly exceeding pathologist’s capacities, AI can capture prognostically relevant tissue features and thus predict clinical outcome across GI and liver cancer types. Finally, AI has demonstrated its capacity to infer molecular and genetic alterations of cancer tissues from histological digital slides. These are likely only the first of many AI applications that will have important clinical implications. Thus, pathologists and clinicians alike should be aware of the principles of AI-based pathology and its ability to solve clinically relevant problems, along with its limitations and biases.

scholarly journals Intracellular water – an overlooked drug target? Cisplatin impact in cancer cells probed by neutrons

2017 ◽  
Vol 19 (4) ◽  
pp. 2702-2713 ◽  
Author(s):  
M. P. M. Marques ◽  
A. L. M. Batista de Carvalho ◽  
V. Garcia Sakai ◽  
L. Hatter ◽  
L. A. E. Batista de Carvalho
Keyword(s):  
Cancer Cells ◽  
Drug Target ◽  
Intracellular Water ◽  
Pharmacological Target

Intracellular water as a secondary pharmacological target?

scholarly journals Pan-cancer analysis of longitudinal metastatic tumors reveals genomic alterations and immune landscape dynamics associated with pembrolizumab sensitivity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
S. Y. Cindy Yang ◽  
Scott C. Lien ◽  
Ben X. Wang ◽  
Derek L. Clouthier ◽  
Youstina Hanna ◽  
...  
Keyword(s):  
Myeloid Cell ◽  
Circulating Tumor Dna ◽  
Immune Checkpoint Blockade ◽  
Tumor Burden ◽  
Adaptive Resistance ◽  
Mutation Burden ◽  
Potential Biomarker ◽  
Depth Analysis ◽  
Cancer Types ◽  
Tumor Genome

AbstractSerial circulating tumor DNA (ctDNA) monitoring is emerging as a non-invasive strategy to predict and monitor immune checkpoint blockade (ICB) therapeutic efficacy across cancer types. Yet, limited data exist to show the relationship between ctDNA dynamics and tumor genome and immune microenvironment in patients receiving ICB. Here, we present an in-depth analysis of clinical, whole-exome, transcriptome, and ctDNA profiles of 73 patients with advanced solid tumors, across 30 cancer types, from a phase II basket clinical trial of pembrolizumab (NCT02644369) and report changes in genomic and immune landscapes (primary outcomes). Patients stratified by ctDNA and tumor burden dynamics correspond with survival and clinical benefit. High mutation burden, high expression of immune signatures, and mutations in BRCA2 are associated with pembrolizumab molecular sensitivity, while abundant copy-number alterations and B2M loss-of-heterozygosity corresponded with resistance. Upon treatment, induction of genes expressed by T cell, B cell, and myeloid cell populations are consistent with sensitivity and resistance. We identified the upregulated expression of PLA2G2D, an immune-regulating phospholipase, as a potential biomarker of adaptive resistance to ICB. Together, these findings provide insights into the diversity of immunogenomic mechanisms that underpin pembrolizumab outcomes.

scholarly journals A Pan-Cancer Analysis of Transcriptome and Survival Reveals Prognostic Differentially Expressed LncRNAs and Predicts Novel Drugs for Glioblastoma Multiforme Therapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Rongchuan Zhao ◽  
Xiaohan Sa ◽  
Nan Ouyang ◽  
Hong Zhang ◽  
Jiao Yang ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Survival Data ◽  
Drug Target ◽  
Differentially Expressed ◽  
Prognostic Biomarkers ◽  
Cancer Type ◽  
Cancer Pathogenesis ◽  
Cancer Types ◽  
Novel Drug ◽  
Pan Cancer

Numerous studies have identified various prognostic long non-coding RNAs (LncRNAs) in a specific cancer type, but a comprehensive pan-cancer analysis for prediction of LncRNAs that may serve as prognostic biomarkers is of great significance to be performed. Glioblastoma multiforme (GBM) is the most common and aggressive malignant adult primary brain tumor. There is an urgent need to identify novel therapies for GBM due to its poor prognosis and universal recurrence. Using available LncRNA expression data of 12 cancer types and survival data of 30 cancer types from online databases, we identified 48 differentially expressed LncRNAs in cancers as potential pan-cancer prognostic biomarkers. Two candidate LncRNAs were selected for validation in GBM. By the expression detection in GBM cell lines and survival analysis in GBM patients, we demonstrated the reliability of the list of pan-cancer prognostic LncRNAs obtained above. By constructing LncRNA-mRNA-drug network in GBM, we predicted novel drug-target interactions for GBM correlated LncRNA. This analysis has revealed common prognostic LncRNAs among cancers, which may provide insights into cancer pathogenesis and novel drug target in GBM.

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