24 research outputs found
The Ubiquitin Proteasome System in Hematological Malignancies: New Insight into Its Functional Role and Therapeutic Options
The ubiquitin proteasome system (UPS) is the main cellular degradation machinery designed for controlling turnover of critical proteins involved in cancer pathogenesis, including hematological malignancies. UPS plays a functional role in regulating turnover of key proteins involved in cell cycle arrest, apoptosis and terminal differentiation. When deregulated, it leads to several disorders, including cancer. Several studies indicate that, in some subtypes of human hematological neoplasms such as multiple myeloma and Burkitt's lymphoma, abnormalities in the UPS made it an attractive therapeutic target due to pro-cancer activity. In this review, we discuss the aberrant role of UPS evaluating its impact in hematological malignancies. Finally, we also review the most promising therapeutic approaches to target UPS as powerful strategies to improve treatment of blood cancers
Unexpected and durable response with regorafenib in a metastatic colorectal cancer patient without KDR mutation: A case report
Regorafenib is an oral multikinase inhibitor and is approved as salvage therapy in the standard treatment of advanced colorectal cancer (CRC). Due to its limited efficacy, toxicity profile, and cost, it is necessary to identify those patients who may have the most benefit from regorafenib. In a previous case report, kinase insert domain receptor (KDR) mutation has been associated with exceptional clinical response (CR) in an elderly patient treated with a low dose of regorafenib; thus, it was hypothesized that it could represent a new predictive marker of drug response
Discovery of a new class of triazole based inhibitors of acetyl transferase KAT2A
We have recently developed a new synthetic methodology that provided both N-aryl-5-hydroxytriazoles
and N-pyridine-4-alkyl triazoles. A selection of these products was carried through virtual screening
towards targets that are contemporary and validated for drug discovery and development. This study
determined a number of potential structure target dyads of which N-pyridinium-4-carboxylic-5-alkyl triazole
displayed the highest score specificity towards KAT2A. Binding affinity tests of abovementioned triazole
and related analogs towards KAT2A confirmed the predictions of the in-silico assay. Finally, we have
run in vitro inhibition assays of selected triazoles towards KAT2A; the ensemble of binding and inhibition
assays delivered pyridyl-triazoles carboxylates as the prototype of a new class of inhibitors of KAT2A
Metabolic Pathways as a Novel Landscape in Pancreatic Ductal Adenocarcinoma
Metabolism plays a fundamental role in both human physiology and pathology, including
pancreatic ductal adenocarcinoma (PDAC) and other tumors. Anabolic and catabolic processes do
not only have energetic implications but are tightly associated with other cellular activities, such as
DNA duplication, redox reactions, and cell homeostasis. PDAC displays a marked metabolic phenotype
and the observed reduction in tumor growth induced by calorie restriction with in vivo
models supports the crucial role of metabolism in this cancer type. The aggressiveness of PDAC
might, therefore, be reduced by interventions on bioenergetic circuits. In this review, we describe
the main metabolic mechanisms involved in PDAC growth and the biological features that may
favor its onset and progression within an immunometabolic context. We also discuss the need to
bridge the gap between basic research and clinical practice in order to offer alternative therapeutic
approaches for PDAC patients in the more immediate future
Looking Beyond the Glioblastoma Mask: Is Genomics the Right Path?
Glioblastomas are the most frequent and malignant brain tumor hallmarked by an
invariably poor prognosis. They have been classically differentiated into primary
isocitrate dehydrogenase 1 or 2 (IDH1 -2) wild-type (wt) glioblastoma (GBM) and
secondary IDH mutant GBM, with IDH wt GBMs being commonly associated with older
age and poor prognosis. Recently, genetic analyses have been integrated with epigenetic
investigations, strongly implementing typing and subtyping of brain tumors, including
GBMs, and leading to the new WHO 2021 classification. GBM genomic and epigenomic
profile influences evolution, resistance, and therapeutic responses. However, differently
from other tumors, there is a wide gap between the refined GBM profiling and the limited
therapeutic opportunities. In addition, the different oncogenes and tumor suppressor
genes involved in glial cell transformation, the heterogeneous nature of cancer, and the
restricted access of drugs due to the blood–brain barrier have limited clinical
advancements. This review will summarize the more relevant genetic alterations found
in GBMs and highlight their potential role as potential therapeutic targets
Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia
Background: Acute myeloid leukemia (AML) is a heterogeneous and aggressive blood cancer that results from
diverse genetic aberrations in the hematopoietic stem or progenitor cells (HSPCs) leading to the expansion of blasts
in the hematopoietic system. The heterogeneity and evolution of cancer blasts can render therapeutic interventions ineffective in a yet poorly understood patient-specific manner. In this study, we investigated the clonal heterogeneity
of diagnosis (Dx) and relapse (Re) pairs at genetic and transcriptional levels, and unveiled the underlying pathways and genes contributing to recurrence.
Methods: Whole-exome sequencing was used to detect somatic mutations and large copy number variations
(CNVs). Single cell RNA-seq was performed to investigate the clonal heterogeneity between Dx-Re pairs and amongst patients.
Results: scRNA-seq analysis revealed extensive expression differences between patients and Dx-Re pairs, even for those with the same -presumed- initiating events. Transcriptional differences between and within patients are associated with clonal composition and evolution, with the most striking differences in patients that gained large-scale copy number variations at relapse. These differences appear to have significant molecular implications, exemplified by a DNMT3A/FLT3-ITD patient where the leukemia switched from an AP-1 regulated clone at Dx to a mTOR signaling driven clone at Re. The two distinct AML1-ETO pairs share genes related to hematopoietic stem cell maintenance and cell migration suggesting that the Re leukemic stem cell-like (LSC-like) cells evolved from the Dx cells.
Conclusions: In summary, the single cell RNA data underpinned the tumor heterogeneity not only amongst patient blasts with similar initiating mutations but also between each Dx-Re pair. Our results suggest alternatively and currently unappreciated and unexplored mechanisms leading to therapeutic resistance and AML recurrence
Efficacy of selective histone deacetylase 6 inhibition in mouse models of Pseudomonas aeruginosa infection: A new glimpse for reducing inflammation and infection in cystic fibrosis
The latest studies identified the histone deacetylase (HDAC) class of enzymes as strategic components of the complex molecular machinery underlying inflammation in cystic fibrosis (CF). Compelling new support has been provided for HDAC6 isoform as a key player in the generation of the dysregulated proinflammatory phenotype in CF, as well as in the immune response to the persistent bacterial infection accompanying CF patients. We herein provide in vivo proof-of-concept (PoC) of the efficacy of selective HDAC6 inhibition in contrasting the pro-inflammatory phenotype in a mouse model of chronic P. aeruginosa respiratory infection. Upon careful selection and in-house re-profiling (in vitro and cell-based assessment of acetylated tubulin level through Western blot analysis) of three potent and selective HDAC6 inhibitors as putative candidates for the PoC, we engaged the best performing compound 2 for pre-clinical studies. Compound 2 demonstrated no toxicity and robust anti-inflammatory profile in a mouse model of chronic P. aeruginosa respiratory infection upon repeated aerosol administration. A significant reduction of leukocyte recruitment in the airways, in particular neutrophils, was observed in compound 2-treated mice in comparison with the vehicle; moreover, quantitative immunoassays confirmed a significant reduction of chemokines and cytokines in lung homogenate. This effect was also associated with a modest reduced bacterial load after compound 2-treatment in mice compared to the vehicle. Our study is of particular significance since it demonstrates for the first time the utility of selective drug-like HDAC6 inhibitors in a relevant in vivo model of chronic P. aeruginosa infection, thus supporting their potential application for reverting CF phenotype
CBX2 shapes chromatin accessibility promoting AML via p38 MAPK signaling pathway
Abstract
Background: The dynamic epigenome and proteins specialized in the interpretation of epigenetic marks critically
contribute to leukemic pathogenesis but also offer alternative therapeutic avenues. Targeting newly discovered
chromatin readers involved in leukemogenesis may thus provide new anticancer strategies. Accumulating evidence
suggests that the PRC1 complex member CBX2 is overexpressed in solid tumors and promotes cancer cell survival.
However, its role in leukemia is still unclear.
Methods: We exploited reverse genetic approaches to investigate the role of CBX2 in human leukemic cell lines and
ex vivo samples. We also analyzed phenotypic effects following CBX2 silencing using cellular and molecular assays
and related functional mechanisms by ATAC-seq and RNA-seq. We then performed bioinformatic analysis of ChIPseq
data to explore the influence of histone modifications in CBX2-mediated open chromatin sites. Lastly, we used
molecular assays to determine the contribution of CBX2-regulated pathways to leukemic phenotype.
Results: We found CBX2 overexpressed in leukemia both in vitro and ex vivo samples compared to CD34+
cells.
Decreased CBX2 RNA levels prompted a robust reduction in cell proliferation and induction of apoptosis. Similarly,
sensitivity to CBX2 silencing was observed in primary acute myeloid leukemia samples. CBX2 suppression increased
genome-wide chromatin accessibility followed by alteration of leukemic cell transcriptional programs, resulting in
enrichment of cell death pathways and downregulation of survival genes. Intriguingly, CBX2 silencing induced epigenetic
reprogramming at p38 MAPK-associated regulatory sites with consequent deregulation of gene expression.
Conclusions: Our results identify CBX2 as a crucial player in leukemia progression and highlight a potential druggable CBX2-p38 MAPK network in AML
MicroRNA Expression Profiling Using Agilent One-Color Microarray
MicroRNA (miRNA) expression profiling is an important tool to identify miRNA regulation in physiological or pathological states. This technique has a large number of molecular diagnostic applications, including cancer, cardiovascular and autoimmune diseases, and forensics. To date, a multitude of high-throughput genomic approaches have been developed. Here, we focus on miRNA expression profiling by microarray using SurePrint technology, providing a description of both the workflow and methods for expression profiling by Agilent One-Color Microarray