scholarly journals Ion Channels as Therapeutic Targets in High Grade Gliomas

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3068
Author(s):  
Michaela Griffin ◽  
Raheela Khan ◽  
Surajit Basu ◽  
Stuart Smith
Keyword(s):  
Ion Channels ◽  
Treatment Options ◽  
Cell Cycle Control ◽  
Therapeutic Targets ◽  
High Grade ◽  
Neoplastic Progression ◽  
Invasion And Migration ◽  
Average Survival ◽  
High Grade Gliomas ◽  
And Migration

Glioblastoma multiforme (GBM) is a lethal brain cancer with an average survival of 14–15 months even with exhaustive treatment. High grade gliomas (HGG) represent the leading cause of CNS cancer-related death in children and adults due to the aggressive nature of the tumour and limited treatment options. The scarcity of treatment available for GBM has opened the field to new modalities such as electrotherapy. Previous studies have identified the clinical benefit of electrotherapy in combination with chemotherapeutics, however the mechanistic action is unclear. Increasing evidence indicates that not only are ion channels key in regulating electrical signaling and membrane potential of excitable cells, they perform a crucial role in the development and neoplastic progression of brain tumours. Unlike other tissue types, neural tissue is intrinsically electrically active and reliant on ion channels and their function. Ion channels are essential in cell cycle control, invasion and migration of cancer cells and therefore present as valuable therapeutic targets. This review aims to discuss the role that ion channels hold in gliomagenesis and whether we can target and exploit these channels to provide new therapeutic targets and whether ion channels hold the mechanistic key to the newfound success of electrotherapies.

scholarly journals Against the Resilience of High-Grade Gliomas: The Immunotherapeutic Approach (Part I)

2021 ◽  
Vol 11 (3) ◽  
pp. 386
Author(s):  
Alice Giotta Lucifero ◽  
Sabino Luzzi
Keyword(s):  
Monoclonal Antibodies ◽  
Natural Killer ◽  
Immune Escape ◽  
Meta Analysis ◽  
Treatment Options ◽  
High Grade Glioma ◽  
High Grade ◽  
Future Challenges ◽  
Genetic Landscape ◽  
High Grade Gliomas

The resilience of high-grade gliomas (HGGs) against conventional chemotherapies is due to their heterogeneous genetic landscape, adaptive phenotypic changes, and immune escape mechanisms. Innovative immunotherapies have been developed to counteract the immunosuppressive capability of gliomas. Nevertheless, further research is needed to assess the efficacy of the immuno-based approach. The aim of this study is to review the newest immunotherapeutic approaches for glioma, focusing on the drug types, mechanisms of action, clinical pieces of evidence, and future challenges. A PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis)-based literature search was performed on PubMed/Medline and ClinicalTrials.gov databases using the keywords “active/adoptive immunotherapy,” “monoclonal antibodies,” “vaccine,” and “engineered T cell.”, combined with “malignant brain tumor”, “high-grade glioma.” Only articles written in English published in the last 10 years were selected, filtered based on best relevance. Active immunotherapies include systemic temozolomide, monoclonal antibodies, and vaccines. In several preclinical and clinical trials, adoptive immunotherapies, including T, natural killer, and natural killer T engineered cells, have been shown to be potential treatment options for relapsing gliomas. Systemic temozolomide is considered the backbone for newly diagnosed HGGs. Bevacizumab and rindopepimut are promising second-line treatments. Adoptive immunotherapies have been proven for relapsing tumors, but further evidence is needed.

scholarly journals MiRNA-107 enhances the malignant progression of pancreatic cancer by targeting TGFBR3

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0249375
Author(s):  
Tingke Tian ◽  
Quanzhong Yang ◽  
Cuijuan Zhang ◽  
Xiaokun Li ◽  
Jiancheng Cheng
Keyword(s):  
Pancreatic Cancer ◽  
Molecular Mechanisms ◽  
Bioinformatics Analysis ◽  
Therapeutic Targets ◽  
Biological Functions ◽  
Chain Reaction ◽  
Invasion And Migration ◽  
Qrt Pcr ◽  
Polymerase Chain ◽  
And Migration

Background The prognosis of pancreatic cancer (PC) is relatively dismal due to the lack of effective therapy. In this study, we explored the specific functions and molecular mechanisms of miR-107 to uncover effective therapeutic targets for PC. Method The miR-107 expression in PC cell lines was assessed via quantitative real-time polymerase chain reaction (qRT-PCR). Besides, online bioinformatics analysis was adopted to predict the underlying targets of miR-107. Meanwhile, TCGA database was employed to explore the prognosis of PC patients. In addition, MTT and transwell assays were conducted to explore the PC cells’ biological functions. Result MiR-107 was remarkably increased in PC cells which could promote the proliferation, invasion and migration of PC cells. In addition, miR-107 could directly down-regulate TGFBR3 expression through binding to TGFBR3 3’UTR. Survival analysis from TCGA suggested that PC patients with higher miR-107 expression was significantly involved in poorer prognosis. Conclusion We concluded that miR-107 promoted proliferation, invasion and migration of PC cells via targeting TGFBR3, which may provide novel underlying therapeutic targets.

scholarly journals Roles of Long Noncoding RNAs in Conferring Glioma Progression and Treatment

2021 ◽  
Vol 11 ◽  
Author(s):  
Jie Qin ◽  
Chuanlu Jiang ◽  
Jinquan Cai ◽  
Xiangqi Meng
Keyword(s):  
Prognostic Markers ◽  
Postoperative Radiotherapy ◽  
Noncoding Rnas ◽  
Therapeutic Targets ◽  
Long Noncoding Rnas ◽  
Invasion And Migration ◽  
High Relapse Rate ◽  
Dismal Prognosis ◽  
Underlying Mechanisms ◽  
And Migration

Accompanying the development of biomedicine, our knowledge of glioma, one of the most common primary intracranial carcinomas, is becoming more comprehensive. Unfortunately, patients with glioblastoma (GBM) still have a dismal prognosis and a high relapse rate, even with standard combination therapy, namely, surgical resection, postoperative radiotherapy and chemotherapy. The absence of validated biomarkers is responsible for the majority of these poor outcomes, and reliable therapeutic targets are indispensable for improving the prognosis of patients suffering from gliomas. Identification of both precise diagnostic and accurate prognostic markers and promising therapeutic targets has therefore attracted considerable attention from researchers. Encouragingly, accumulating evidence has demonstrated that long noncoding RNAs (lncRNAs) play important roles in the pathogenesis and oncogenesis of various categories of human tumors, including gliomas. Nevertheless, the underlying mechanisms by which lncRNAs regulate diverse biological behaviors of glioma cells, such as proliferation, invasion and migration, remain poorly understood. Consequently, this review builds on previous studies to further summarize the progress in the field of lncRNA regulation of gliomas over recent years and addresses the potential of lncRNAs as diagnostic and prognostic markers and therapeutic targets.

Retrospective review of safety and efficacy of checkpoint inhibition in refractory high-grade gliomas.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2033-2033 ◽  
Author(s):  
Samantha Reiss ◽  
Prakirthi Yerram ◽  
Lisa Modelevsky ◽  
Christian Grommes
Keyword(s):  
Treatment Options ◽  
Single Agent ◽  
Progression Free Survival ◽  
Median Number ◽  
Cancer Center ◽  
High Grade ◽  
Concomitant Therapy ◽  
Safety And Efficacy ◽  
Number Of Patients ◽  
High Grade Gliomas

2033 Background: Treatment options for refractory high grade gliomas (HGG) are limited. Programmed cell death ligand-1 (PD-L1) expression has been reported in 0-61% of HGGs and therefore might be a suitable target in HGG. The purpose of this study was to describe safety and efficacy of PD-1 inhibition in patients with refractory HGGs. Methods: This IRB approved single center retrospective study at Memorial Sloan Kettering Cancer Center included pathologically confirmed HGG with an age ≥18 years who received a PD-1 inhibitor between 9/2014 and 10/2016 outside of a clinical trial. Results: Twenty five HGGs were identified. All patients received the PD-1 inhibitor pembrolizumab (pembro) as part of compassionate use. Median age was 49 years (range 30-72); 44% were men; 13 had glioblastoma (52%), 7 anaplastic astrocytoma (28%), 2 anaplastic oligodendroglioma (8%), 2 unspecified HGG (8%), and 1 gliosarcoma (4%). Patients received a median of 4 prior lines of therapy (range 1-9). Nineteen (76%) previously failed bevacizumab. Median baseline KPS was 80 (range 50-100). Concurrent treatment included bevacizumab in 17 (68%) or bevacizumab and temozolomide in 2 (8%) patients. Median number of doses administered was 3 (range 1-14). Treatment toxicity and response was assessed in 24 patients. PD-1 inhibitor related adverse events (AEs) included LFT elevations (33%), hypothyroidism (17%), diarrhea (17%), myalgias/arthralgias (13%), and rash (8%). Other common AEs were hyperglycemia, fatigue, thrombocytopenia, lymphopenia, headache, and nausea in the setting of concomitant therapy and additional supportive care (dexamethasone). Grade 3 AEs included seizure (4%), headache (4%), nausea (4%), and vomiting (4%). Best radiographic response was partial response (n = 2), stable disease (n = 5), and progressive disease (n = 17). Median progression free survival (PFS) was 42 days (range 7-282) and median overall survival was 121 days (range 15-415). Three patients (12%) had a PFS > 90 days; of these, 2 received single agent pembro. Conclusions: Patients with HGG had low response rates. However, a small number of patients had prolonged PFS. Pembro was tolerated with few serious AEs, even in patients receiving concomitant therapy.

scholarly journals Fusion Genes Altered in Adult Malignant Gliomas

2021 ◽  
Vol 12 ◽  
Author(s):  
Gan You ◽  
Xing Fan ◽  
Huimin Hu ◽  
Tao Jiang ◽  
Clark C. Chen
Keyword(s):  
Genetic Background ◽  
Molecular Genetic ◽  
Malignant Gliomas ◽  
Therapeutic Targets ◽  
High Grade ◽  
Gene Fusions ◽  
Fusion Genes ◽  
High Grade Gliomas ◽  
The Many

Malignant gliomas are highly heterogeneous brain tumors in molecular genetic background. Despite the many recent advances in the understanding of this disease, patients with adult high-grade gliomas retain a notoriously poor prognosis. Fusions involving oncogenes have been reported in gliomas and may serve as novel therapeutic targets to date. Understanding the gene fusions and how they regulate oncogenesis and malignant progression will contribute to explore new approaches for personalized treatment. By now, studies on gene fusions in gliomas remain limited. However, some current clinical trials targeting fusion genes have presented exciting preliminary findings. The aim of this review is to summarize all the reported fusion genes in high-grade gliomas so far, discuss the characterization of some of the most popular gene fusions occurring in malignant gliomas, as well as their function in tumorigenesis, and the underlying clinical implication as therapeutic targets.

scholarly journals Evaluation of PARP and PDL-1 as potential therapeutic targets for women with high-grade neuroendocrine carcinomas of the cervix

2020 ◽  
Vol 30 (9) ◽  
pp. 1303-1307 ◽  
Author(s):  
Matthew Ryan Carroll ◽  
Preetha Ramalingam ◽  
Gloria Salvo ◽  
Junya Fujimoto ◽  
Luisa Maren Solis Soto ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Treatment Options ◽  
Therapeutic Targets ◽  
Large Cell ◽  
Small Cell ◽  
Cancer Center ◽  
High Grade ◽  
Mismatch Repair Proteins ◽  
Parp 1 ◽  
Neuroendocrine Carcinomas

ObjectivesWomen with recurrent high-grade neuroendocrine cervical cancer have few effective treatment options. The aim of this study was to identify potential therapeutic targets for women with this disease.MethodsSpecimens from patients with high-grade neuroendocrine carcinomas of the cervix were identified from pathology files at MD Anderson Cancer Center. Immunohistochemical stains for PD-L1 (DAKO, clone 22-C3), mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), somatostatin, and Poly (ADP-ribose) polymerase (PARP) were performed on sections from formalin-fixed paraffin-embedded tissue blocks. Nuclear PARP-1 staining was quantified using the H-score with a score of <40 considered low, 40–100 moderate, and ≥100 high.ResultsForty pathologic specimens from patients with high-grade neuroendocrine carcinomas of the cervix were examined (23 small cell, 5 large cell, 3 high-grade neuroendocrine, not otherwise specified, and 9 mixed). The mean age of the cohort was 43 years and the majority of patients (70%) were identified as white non-Hispanic. All 28 (100%) samples tested stained for mismatch repair proteins demonstrated intact expression, suggesting they were microsatellite stable tumors. Of the 31 samples tested for PD-L1 expression, only two (8%) of the 25 pure high-grade neuroendocrine carcinomas were positive whereas three (50%) of the six mixed carcinoma tumors tested positive. Of the 11 small cell specimens tested for PARP-1, 10 (91%) showed PARP expression with six (55%) demonstrating high expression and four (36%) showing moderate expression. Somatostatin staining was negative in 18 of 19 small cell cases (95%).ConclusionsPure high-grade neuroendocrine cervical carcinomas were microsatellite stable and overwhelmingly negative for PD-L1 expression. As the majority of tumors tested expressed PARP-1, inclusion of PARP inhibitors in future clinical trials may be considered.

scholarly journals Treatment options for recurrent high-grade gliomas

CNS Oncology ◽  
2017 ◽  
Vol 6 (1) ◽  
pp. 61-70 ◽  
Author(s):  
Harjus S Birk ◽  
Seunggu J Han ◽  
Nicholas A Butowski
Keyword(s):  
Treatment Options ◽  
High Grade ◽  
High Grade Gliomas

scholarly journals Engineering approaches to studying cancer cell migration in three-dimensional environments

2019 ◽  
Vol 374 (1779) ◽  
pp. 20180219 ◽  
Author(s):  
Noam Zuela-Sopilniak ◽  
Jan Lammerding
Keyword(s):  
Cell Migration ◽  
Cancer Cell ◽  
Primary Tumour ◽  
Treatment Options ◽  
Three Dimensional ◽  
Basement Membranes ◽  
Invasion And Migration ◽  
Interdisciplinary Approaches ◽  
And Migration

Cancer is one of the most devastating diseases of our time, with 17 million new cancer cases and 9.5 million cancer deaths in 2018 worldwide. The mortality associated with cancer results primarily from metastasis, i.e. the spreading of cancer cells from the primary tumour to other organs. The invasion and migration of cells through basement membranes, tight interstitial spaces and endothelial cell layers are key steps in the metastatic cascade. Recent studies demonstrated that cell migration through three-dimensional environments that mimic the in vivo conditions significantly differs from their migration on two-dimensional surfaces. Here, we review recent technological advances made in the field of cancer research that provide more ‘true to the source’ experimental platforms and measurements for the study of cancer cell invasion and migration in three-dimensional environments. These include microfabrication, three-dimensional bioprinting and intravital imaging tools, along with force and stiffness measurements of cells and their environments. These techniques will enable new studies that better reflect the physiological environment found in vivo , thereby producing more robust results. The knowledge achieved through these studies will aid in the development of new treatment options with the potential to ultimately lighten the devastating cost cancer inflicts on patients and their families. This article is part of a discussion meeting issue ‘Forces in cancer: interdisciplinary approaches in tumour mechanobiology’.

Versican isoform V1 regulates proliferation and migration in high-grade gliomas

2014 ◽  
Vol 120 (1) ◽  
pp. 73-83 ◽  
Author(s):  
Julia Onken ◽  
Sylvia Moeckel ◽  
Petra Leukel ◽  
Verena Leidgens ◽  
Fusun Baumann ◽  
...  
Keyword(s):  
High Grade ◽  
High Grade Gliomas ◽  
And Migration ◽  
Proliferation And Migration

EXTH-34. ION CHANNELS AS A THERAPEUTIC TARGET IN PAEDIATRIC HIGH-GRADE GLIOMAS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi170-vi171
Author(s):  
Michaela Griffin ◽  
Stuart Smith ◽  
Raheela Khan ◽  
Surajit Basu ◽  
Joshua Branter
Keyword(s):  
Ion Channels ◽  
Cell Lines ◽  
Brain Tumours ◽  
Cell Cycle Control ◽  
Expression Patterns ◽  
Low Frequency ◽  
High Grade Glioma ◽  
Data Sets ◽  
High Grade ◽  
Poor Overall Survival

Abstract Pediatric Glioblastoma Multiforme (GBM) is a leading cause of CNS cancer-related death in children. The scarcity of treatments for GBM has opened the field to new pathways in adults, such as tumour treating fields(TTF). Studies have identified the clinical benefit of electrotherapy in combination with chemotherapeutics, however the mechanistic action is unclear. Increasing evidence suggests that ion channels not only regulate electrical signalling of excitable cells, but are also crucial in the development/progression of brain tumours. Ion channels are essential in cell-cycle control, invasion and migration of cancer cells, therefore presenting as valuable therapeutic targets. Candidate ion channel genes(ICG) associated with high-grade glioma (HGG) were identified via analysis of inhouse and publicly available data sets. Expression patterns of selected ICGs were assessed along with clinician correlations.. Protein and RNA expression of target ICGs was assessed in pGBM cell lines/ TMAs. Finally, the Human ClariomTMS array was used for whole transcriptome gene expression analysis of paediatric GBM cell lines treated with tumour treating fields or low frequency electrical fields via deep brain stimulating electrodes. Paediatric brain tumour cells were exposed to genetic and pharmacological manipulation of CLIC1 and CLIC4 ion channels individually or in combination. We have shown that HGG exhibit increased expression of CLIC4 and CLIC1 at protein and RNA levels in both publically available data sets and inhouse cell lines / TMAs. Clinical correlation determined that high CLIC4 and CLIC1 expression was associated with poor overall survival. Further to this, DNA array analysis revealed a downregulation of CLIC1 and CLIC4 ion channels genes in KNS42 cells when treated with electrotherapy compared to untreated cells. Inhibition of CLIC1 and CLIC4 reduces Cl- flux across cell membranes and reduces cell proliferation. These data provide rationale that manipulation of ICGs will reduce the capacity of childhood brain tumours to proliferate and invade.

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