scholarly journals Targeting the p53 Pathway in CLL: State of the Art and Future Perspectives

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4681
Author(s):  
Marwan Kwok ◽  
Angelo Agathanggelou ◽  
Nicholas Davies ◽  
Tatjana Stankovic
Keyword(s):  
Synthetic Lethality ◽  
Clonal Evolution ◽  
Critical Role ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Genome Maintenance ◽  
Therapeutic Approaches ◽  
P53 Pathway ◽  
Genomic Aberrations ◽  
Tumor Suppressive Function

The p53 pathway is a desirable therapeutic target, owing to its critical role in the maintenance of genome integrity. This is exemplified in chronic lymphocytic leukemia (CLL), one of the most common adult hematologic malignancies, in which functional loss of p53 arising from genomic aberrations are frequently associated with clonal evolution, disease progression, and therapeutic resistance, even in the contemporary era of CLL targeted therapy and immunotherapy. Targeting the ‘undruggable’ p53 pathway therefore arguably represents the holy grail of cancer research. In recent years, several strategies have been proposed to exploit p53 pathway defects for cancer treatment. Such strategies include upregulating wild-type p53, restoring tumor suppressive function in mutant p53, inducing synthetic lethality by targeting collateral genome maintenance pathways, and harnessing the immunogenicity of p53 pathway aberrations. In this review, we will examine the biological and clinical implications of p53 pathway defects, as well as our progress towards development of therapeutic approaches targeting the p53 pathway, specifically within the context of CLL. We will appraise the opportunities and pitfalls associated with these therapeutic strategies, and evaluate their place amongst the array of new biological therapies for CLL.

Clonal Evolution in Chronic Lymphocytic Leukemia: Acquisition of High-Risk Genomic Aberrations Associated with Unmutated VH, Resistance to Therapy, and Short Survival.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 296-296 ◽  
Author(s):  
Stephan Stilgenbauer ◽  
Sandrine Sander ◽  
Lars Bullinger ◽  
Axel Benner ◽  
Elke Leupolt ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Clonal Evolution ◽  
Lymphocytic Leukemia ◽  
Single Institution ◽  
Need For Treatment ◽  
Rate Of Progression ◽  
Genomic Aberrations ◽  
Adverse Factor

Abstract Genomic aberrations were analyzed by fluorescence in situ hybridization (FISH) at various time points during the disease course of 64 patients with chronic lymphocytic leukemia (CLL) from a single institution. After a median time of 42 (23–73) months, 11 of the 64 (17%) patients acquired the following additional aberrations: del(17p13) (n=4), del(6q21) (n=3), del(11q23) (n=2), +(8q24) (n=1), and evolution from monoallelic to biallelic del(13q14) (n=3). The baseline clinical characteristics of the patients with and without clonal evolution were not significantly different. Remarkably, clonal evolution occurred exclusively among cases with unmutated VH status (Figure 1). The group with clonal evolution showed a higher rate of progression in stage (82% vs. 28%), a greater need for treatment (100% vs. 62%), and a higher death rate (67% vs. 28%). The median survival time after the occurrence of clonal evolution was 22 months. Expansion of the clone with del(17p13) was observed in all patients during chemotherapy (chlorambucil n=4, fludarabine n=3, FC n=2, rituximab n=1) indicating in-vivo resistance to treatment (Figure 2). In multivariate analysis, clonal evolution was identified as independent adverse factor with regard to overall survival. Figure 1 Figure 1. Figure 2 Figure 2.

scholarly journals Genetic Abnormalities in Chronic Lymphocytic Leukemia: Where We Are and Where We Go

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Anna Puiggros ◽  
Gonzalo Blanco ◽  
Blanca Espinet
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Chromosomal Abnormalities ◽  
Clonal Evolution ◽  
Gene Mutations ◽  
Therapeutic Strategies ◽  
Lymphocytic Leukemia ◽  
Wide Range ◽  
Trisomy 12 ◽  
Genomic Aberrations ◽  
Next Generation Sequencing Ngs

Chromosomal abnormalities in chronic lymphocytic leukemia (CLL) are detected in up to 80% of patients. Among them, deletions of 11q, 13q, 17p, and trisomy 12 have a known prognostic value and play an important role in CLL pathogenesis and evolution, determining patients outcome and therapeutic strategies. Standard methods used to identify these genomic aberrations include both conventional G-banding cytogenetics (CGC) and fluorescencein situhybridization (FISH). Although FISH analyses have been implemented as the gold standard, CGC allows the identification of chromosomal translocations and complex karyotypes, the latest associated with poor outcome. Genomic arrays have a higher resolution that allows the detection of cryptic abnormalities, although these have not been fully implemented in routine laboratories. In the last years, next generation sequencing (NGS) methods have identified a wide range of gene mutations (e.g.,TP53, NOTCH1, SF3B1,andBIRC3) which have improved our knowledge about CLL development, allowing us to refine both the prognostic subgroups and better therapeutic strategies. Clonal evolution has also recently arisen as a key point in CLL, integrating cytogenetic alterations and mutations in a dynamic model that improve our understanding about its clinical course and relapse.

Clonal Evolution in Chronic Lymphocytic Leukemia is Scant in Relapsed But Accelerated in Refractory Cases

2019 ◽  
Author(s):  
Marc Zapatka ◽  
Eugen Tausch ◽  
Selcen Öztürk ◽  
Martina Seiffert ◽  
Thorsten Zenz ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Clonal Evolution ◽  
Lymphocytic Leukemia

scholarly journals DDRE-06. CELLULAR STRESS RESPONSE IN DIPG THERAPY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii62-ii62
Author(s):  
Sreepradha Sridharan ◽  
Arif Harmanci ◽  
Robert Siddaway ◽  
Tara Dobson ◽  
Jyothishmathi Swaminathan ◽  
...  
Keyword(s):  
Stress Response ◽  
Single Cell ◽  
Synthetic Lethality ◽  
Clonal Evolution ◽  
Single Agent ◽  
Objective Response ◽  
Hdac Inhibitors ◽  
Pediatric Brain Tumor ◽  
Dominant Negative ◽  
Cellular Stress Response

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable pediatric brain tumor of the pons and brainstem. Therefore, there is a desperate need for new therapeutics. Genomic profiling of tumors identified a highly prevalent dominant negative somatic mutation at lysine (K)-27 in histone genes HIST1H3B and H3F3A. Clonal evolution modeling suggests these mutations are truncal, and studies have demonstrated their contribution to tumorigenesis. ONC201, a first-in-class DRD2 antagonist and ClpP agonist is an anticancer drug developed by Oncoceutics, which targets the unfolded protein response (UPR) and integrated stress response (ISR) signaling and is actively being investigated in patients with recurrent H3 K27M-mutant gliomas. In adults with recurrent glioma, single agent studies showed benign-safety, no dose-limiting toxicities and a durable objective response when administered orally. In addition, intra-tumoral drug levels exceeded therapeutic thresholds, and induced tumor cell apoptosis. Based on this and response seen in a pediatric patient with DIPG for whom compassionate use of ONC201 was approved, a multi-arm, non-randomized multi-institutional Phase I clinical trial (NCT03416530) is actively accruing patients. However, the strength of UPR and ISR in DIPGs and their effect on DIPG response to ONC201 is not known. Our group employed bulk/single cell transcriptomic and single cell proteomic approaches to demonstrate substantial heterogeneity in UPR and ISR signaling in human DIPG samples. Consistent with this, DIPG cell lines exhibited considerable variability in sensitivity to ONC201. Single cell profiling identified tumor sub-populations with significant proliferative capacity even after ONC201 exposure. Incomplete response promotes recurrence. To target these cells, we performed a synthetic lethality screen with a library of 360 FDA-approved CNS penetrant compounds, which identified HDAC inhibitors and DNA damage-inducing chemotherapy as having synergy with ONC201. Thus, we suggest that tumor heterogeneity impacts sensitivity to ONC201 and that this can be reduced by combination treatments.

scholarly journals Upregulation of Serum lncRNA DLEU1 Predicts Progression of Premalignant Endometrial Lesion and Unfavorable Clinical Outcome of Endometrial Cancer

2020 ◽  
Vol 19 ◽  
pp. 153303382096558
Author(s):  
Lixia Shan ◽  
Tao Zhao ◽  
Yu Wang
Keyword(s):  
Endometrial Cancer ◽  
Endometrial Hyperplasia ◽  
Cox Regression ◽  
Quantitative Polymerase Chain Reaction ◽  
Critical Role ◽  
Disease Free Survival ◽  
Lymphocytic Leukemia ◽  
Healthy Controls ◽  
Clinical Value ◽  
Cox Regression Analysis

Objective: Long non-coding RNAs (lncRNAs) play a critical role in tumorigenesis. Upregulation of lncRNA deleted in lymphocytic leukemia 1 (DLEU1) has been reported in endometrial cancer (EC) tissues. This prospective study aimed to determine the potential clinical significance of serum lncRNA DLEU1 in EC. Methods: The serum lncRNA DLEU1 level was detected in EC patients, patients with endometrial hyperplasia and healthy controls by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Then its clinical value in EC was further evaluated. Results: Our results demonstrated that serum lncRNA DLEU1 levels were significantly increased in patients with EC, and serum lncRNA DLEU1 showed good performance for discriminating EC patients from patients with endometrial hyperplasia and healthy controls. In addition, EC patients with advanced clinicopathological features had higher circulating lncRNA DLEU1 level than those with favorable clinical characteristics. Moreover, EC patients in the high serum lncRNA DLEU1 group suffered worse overall survival and disease-free survival than those in the low serum lncRNA DLEU1 group. Furthermore, multivariate cox regression analysis displayed that the serum lncRNA DLEU1 served as an independent prognostic factor for EC. Conclusions: Collectively, our study suggests that serum lncRNA DLEU1 is a novel and promising biomarker for prognostic estimation of EC.

scholarly journals Immunological and genetic kinetics from diagnosis to clinical progression in chronic lymphocytic leukemia

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Isabel Jiménez ◽  
Bárbara Tazón-Vega ◽  
Pau Abrisqueta ◽  
Juan C. Nieto ◽  
Sabela Bobillo ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Ex Vivo ◽  
Clonal Evolution ◽  
Lymphocytic Leukemia ◽  
Clinical Progression ◽  
Molecular Changes ◽  
Main Driver ◽  
Altered Gene

Abstract Background Mechanisms driving the progression of chronic lymphocytic leukemia (CLL) from its early stages are not fully understood. The acquisition of molecular changes at the time of progression has been observed in a small fraction of patients, suggesting that CLL progression is not mainly driven by dynamic clonal evolution. In order to shed light on mechanisms that lead to CLL progression, we investigated longitudinal changes in both the genetic and immunological scenarios. Methods We performed genetic and immunological longitudinal analysis using paired primary samples from untreated CLL patients that underwent clinical progression (sampling at diagnosis and progression) and from patients with stable disease (sampling at diagnosis and at long-term asymptomatic follow-up). Results Molecular analysis showed limited and non-recurrent molecular changes at progression, indicating that clonal evolution is not the main driver of clinical progression. Our analysis of the immune kinetics found an increasingly dysfunctional CD8+ T cell compartment in progressing patients that was not observed in those patients that remained asymptomatic. Specifically, terminally exhausted effector CD8+ T cells (T-betdim/−EomeshiPD1hi) accumulated, while the the co-expression of inhibitory receptors (PD1, CD244 and CD160) increased, along with an altered gene expression profile in T cells only in those patients that progressed. In addition, malignant cells from patients at clinical progression showed enhanced capacity to induce exhaustion-related markers in CD8+ T cells ex vivo mainly through a mechanism dependent on soluble factors including IL-10. Conclusions Altogether, we demonstrate that the interaction with the immune microenvironment plays a key role in clinical progression in CLL, thereby providing a rationale for the use of early immunotherapeutic intervention.

scholarly journals Specialized Pro-Resolving Lipid Mediators in Neonatal Cardiovascular Physiology and Diseases

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 933
Author(s):  
Andrea Gila-Diaz ◽  
Gloria Herranz Carrillo ◽  
Pratibha Singh ◽  
David Ramiro-Cortijo
Keyword(s):  
Tissue Repair ◽  
Cardiovascular Health ◽  
Critical Role ◽  
Potential Effect ◽  
Lipid Mediators ◽  
Physiological Effects ◽  
Therapeutic Approaches ◽  
The Impact ◽  
Long Chain

Cardiovascular disease remains a leading cause of mortality worldwide. Unresolved inflammation plays a critical role in cardiovascular diseases development. Specialized Pro-Resolving Mediators (SPMs), derived from long chain polyunsaturated fatty acids (LCPUFAs), enhances the host defense, by resolving the inflammation and tissue repair. In addition, SPMs also have anti-inflammatory properties. These physiological effects depend on the availability of LCPUFAs precursors and cellular metabolic balance. Most of the studies have focused on the impact of SPMs in adult cardiovascular health and diseases. In this review, we discuss LCPUFAs metabolism, SPMs, and their potential effect on cardiovascular health and diseases primarily focusing in neonates. A better understanding of the role of these SPMs in cardiovascular health and diseases in neonates could lead to the development of novel therapeutic approaches in cardiovascular dysfunction.

scholarly journals Graph contextualized attention network for predicting synthetic lethality in human cancers

2021 ◽  
Author(s):  
Yahui Long ◽  
Min Wu ◽  
Yong Liu ◽  
Jie Zheng ◽  
Chee Keong Kwoh ◽  
...  
Keyword(s):  
Synthetic Lethality ◽  
Critical Role ◽  
Design Feature ◽  
Cost Effective ◽  
Attention Network ◽  
New Genes ◽  
Lab Experiments ◽  
Proposed Model ◽  
Multiple Feature ◽  
Wet Lab

Abstract Motivation Synthetic Lethality (SL) plays an increasingly critical role in the targeted anticancer therapeutics. In addition, identifying SL interactions can create opportunities to selectively kill cancer cells without harming normal cells. Given the high cost of wet-lab experiments, in silico prediction of SL interactions as an alternative can be a rapid and cost-effective way to guide the experimental screening of candidate SL pairs. Several matrix factorization-based methods have recently been proposed for human SL prediction. However, they are limited in capturing the dependencies of neighbors. In addition, it is also highly challenging to make accurate predictions for new genes without any known SL partners. Results In this work, we propose a novel graph contextualized attention network named GCATSL to learn gene representations for SL prediction. First, we leverage different data sources to construct multiple feature graphs for genes, which serve as the feature inputs for our GCATSL method. Second, for each feature graph, we design node-level attention mechanism to effectively capture the importance of local and global neighbors and learn local and global representations for the nodes, respectively. We further exploit multi-layer perceptron (MLP) to aggregate the original features with the local and global representations and then derive the feature-specific representations. Third, to derive the final representations, we design feature-level attention to integrate feature-specific representations by taking the importance of different feature graphs into account. Extensive experimental results on three datasets under different settings demonstrated that our GCATSL model outperforms 14 state-of-the-art methods consistently. In addition, case studies further validated the effectiveness of our proposed model in identifying novel SL pairs. Availability Python codes and dataset are freely available on GitHub (https://github.com/longyahui/GCATSL) and Zenodo (https://zenodo.org/record/4522679) under the MIT license.

scholarly journals Development of cancer metabolism as a therapeutic target: new pathways, patient studies, stratification and combination therapy

2019 ◽  
Vol 122 (1) ◽  
pp. 1-3 ◽  
Author(s):  
Adrian L. Harris
Keyword(s):  
Metabolic Pathways ◽  
Trial Design ◽  
Cancer Metabolism ◽  
Aerobic Glycolysis ◽  
Critical Role ◽  
Therapeutic Approaches ◽  
Preclinical Models ◽  
Wide Range ◽  
Patient Studies

AbstractCancer metabolism has undergone a resurgence in the last decade, 70 years after Warburg described aerobic glycolysis as a feature of cancer cells. A wide range of techniques have elucidated the complexity and heterogeneity in preclinical models and clinical studies. What emerges are the large differences between tissues, tumour types and intratumour heterogeneity. However, synergies with inhibition of metabolic pathways have been found for many drugs and therapeutic approaches, and a critical role of window studies and translational trial design is key to success.

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