Cancer Research and Treatment

Original Articles

Single-Cell Heterogeneity of EGFR Pathway Is Linked to Unique Signatures of Drug Response and Malignancy in Patient Derived Glioblastoma Stem Cells: Michael D. Masterman-Smith, Nicholas A. Graham, Eduard H. Panosyan, Jack Mottahedeh, Eric R. Samuels, Araceli Nunez, Tiffany Phillips, Meeryo Choe, Timothy F. Cloughesy, Jorge A. Lazareff, Linda M. Liau, William H. Yong, Thomas G. Graeber, Harley I. Kornblum, Ming-Fei Lang, Yanzhao Li, Jing Sun; Received September 4, 2024 Accepted January 6, 2025 Published online January 7, 2025; DOI: https://doi.org/10.4143/crt.2024.859 [Accepted]

Abstract PDF: Purpose
In glioblastoma, the therapeutically intractable and resistant phenotypes can be derived from glioma stem cells, which often have different underlying mechanisms from non-stem glioma cells. Aberrant signaling across the EGFR-PTEN-AKT-mTOR pathways have been shown as common drivers of glioblastoma. Revealing the inter and intra-cellular heterogeneity within glioma stem cell populations in relations to signaling patterns through these pathways may be key to precision diagnostic and therapeutic targeting of these cells.
Materials and Methods
Single cell parallel proteomic heterogeneity profiling of the EGFR-PTEN-AKT-mTOR pathways was conducted in a panel of fifteen glioma stem cell models derived from patient glioblastoma biopsies.
Results
The analysis included 59,464 data points from 14,866 cells and identified forty-nine molecularly distinct signaling phenotypes. High content bioinformatics resolved two unique patient clusters diverging on EGFR expression and AKT/TORC1 activation. Phenotypic validation indicated drug responsive phenotypes to EGFR blocking in the high EGFR expressing cluster with lower tumor initiating potential in comparison to the AKT/TORC1 activated cluster. High EGFR expression trended with improved patient prognosis while AKT/TORC1 activated samples trended with poorer patient outcomes. Genetic heterogeneity was observed in both clusters with proneural, classical and mesenchymal subtypes observed.
Conclusion
Quantitative single cell heterogeneity profiling reveals divergent EGFR-PTEN-AKT-mTOR pathways of patient derived glioma stem cells, which would inform future research and personalized therapeutic strategies.

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To Use or Not to Use: Temozolomide in Elderly Patients with IDH Wild-Type MGMT Promoter Unmethylated Glioblastoma Treated with Radiotherapy: Chan Woo Wee, Joo Ho Lee, Hye In Lee, Jina Kim, Jong Hee Chang, Seok-Gu Kang, Eui Hyun Kim, Ju Hyung Moon, Jaeho Cho, Chul-Kee Park, Chae-Yong Kim, Kihwan Hwang, Hong In Yoon, In Ah Kim; Received September 27, 2024 Accepted November 8, 2024 Published online November 11, 2024; DOI: https://doi.org/10.4143/crt.2024.945 [Epub ahead of print]

Abstract PDF PubReader ePub: Purpose
This study aimed to identify a specific subgroup of patients among elderly glioblastoma patients aged 70 years or older with unmethylated O6-methylguanine-DNA methyltransferase promoters (eGBM-unmethylated) who would significantly benefit from the addition of temozolomide (TMZ) to radiotherapy (RT).
Materials and Methods
Newly diagnosed patients with Isocitrate dehydrogenase wild-type eGBM-unmethylated treated with RT were included in this multicenter analysis (n=182). RT dose was 45 Gy in 15 fractions (62.3%), 60 Gy in 30 fractions, or 61.2 Gy in 34 fractions. For patients treated with RT plus TMZ (60.4%), TMZ was administered concurrently with RT, followed by six adjuvant cycles. The primary endpoint was overall survival.
Results
During a median follow-up of 11.3 months for survivors, the median survival was 12.2 months. The median survival duration significantly improved with the addition of TMZ to RT compared with that with RT alone (13.6 months vs. 10.5 months, p=0.028). In the multivariable analysis adjusted for clinical, radiological, and genetic biomarkers, the addition of TMZ significantly improved overall survival (hazard ratio, 0.459; p=0.006). In subgroup analysis, median survival was especially improved by 4-5 months in patients with residual disease (p < 0.001), Karnofsky performance status ≥ 60 (p=0.033), and age ≤ 75 years (p=0.090). A significant benefit of TMZ was noted only in patients with two or three of the above factors (median survival, 14.1 months vs. 10.5 months; p=0.014).
Conclusion
The addition of TMZ significantly improved the survival of patients with eGBM-unmethylated treated with RT. The suggested criteria for the specific subgroup in these patients warrant external validation for clinical application.

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CNS cancer

Choosing Wisely between Radiotherapy Dose-Fractionation Schedules: The Molecular Graded Prognostic Assessment for Elderly Glioblastoma Patients: Hye In Lee, Jina Kim, In Ah Kim, Joo Ho Lee, Jaeho Cho, Rifaquat Rahman, Geoffrey Fell, Chan Woo Wee, Hong In Yoon; Cancer Res Treat. 2025;57(2):378-386. Published online September 11, 2024; DOI: https://doi.org/10.4143/crt.2024.680

Abstract PDF Supplementary Material PubReader ePub: Purpose
This study aimed to develop a graded prognostic assessment (GPA) model integrating genomic characteristics for elderly patients with glioblastoma (eGBM), and to compare the efficacy of different radiotherapy schedules.
Materials and Methods
This multi-institutional retrospective study included patients aged ≥ 65 years who underwent surgical resection followed by radiotherapy with or without temozolomide (TMZ) for newly diagnosed eGBM. Based on the significant factors identified in the multivariate analysis for overall survival (OS), the molecular GPA for eGBM (eGBM-molGPA) was established.
Results
A total of 334 and 239 patients who underwent conventionally fractionated radiotherapy (CFRT) and hypofractionated radiotherapy (HFRT) were included, respectively, with 86% of patients receiving TMZ-based chemoradiation. With a median follow-up of 17.4 months (range, 3.3 to 149.9 months), the median OS was 18.7 months for CFRT+TMZ group, 15.1 months for HFRT+TMZ group, and 10.4 months for radiotherapy alone group (CFRT+TMZ vs. HFRT+TMZ: hazard ratio [HR], 1.52; p < 0.001 and CFRT+TMZ vs. radiotherapy alone: HR, 2.52; p < 0.001). In a combined analysis with the NOA-08 and Nordic trials, CFRT+TMZ group exhibited the highest survival rates among all treatment groups. The eGBM-molGPA, which integrated four clinical and three molecular parameters, stratified patients into low-, intermediate-, and high-risk groups. CFRT+TMZ significantly improved OS compared to HFRT+TMZ or radiotherapy alone in the low-risk (p=0.023) and intermediate-risk groups (p < 0.001). However, in the high-risk group, there was no significant difference in OS between treatment options (p=0.770).
Conclusion
CFRT+TMZ may be more effective than HFRT+TMZ or radiotherapy alone for selected eGBM patients. The novel eGBM-molGPA model can guide treatment selection for this patient population.

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Association between Levetiracetam Use and Survival in Patients with Glioblastoma: A Nationwide Population-Based Study: Yeonhu Lee, Eunyoung Lee, Tae Hoon Roh, Se-Hyuk Kim; Cancer Res Treat. 2025;57(2):369-377. Published online September 6, 2024; DOI: https://doi.org/10.4143/crt.2024.355

Abstract PDF PubReader ePub: Purpose
This study aimed to investigate whether levetiracetam (LEV), the most used antiepileptic drug, influences survival in patients with glioblastoma (GBM), using a national database.
Materials and Methods
This study used data from the Korea Health Insurance Review and Assessment database. Patients diagnosed with GBM between 2007-2018 treated with standard therapy were included. The study population was divided into long-term (≥ 60 days) and short-term (< 30 days) LEV groups. A separate long-term valproic acid (VPA) group (≥ 60 days) was identified for comparison. Demographics, disease characteristics, and treatment parameters were collected. Kaplan-Meier method and Cox regression were used to compare survival outcomes between the groups.
Results
Overall, 2,971 patients were included, with 1,319 and 1,652 in the short-term and long-term LEV groups, respectively. The median overall survival (OS) for the entire population was 19.15 months post-surgery. Kaplan-Meier analysis revealed a significantly longer median OS in the long-term LEV group versus the short-term LEV group. After adjusting for confounders, Cox proportional hazard analysis revealed an association of long-term LEV use with improved survival, which was also observed in a subgroup analysis of patients without preoperative seizure history. The long-term LEV group demonstrated longer median OS, compared with the long-term VPA group.
Conclusion
Our nationwide population-based study found an association between long-term LEV use and improved survival in patients with GBM, regardless of preoperative seizure history. Prospective studies are needed to validate these findings and investigate the potential impact of LEV on the survival outcomes of patients with GBM.

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Detection of TERT Promoter Mutations Using Targeted Next-Generation Sequencing: Overcoming GC Bias through Trial and Error: Hyunwoo Lee, Boram Lee, Deok Geun Kim, Yoon Ah Cho, Jung-Sun Kim, Yeon-Lim Suh; Cancer Res Treat. 2022;54(1):75-83. Published online May 3, 2021; DOI: https://doi.org/10.4143/crt.2021.107

Abstract PDF Supplementary Material PubReader ePub

Purpose
Detection of telomerase reverse transcriptase (TERT) promoter mutations is a crucial process in the integrated diagnosis of glioblastomas. However, the TERT promoter region is difficult to amplify because of its high guanine-cytosine (GC) content (> 80%). This study aimed to analyze the capturing of TERT mutations by targeted next-generation sequencing (NGS) using formalin-fixed paraffin-embedded tissues.
Materials and Methods
We compared the detection rate of TERT mutations between targeted NGS and Sanger sequencing in 25 cases of isocitrate dehydrgenase (IDH)-wildtype glioblastomas and 10 cases of non-neoplastic gastric tissues. Our customized panel consisted of 232 essential glioma-associated genes.
Results
Sanger sequencing detected TERT mutations in 17 out of 25 glioblastomas, but all TERT mutations were missed by targeted NGS. After the manual visualization of the NGS data using an integrative genomics viewer, 16 cases showed a TERT mutation with a very low read depth (mean, 21.59; median, 25), which revealed false-negative results using auto-filtering. We optimized our customized panel by extending the length of oligonucleotide baits and increasing the number of baits spanning the coverage of the TERT promoter, which did not amplify well due to the high GC content.
Conclusion
Our study confirmed that it is crucial to consider the recognition of molecular bias and to carefully interpret NGS data.

Citations

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John Rafanan, Nabih Ghani, Sarah Kazemeini, Ahmed Nadeem-Tariq, Ryan Shih, Thomas A. Vida
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Subit Barua, Susan Hsiao, Emily Clancy, Christopher Freeman, Mahesh Mansukhani, Helen Fernandes
Journal of Clinical Pathology.2024; 77(1): 46. CrossRef
Diagnostic utility of genetic alterations in distinguishing IDH‐wildtype glioblastoma from lower‐grade gliomas: Insight from next‐generation sequencing analysis of 479 cases
Boram Lee, Soohyun Hwang, Hyunsik Bae, Kyue‐Hee Choi, Yeon‐Lim Suh
Brain Pathology.2024;[Epub] CrossRef
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Ákos Kovács, Farkas Sükösd, Levente Kuthi, Imre M. Boros, Balázs Vedelek
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Jinhee Kim, Seokhwan Ko, Moonsik Kim, Nora Jee-Young Park, Hyungsoo Han, Junghwan Cho, Ji Young Park
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Yuanbin Wu, Xuning Wang, Meng Zhang, Dongdong Wu
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Novel, clinically relevant genomic patterns identified by comprehensive genomic profiling in ATRX-deficient IDH-wildtype adult high-grade gliomas
Gábor Bedics, Péter Szőke, Bence Bátai, Tibor Nagy, Gergő Papp, Noémi Kránitz, Hajnalka Rajnai, Lilla Reiniger, Csaba Bödör, Bálint Scheich
Scientific Reports.2023;[Epub] CrossRef

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A Radiosensitivity Gene Signature and PD-L1 Status Predict Clinical Outcome of Patients with Glioblastoma Multiforme in The Cancer Genome Atlas Dataset: Bum-Sup Jang, In Ah Kim; Cancer Res Treat. 2020;52(2):530-542. Published online November 20, 2019; DOI: https://doi.org/10.4143/crt.2019.440

Abstract PDF Supplementary Material PubReader ePub

Purpose
Combination of radiotherapy and immune checkpoint blockade such as programmed death- 1 (PD-1) or programmed death-ligand 1 (PD-L1) blockade is being actively tested in clinical trial. We aimed to identify a subset of patients that could potentially benefit from this strategy using The Cancer Genome Atlas (TCGA) dataset for glioblastoma (GBM).
Materials and Methods
A total of 399 cases were clustered into radiosensitive versus radioresistant (RR) groups based on a radiosensitivity gene signature and were also stratified as PD-L1 high versus PD-L1 low groups by expression of CD274 mRNA. Differential and integrated analyses with expression and methylation data were performed. CIBERSORT was used to enumerate the immune repertoire that resulted from transcriptome profiles.
Results
We identified a subset of GBM, PD-L1-high-RR group which showed worse survival compared to others. In PD-L1-high-RR, differentially expressed genes (DEG) were highly enriched for immune response and mapped into activation of phosphoinositide 3-kinase–AKT and mitogen-activated protein kinase (MAPK) signaling pathways. Integration of DEG and differentially methylated region identified that the kinase MAP3K8-involved in T-cell receptor signaling was upregulated and BAI1, a factor which inhibits angiogenesis, was silenced. CIBERSORT showed that a higher infiltration of the immune repertoire, which included M2 macrophages and regulatory T cells.
Conclusion
Taken together, PD-L1-high-RR group could potentially benefit from radiotherapy combined with PD-1/PD-L1 blockade and angiogenesis inhibition.

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Clinical Biomarkers of Tumour Radiosensitivity and Predicting Benefit from Radiotherapy: A Systematic Review
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Zhuo Chen, Zhuoling Zou, Min Qian, Qin Xu, Guojuan Xue, Juan Yang, Tinglan Luo, Lianjie Hu, Bin Wang
Translational Oncology.2024; 44: 101955. CrossRef
Understanding the immunosuppressive microenvironment of glioma: mechanistic insights and clinical perspectives
Hao Lin, Chaxian Liu, Ankang Hu, Duanwu Zhang, Hui Yang, Ying Mao
Journal of Hematology & Oncology.2024;[Epub] CrossRef
PSF-lncRNA interaction as a target for novel targeted anticancer therapies
Ren Liu, Xiaojing Wang, Min Zhou, Jingfang Zhai, Jie Sun
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Bladder Cancer Treatments in the Age of Personalized Medicine: A Comprehensive Review of Potential Radiosensitivity Biomarkers
Charbel Feghaly, Rafka Challita, Hanine Bou Hadir, Tala Mobayed, Tarek Al Bitar, Mohammad Harbi, Hala Ghorayeb, Rana El-Hassan, Larry Bodgi
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Zhiru Gao, Qian Zhao, Yiyue Xu, Linlin Wang
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Michael Zhang, Quan Zhou, Chinghsin Huang, Carmel T. Chan, Wei Wu, Gordon Li, Michael Lim, Sanjiv S. Gambhir, Heike E. Daldrup-Link
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Daniel Kreatsoulas, Chelsea Bolyard, Bill X. Wu, Hakan Cam, Pierre Giglio, Zihai Li
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Disulfiram, a Re-positioned Aldehyde Dehydrogenase Inhibitor, Enhances Radiosensitivity of Human Glioblastoma Cells In Vitro: Hyeon Kang Koh, Soo Yeon Seo, Jin Ho Kim, Hak Jae Kim, Eui Kyu Chie, Seung-Ki Kim, Il Han Kim; Cancer Res Treat. 2019;51(2):696-705. Published online August 13, 2018; DOI: https://doi.org/10.4143/crt.2018.249

Abstract PDF PubReader ePub

Purpose
Glioblastoma, the most common brain tumor in adults, has poor prognosis. The purpose of this study was to determine the effect of disulfiram (DSF), an aldehyde dehydrogenase inhibitor, on in vitro radiosensitivity of glioblastoma cells with different methylation status of O⁶-methylguanine-DNA methyltransferase (MGMT) promoter and the underlying mechanism of such effect.
Materials and Methods
Five human glioblastoma cells (U138MG, T98G, U251MG, U87MG, and U373MG) and one normal human astrocyte (NHA) cell were cultured and treated with DSF or 6MV X-rays (0, 2, 4, 6, and 8 Gy). For combined treatment, cells were treated with DSF before irradiation. Surviving fractions fit from cell survival based on colony forming ability. Apoptosis, DNA damage repair, and cell cycle distributionwere assayed bywestern blot for cleaved caspase-3, γH2AX staining, and flow cytometry, respectively.
Results
DSF induced radiosensitization in most of the glioblastoma cells, especially, in the cells with radioresistance as wildtype unmethylated promoter (MGMT-wt), but did not in normal NHA cell. DSF augmented or induced cleavage of caspase-3 in all cells after irradiation. DSF inhibited repair of radiation-induced DNA damage in MGMT-wt cells, but not in cells with methylated MGMT promoter. DSF abrogated radiation-induced G2/M arrest in T98G and U251MG cells.
Conclusion
Radiosensitivity of glioblastoma cells were preferentially enhanced by pre-irradiation DSF treatment compared to normal cell, especially radioresistant cells such as MGMT-wt cells. Induction of apoptosis or inhibition of DNA damage repair may underlie DSF-induced radiosensitization. Clinical benefit of combining DSF with radiotherapy should be investigated in the future.

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The Kaohsiung Journal of Medical Sciences.2024; 40(2): 161. CrossRef
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Elena Obrador, Paz Moreno-Murciano, María Oriol-Caballo, Rafael López-Blanch, Begoña Pineda, Julia Gutiérrez-Arroyo, Alba Loras, Luis Gonzalez-Bonet, Conrado Martinez-Cadenas, José Estrela, María Marqués-Torrejón
International Journal of Molecular Sciences.2024; 25(5): 2529. CrossRef
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Ibrahim Dumbuya, Ana Maria Pereira, Ibrahim Tolaymat, Adnan Al Dalaty, Basel Arafat, Matt Webster, Barbara Pierscionek, Mouhamad Khoder, Mohammad Najlah
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Targeting Retinaldehyde Dehydrogenases to Enhance Temozolomide Therapy in Glioblastoma
Rafael Jiménez, Andrada Constantinescu, Muhube Yazir, Paula Alfonso-Triguero, Raquel Pequerul, Xavier Parés, Mileidys Pérez-Alea, Ana Paula Candiota, Jaume Farrés, Julia Lorenzo
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High-Dose Metformin Plus Temozolomide Shows Increased Anti-tumor Effects in Glioblastoma In Vitro and In Vivo Compared with Monotherapy: Jung Eun Lee, Ji Hee Lim, Yong Kil Hong, Seung Ho Yang; Cancer Res Treat. 2018;50(4):1331-1342. Published online January 10, 2018; DOI: https://doi.org/10.4143/crt.2017.466

Abstract PDF Supplementary Material PubReader ePub

Purpose
The purpose of the study is to investigate the efficacy of combined treatment with temozolomide (TMZ) and metformin for glioblastoma (GBM) in vitro and in vivo.
Materials and Methods
We investigated the efficacy of combined treatment with TMZ and metformin using cell viability and apoptosis assays. A GBM orthotopic mice model was established by inoculation of 5×105 U87 cells and treatedwith metformin, TMZ, and the combination for 4weeks. Western blotting and immunofluorescence of tumor specimens were analyzed to investigate AMP-activated protein kinase (AMPK) and AKT pathway.
Results
The combination of TMZ and metformin showed higher cytotoxicity than single agents in U87, U251, and A172 cell lines. A combination of high-dose metformin and TMZ showed the highest apoptotic activity. The combination of TMZ and metformin enhanced AMPK phosphorylation and inhibited mammalian target of rapamycin phosphorylation, AKT phosphorylation, and p53 expression. The median survival of each group was 43.6, 55.2, 53.2, 65.2, and 71.3 days for control, metformin treatment (2 mg/25 g/day or 10 mg/25 g/day), TMZ treatment (15 mg/kg/day), combination treatment with low-dose metformin and TMZ, and combination treatment with high-dose metformin and TMZ, respectively. Expression of fatty acid synthase (FASN) was significantly decreased in tumor specimens treated with metformin and TMZ.
Conclusion
The combination of metformin and TMZ was superior to monotherapy using metformin or TMZ in terms of cell viability in vitro and survival in vivo. The combination of high-dose metformin and TMZ inhibited FASN expression in an orthotopic model. Inhibition of FASN might be a potential therapeutic target of GBM.

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Metformin and glioma: Targeting metabolic dysregulation for enhanced therapeutic outcomes
Haneen A. Basheer, Nadeem M. Salman, Rami M. Abdullah, Lina Elsalem, Kamyar Afarinkia
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Metformin as an Adjunct Treatment to Temozolomide for High-Grade Gliomas: A Systematic Review and Meta-Analysis
Eloísa Bittencurt Thomaz de Assis, Marcio Yuri Ferreira, Jéssica Sales de Oliveira, Lucas Pari Mitre, Eduardo Mendes Correa da Silva, Luciano Lobão Salim Coelho, Daniel Antunes Moreno, Allan Dias Polverini
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Anti-SEMA3A Antibody: A Novel Therapeutic Agent to Suppress Glioblastoma Tumor Growth: Jaehyun Lee, Yong Jae Shin, Kyoungmin Lee, Hee Jin Cho, Jason K. Sa, Sang-Yun Lee, Seok-Hyung Kim, Jeongwu Lee, Yeup Yoon, Do-Hyun Nam; Cancer Res Treat. 2018;50(3):1009-1022. Published online November 10, 2017; DOI: https://doi.org/10.4143/crt.2017.315

Abstract PDF Supplementary Material PubReader ePub

Purpose
Glioblastoma (GBM) is classified as one of the most aggressive and lethal brain tumor. Great strides have been made in understanding the genomic and molecular underpinnings of GBM, which translated into development of new therapeutic approaches to combat such deadly disease. However, there are only few therapeutic agents that can effectively inhibit GBM invasion in a clinical framework. In an effort to address such challenges, we have generated anti-SEMA3A monoclonal antibody as a potential therapeutic antibody against GBM progression.
Materials and Methods
We employed public glioma datasets, Repository of Molecular Brain Neoplasia Data and The Cancer Genome Atlas, to analyze SEMA3AmRNA expression in human GBM specimens. We also evaluated for protein expression level of SEMA3A via tissue microarray (TMA) analysis. Cell migration and proliferation kinetics were assessed in various GBM patient-derived cells (PDCs) and U87-MG cell-line for SEMA3A antibody efficacy. GBM patient-derived xenograft (PDX) models were generated to evaluate tumor inhibitory effect of anti-SEMA3A antibody in vivo.
Results
By combining bioinformatics and TMA analysis, we discovered that SEMA3A is highly expressed in human GBM specimens compared to non-neoplastic tissues. We developed three different anti-SEMA3A antibodies, in fully human IgG form, through screening phage-displayed synthetic antibody library using a classical panning method. Neutralization of SEMA3A significantly reduced migration and proliferation capabilities of PDCs and U87-MG cell line in vitro. In PDX models, treatment with anti-SEMA3A antibody exhibited notable tumor inhibitory effect through down-regulation of cellular proliferative kinetics and tumor-associated macrophages recruitment.
Conclusion
In present study, we demonstrated tumor inhibitory effect of SEMA3A antibody in GBM progression and present its potential relevance as a therapeutic agent in a clinical framework.

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Development of an orthotopic medulloblastoma zebrafish model for rapid drug testing
Niek van Bree, Ann-Sophie Oppelt, Susanne Lindström, Leilei Zhou, Lola Boutin, Beth Coyle, Fredrik J Swartling, John Inge Johnsen, Lars Bräutigam, Margareta Wilhelm
Neuro-Oncology.2025; 27(3): 779. CrossRef
Expression of semaphorin 3A (SEMA3A) in breast cancer subtypes
Natalia Andryszak, Paweł Kurzawa, Monika Krzyżaniak, Marek Ruchała, Michał Nowicki, Dariusz Iżycki, Rafał Czepczyński
Scientific Reports.2024;[Epub] CrossRef
Hypoxia-induced Semaphorin 3A promotes the development of endometriosis through regulating macrophage polarization
Ruyu Yang, Fan Yang, Yajing Wei, Biqi Huang, Tiefeng Cao, Hao Tan, Duo Liu, Qiuyu Zou, Jinjuan Wen, Lei Wen, Xi Lu, Changyang Yu, Heng Cai, Xiaofei Xie, Shaoru Jiang, Shuzhong Yao, Yanchun Liang
International Immunopharmacology.2024; 138: 112559. CrossRef
Semaphorins: Novel Insights on Their Emerging Multifaceted Roles in the Evolving Landscape of Breast Cancer
Ts. Popov
Acta Medica Bulgarica.2024; 51(s2): 153. CrossRef
Role of semaphorins, neuropilins and plexins in cancer progression
P. Fernández-Nogueira, P. Linzoain- Agos, M. Cueto-Remacha, I. De la Guia-Lopez, L. Recalde-Percaz, A. Parcerisas, P. Gascon, N. Carbó, A. Gutierrez-Uzquiza, G. Fuster, P. Bragado
Cancer Letters.2024; 606: 217308. CrossRef
Semaphorins and Their Roles in Breast Cancer: Implications for Therapy Resistance
Radhika Aiyappa-Maudsley, Louis F. V. McLoughlin, Thomas A. Hughes
International Journal of Molecular Sciences.2023; 24(17): 13093. CrossRef
Pinpointing the interaction site between semaphorin‐3A and its inhibitory peptide
Kevin Kretschmer, Jan Stichel, Kathrin Bellmann‐Sickert, Lars Baumann, Donald Bierer, Bernd Riedl, Annette G. Beck‐Sickinger
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Semaphorin 3A influences neuronal processes that are altered in patients with autism spectrum disorder: Potential diagnostic and therapeutic implications
Carmela Matrone, Gabriella Ferretti
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Semaphorins as Potential Immune Therapeutic Targets for Cancer
Jun Jiang, Fang Zhang, Yi Wan, Ke Fang, Ze-dong Yan, Xin-ling Ren, Rui Zhang
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Semaphorin Regulation by the Chromatin Remodeler CHD7: An Emerging Genetic Interaction Shaping Neural Cells and Neural Crest in Development and Cancer
Antonella Lettieri, Roberto Oleari, Alyssa J. J. Paganoni, Cristina Gervasini, Valentina Massa, Alessandro Fantin, Anna Cariboni
Frontiers in Cell and Developmental Biology.2021;[Epub] CrossRef
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Irina Larionova, Elena Kazakova, Tatiana Gerashchenko, Julia Kzhyshkowska
Cancers.2021; 13(13): 3253. CrossRef
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Xiangyu Li, Ming Liu, Junfeng Zhao, Tong Ren, Xin Yan, Lijun Zhang, Xun Wang
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The Prognostic Value of Serum Semaphorin3A and VEGF Levels in Patients with Metastatic Colorectal Cancer
Tuba Karpuz, Murat Araz, Levent Korkmaz, Ibrahim Kılınc, Sidika Findik, Mustafa Karaagaç, Melek Karakurt Eryilmaz, Mehmet Artac
Journal of Gastrointestinal Cancer.2020; 51(2): 491. CrossRef
Immunity, Hypoxia, and Metabolism–the Ménage à Trois of Cancer: Implications for Immunotherapy
Carla Riera-Domingo, Annette Audigé, Sara Granja, Wan-Chen Cheng, Ping-Chih Ho, Fátima Baltazar, Christian Stockmann, Massimiliano Mazzone
Physiological Reviews.2020; 100(1): 1. CrossRef
SEMA3AExon 9 Expression Is a Potential Prognostic Marker of Unfavorable Recurrence-Free Survival in Patients with Tongue Squamous Cell Carcinoma
Tian Tian, Lingnan Zhang, Kailiang Tang, Aiqin Wang, Jing Wang, Jingjing Wang, Fang Wang, Wenlong Wang, Xiangrui Ma
DNA and Cell Biology.2020; 39(4): 555. CrossRef
Sphere-Forming Culture for Expanding Genetically Distinct Patient-Derived Glioma Stem Cells by Cellular Growth Rate Screening
Kayoung Shin, Hyemi Shin, Hee Jin Cho, Hyunju Kang, Jin-Ku Lee, Yun Jee Seo, Yong Jae Shin, Donggeon Kim, Harim Koo, Doo-Sik Kong, Ho Jun Seol, Jung-Il Lee, Hye Won Lee, Do-Hyun Nam
Cancers.2020; 12(3): 549. CrossRef
A comprehensive review of tumor proliferative and suppressive role of semaphorins and therapeutic approaches
Ishtiaque Ahammad
Biophysical Reviews.2020; 12(5): 1233. CrossRef
Neuropilin-1: a checkpoint target with unique implications for cancer immunology and immunotherapy
Christopher A Chuckran, Chang Liu, Tullia C Bruno, Creg J Workman, Dario AA Vignali
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Class-3 Semaphorins and Their Receptors: Potent Multifunctional Modulators of Tumor Progression
Shira Toledano, Inbal Nir-Zvi, Rotem Engelman, Ofra Kessler, Gera Neufeld
International Journal of Molecular Sciences.2019; 20(3): 556. CrossRef
Multifaceted Functional Role of Semaphorins in Glioblastoma
Cristiana Angelucci, Gina Lama, Gigliola Sica
International Journal of Molecular Sciences.2019; 20(9): 2144. CrossRef

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Effect of Necrosis on the miRNA-mRNA Regulatory Network in CRT-MG Human Astroglioma Cells: So-Hee Ahn, Jung-Hyuck Ahn, Dong-Ryeol Ryu, Jisoo Lee, Min-Sun Cho, Youn-Hee Choi; Cancer Res Treat. 2018;50(2):382-397. Published online May 22, 2017; DOI: https://doi.org/10.4143/crt.2016.551

Abstract PDF PubReader ePub

Purpose
Glioblastoma multiforme (GBM) is the most common adult primary intracranial tumor. The remarkable features of GBM include central necrosis. MicroRNAs (miRNAs) have been considered as diagnostic/prognostic biomarkers for many cancers, including glioblastoma. However, the effect of necrosis on the miRNA expression profile and predicted miRNA-mRNA regulatory information remain unclear. The purpose of this study is to examine the effect of necrotic cells on the modulation of miRNA and mRNA expression profiles and miRNA-mRNA network in CRT-MG cells.
Materials and Methods
We used human astroglioma cells, CRT-MG, treated with necrotic CRT-MG cells to examine the effect of necrosis on the modulation of miRNA and mRNA by next-generation sequencing. For preparation of necrotic cells, CRT-MGcellswere frozen and thawed through cycle of liquid nitrogen–water bath. The putative miRNA-mRNA regulatory relationshipwas inferred through target information, using miRDB.
Results
The necrotic cells induced dysregulation of 106 miRNAs and 887 mRNAs. Among them, 11 miRNAs that had a negative correlation value of p < 0.05 by the hypergeometric test were screened, and their target mRNAs were analyzed by Gene Ontology enrichment analysis. Using the Kyoto Encyclopedia of Genes and Genomes database, we also found several necrotic cell treatment-activated pathways that were modulated by relevant gene targets of differentially expressed miRNAs.
Conclusion
Our result demonstrated that dysregulation of miRNA and mRNA expression profiles occurs when GBM cells are exposed to necrotic cells, suggesting that several miRNAs may have the potential to be used as biomarkers for predicting GBM progression and pathogenesis.

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MiR-4492, a New Potential MicroRNA for Cancer Diagnosis and Treatment: A Mini Review
Aida Alizamir, Mohammad Amin Amini, Ashkan Karbasi, Mehdi Beyrami
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Edgar G. Ordóñez-Rubiano, Nicolás Rincón-Arias, Sebastian Espinosa, William J. Shelton, Andres F. Salazar, Alba Cómbita, Matías Baldoncini, Sabino Luzzi, César Payán-Gómez, Diego F. Gómez- Amarillo, Fernando Hakim, Javier G. Patiño-Gómez, Rafael Parra- Me
Current Research in Pharmacology and Drug Discovery.2024; 7: 100193. CrossRef
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Serena Bonin, Stefano D’Errico, Caterina Medeot, Carlo Moreschi, Solange Sorçaburu Ciglieri, Michela Peruch, Monica Concato, Eros Azzalini, Carlo Previderè, Paolo Fattorini
International Journal of Molecular Sciences.2023; 24(13): 10836. CrossRef
MiR-4461 Inhibits Tumorigenesis of Renal Cell Carcinoma by Targeting PPP1R3C
Yuanyuan Zhao, Gang Ye, You Wang, Dan Luo
Cancer Biotherapy and Radiopharmaceuticals.2022; 37(6): 503. CrossRef
Potential role of microRNAs as biomarkers in human glioblastoma: a mini systematic review from 2015 to 2020
Manuela Rocha de Menezes, Maria Eduarda Azevêdo Acioli, Ana Carolina Lemos da Trindade, Suéllen Pedrosa da Silva, Raul Emídio de Lima, Vanessa Gabryelle da Silva Teixeira, Luydson Richardson Silva Vasconcelos
Molecular Biology Reports.2021; 48(5): 4647. CrossRef
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Federica Caponnetto, Emiliano Dalla, Damiano Mangoni, Silvano Piazza, Slobodanka Radovic, Tamara Ius, Miran Skrap, Carla Di Loreto, Antonio Paolo Beltrami, Ivana Manini, Daniela Cesselli
Biomedicines.2020; 8(12): 564. CrossRef
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Linge Li, Juan Feng, Dinghao Zhang, Jun Yong, Yan Wang, Jianfeng Yao, Rongfu Huang
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Xingsong Li, Xiaokang Yu, Yuting He, Yuhuan Meng, Jinsheng Liang, Lizhen Huang, Hongli Du, Xueping Wang, Wanli Liu
BioMed Research International.2018; 2018: 1. CrossRef

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Underexpression of HOXA11 Is Associated with Treatment Resistance and Poor Prognosis in Glioblastoma: Young-Bem Se, Seung Hyun Kim, Ji Young Kim, Ja Eun Kim, Yun-Sik Dho, Jin Wook Kim, Yong Hwy Kim, Hyun Goo Woo, Se-Hyuk Kim, Shin-Hyuk Kang, Hak Jae Kim, Tae Min Kim, Soon-Tae Lee, Seung Hong Choi, Sung-Hye Park, Il Han Kim, Dong Gyu Kim, Chul-Kee Park; Cancer Res Treat. 2017;49(2):387-398. Published online July 19, 2016; DOI: https://doi.org/10.4143/crt.2016.106

Abstract PDF Supplementary Material PubReader ePub

Purpose
Homeobox (HOX) genes are essential developmental regulators that should normally be in the silenced state in an adult brain. The aberrant expression of HOX genes has been associated with the prognosis of many cancer types, including glioblastoma (GBM). This study examined the identity and role of HOX genes affecting GBM prognosis and treatment resistance.
Materials and Methods
The full series of HOX genes of five pairs of initial and recurrent human GBM samples were screened by microarray analysis to determine the most plausible candidate responsible for GBM prognosis. Another 20 newly diagnosed GBM samples were used for prognostic validation. In vitro experiments were performed to confirm the role of HOX in treatment resistance. Mediators involved in HOX gene regulation were searched using differentially expressed gene analysis, gene set enrichment tests, and network analysis.
Results
The underexpression of HOXA11 was identified as a consistent signature for a poor prognosis among the HOX genes. The overall survival of the GBM patients indicated a significantly favorable prognosis in patients with high HOXA11 expression (31±15.3 months) compared to the prognoses in thosewith lowHOXA11 expression (18±7.3 months, p=0.03). When HOXA11 was suppressed in the GBM cell lines, the anticancer effect of radiotherapy and/or temozolomide declined. In addition, five candidate mediators (TGFBR2, CRIM1, TXNIP, DPYSL2, and CRMP1) that may confer an oncologic effect after HOXA11 suppression were identified.
Conclusion
The treatment resistance induced by the underexpression of HOXA11 can contribute to a poor prognosis in GBM. Further investigation will be needed to confirm the value of HOXA11 as a potential target for overcoming the treatment resistance by developing chemo- or radiosensitizers.

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Zong-Qing Zheng, Gui-Qiang Yuan, Guo-Guo Zhang, Qian-Qian Nie, Zhong Wang
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Zhenghong Yu, Zhendong Liu, Xiaoyu Lian, Xingbo Cheng, Binfeng Liu, Bo Zhang, Hongbo Wang, Jialin Wang, Ang Li, Zhishuai Ren, Bo Pang, Rongjun Qian, Yanzheng Gao
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Céline S. Gonçalves, Elisa Le Boiteux, Philippe Arnaud, Bruno M. Costa
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Jinyun Li, Meng Ye, Chongchang Zhou
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Ana Paço, Simone Aparecida de Bessa Garcia, Renata Freitas
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Zewei Tu, Lei Wu, Peng Wang, Qing Hu, Chuming Tao, Kuangxun Li, Kai Huang, Xingen Zhu
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Lu‐Yan Shen, Ting Zhou, Ya‐Bing Du, Qi Shi, Ke‐Neng Chen
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Youwei Zhang, Yuan Yuan, Yang Li, Peiying Zhang, Pingsheng Chen, Sanyuan Sun
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Long noncoding RNA HOXA11-AS promotes gastric cancer cell proliferation and invasion via SRSF1 and functions as a biomarker in gastric cancer
Yun Liu, Yu-Mei Zhang, Feng-Bo Ma, Su-Rong Pan, Bao-Zhen Liu
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Concurrent Chemoradiotherapy with Temozolomide Followed by Adjuvant Temozolomide for Newly Diagnosed Glioblastoma Patients: A Retrospective Multicenter Observation Study in Korea: Byung Sup Kim, Ho Jun Seol, Do-Hyun Nam, Chul-Kee Park, Il Han Kim, Tae Min Kim, Jeong Hoon Kim, Young Hyun Cho, Sang Min Yoon, Jong Hee Chang, Seok-Gu Kang, Eui Hyun Kim, Chang-Ok Suh, Tae-Young Jung, Kyung-Hwa Lee, Chae-Yong Kim, In Ah Kim, Chang-Ki Hong, Heon Yoo, Jin Hee Kim, Shin-Hyuk Kang, Min Kyu Kang, Eun-Young Kim, Sun-Hwan Kim, Dong-Sup Chung, Sun-Chul Hwang, Joon-Ho Song, Sung Jin Cho, Sun-Il Lee, Youn-Soo Lee, Kook-Jin Ahn, Se Hoon Kim, Do Hun Lim, Ho-Shin Gwak, Se-Hoon Lee, Yong-Kil Hong; Cancer Res Treat. 2017;49(1):193-203. Published online June 27, 2016; DOI: https://doi.org/10.4143/crt.2015.473

Abstract PDF PubReader ePub

Purpose
The purpose of this study was to investigate the feasibility and survival benefits of combined treatment with radiotherapy and adjuvant temozolomide (TMZ) in a Korean sample.
Materials and Methods
A total of 750 Korean patients with histologically confirmed glioblastoma multiforme, who received concurrent chemoradiotherapy with TMZ (CCRT) and adjuvant TMZ from January 2006 until June 2011, were analyzed retrospectively.
Results
After the first operation, a gross total resection (GTR), subtotal resection (STR), partial resection (PR), biopsy alone were achieved in 388 (51.7%), 159 (21.2%), 96 (12.8%), and 107 (14.3%) patients,respectively. The methylation status of O⁶-methylguanine-DNA methyltransferase (MGMT) was reviewed retrospectively in 217 patients. The median follow-up period was 16.3 months and the median overall survival (OS) was 17.5 months. The actuarial survival rates at the 1-, 3-, and 5-year OS were 72.1%, 21.0%, and 9.0%, respectively. The median progression-free survival (PFS) was 10.1 months, and the actuarial PFS at 1-, 3-, and 5-year PFS were 42.2%, 13.0%, and 7.8%, respectively. The patients who received GTR showed a significantly longer OS and PFS than those who received STR, PR, or biopsy alone, regardless of the methylation status of the MGMT promoter. Patients with a methylated MGMT promoter also showed a significantly longer OS and PFS than those with an unmethylated MGMT promoter. Patients who received more than six cycles of adjuvant TMZ had a longer OS and PFS than those who received six or fewer cycles. Hematologic toxicity of grade 3 or 4 was observed in 8.4% of patients during the CCRT period and in 10.2% during the adjuvant TMZ period.
Conclusion
Patients treated with CCRT followed by adjuvant TMZ had more favorable survival rates and tolerable toxicity than those who did not undergo this treatment.

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Post-bevacizumab Clinical Outcomes and the Impact of Early Discontinuation of Bevacizumab in Patients with Recurrent Malignant Glioma: Yongjun Cha, Yu Jung Kim, Se-Hoon Lee, Tae-Min Kim, Seung Hong Choi, Dong-Wan Kim, Chul-Kee Park, Il Han Kim, Jee Hyun Kim, Eunhee Kim, Byungse Choi, Chae-Yong Kim, In Ah Kim, Dae Seog Heo; Cancer Res Treat. 2017;49(1):129-140. Published online May 18, 2016; DOI: https://doi.org/10.4143/crt.2015.466

Abstract PDF PubReader ePub

Purpose
Bevacizumab±irinotecan is effective for treatment of recurrent malignant gliomas. However, the optimal duration of treatment has not been established.
Materials and Methods
Ninety-four consecutive patients with recurrent malignant glioma who were treated with bevacizumab at our institutions were identified. Patients who continued bevacizumab until tumor progression were enrolled in a late discontinuation (LD) group, while those who stopped bevacizumab before tumor progression were enrolled in an early discontinuation (ED) group. Landmark analyses were performed at weeks 9, 18, and 26 for comparison of patient survival between the two groups.
Results
Among 89 assessable patients, 62 (69.7%) and 27 (30.3%) patients were categorized as the LD and ED groups, respectively. According to landmark analysis, survival times from weeks 9, 18, and 26 were not significantly different between the two groups in the overall population. However, the LD group showed a trend toward increased survival compared to the ED group among responders. In the ED group, the median time from discontinuation to disease progression was 11.4 weeks, and none of the patients showed a definite rebound phenomenon. Similar median survival times after disease progression were observed between groups (14.4 weeks vs. 15.7 weeks, p=0.251). Of 83 patients, 38 (45.8%) received further therapy at progression, and those who received further therapy showed longer survival in both the LD and ED groups.
Conclusion
In recurrent malignant glioma, duration of bevacizumab was not associated with survival time in the overall population. However, ED of bevacizumab in responding patients might be associated with decreased survival.

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The Vascular Microenvironment in Glioblastoma: A Comprehensive Review
Alejandra Mosteiro, Leire Pedrosa, Abel Ferrés, Diouldé Diao, Àngels Sierra, José Juan González
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Differential P-Glycoprotein/CD31 Expression as Markers of Vascular Co-Option in Primary Central Nervous System Tumors
Tiziana Annese, Mariella Errede, Antonio d’Amati, Michelina De Giorgis, Loredana Lorusso, Roberto Tamma, Domenico Ribatti
Diagnostics.2022; 12(12): 3120. CrossRef
Identification of diverse tumor endothelial cell populations in malignant glioma
Jeff C Carlson, Manuel Cantu Gutierrez, Brittney Lozzi, Emmet Huang-Hobbs, Williamson D Turner, Burak Tepe, Yiqun Zhang, Alexander M Herman, Ganesh Rao, Chad J Creighton, Joshua D Wythe, Benjamin Deneen
Neuro-Oncology.2021; 23(6): 932. CrossRef
Rechallenge with bevacizumab in patients with glioblastoma progressing off therapy
Charlotte Bronnimann, Cristina Izquierdo, Stéphanie Cartalat, Laure Thomas, Bastien Joubert, Laura Delpech, Marc Barritault, David Meyronet, Jérôme Honnorat, François Ducray
Journal of Neuro-Oncology.2018; 138(1): 141. CrossRef

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In Vitro and In Vivo Radiosensitizing Effect of Valproic Acid on Fractionated Irradiation: Eui Kyu Chie, Jin Hee Shin, Jin Ho Kim, Hak Jae Kim, In Ah Kim, Il Han Kim; Cancer Res Treat. 2015;47(3):527-533. Published online November 24, 2014; DOI: https://doi.org/10.4143/crt.2014.026

Abstract PDF PubReader ePub

Purpose
This study was conducted in order to validate the radiosensitization effect of valproic acid, a biologically available histone deacetylase inhibitor, for fractionated radiation.
Materials and Methods
Radiosensitization effect of valproic acid was tested for the A549 cell line and U87MG cell line in vitro. Fractionated irradiation of 12 Gy in four fractions was administered on D2-5 with valproic acid, 150 mg/Kg, ip, bid for six consecutive days (D1-6) to A549 and U87MG tumors implanted in BALB/c-nude mice. A growth delay curve was formulated.
Results
Radiosensitization effect of valproic acid was found for both cell lines; A549 at 1.5 mM and 3.0 mM concentration and U87MG at 3.0 mM concentration. In growth delay analysis, a statistically significant radiosensitization effect was observed for both tumors (p < 0.001 for both tumors). Difference for change in slope for control and valproic acid versus radiotherapy and radiotherapy plus valproic acid showed borderline significance for the U87MG cell line (p=0.065), indicating beyond additive effect, whereas this difference was statistically insignificant for A549 tumor (p=0.951), indicating additive effect.
Conclusion

Results
of this study indicate that a radiosensitizing effect for fractionated radiotherapy of valproic acid for A549 and U87MG tumors in vivo is evident and that it may be more than additive for U87MG tumors. Further exploitation of histone deacetylase inhibitors in clinical trials is warranted.

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Anti-epileptic drug use during adjuvant chemo-radiotherapy is associated with poorer survival in patients with glioblastoma: A nationwide population-based cohort study
Peng-Yi Lee, Yu-Ting Wei, Kun-San Clifford Chao, Chin-Nan Chu, Wen-Hui Chung, Ti-Hao Wang*
Journal of Cancer Research and Therapeutics.2024; 20(2): 555. CrossRef
Valproic acid as a radio-sensitizer in glioma: A systematic review and meta-analysis
Jessica K Sullivan, Paul P Fahey, Kinglsey E Agho, Simon P Hurley, Zhihui Feng, Richard O Day, David Lim
Neuro-Oncology Practice.2023; 10(1): 13. CrossRef
The function of histone methylation and acetylation regulators in GBM pathophysiology
Colin McCornack, Timothy Woodiwiss, Angela Hardi, Hiroko Yano, Albert H. Kim
Frontiers in Oncology.2023;[Epub] CrossRef
Antitumor Activity of Non-thermal Atmospheric Pressure Plasma and Synergistic Effects of Hyperthermia
TETSUO ADACHI
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Epigenetic-Like Stimulation of Receptor Expression in SSTR2 Transfected HEK293 Cells as a New Therapeutic Strategy
Joerg Kotzerke, Dorothee Buesser, Anne Naumann, Roswitha Runge, Lisa Huebinger, Andrea Kliewer, Robert Freudenberg, Claudia Brogsitter
Cancers.2022; 14(10): 2513. CrossRef
Molecular Mechanisms Underlying Cellular Responses to the Loading of Non-thermal Atmospheric Pressure Plasma-activated Solutions
Tetsuo Adachi
YAKUGAKU ZASSHI.2021; 141(10): 1185. CrossRef
Ability of plasma-activated acetated Ringer’s solution to induce A549 cell injury is enhanced by a pre-treatment with histone deacetylase inhibitors
Tetsuo Adachi, Yumiko Matsuda, Rika Ishii, Tetsuro Kamiya, Hirokazu Hara
Journal of Clinical Biochemistry and Nutrition.2020; 67(3): 232. CrossRef
Effect of valproic acid on overall survival in patients with high-grade gliomas undergoing temozolomide
Yu-Jen Kuo, Yao-Hsu Yang, I-Yun Lee, Pau-Chung Chen, Jen-Tsung Yang, Ting-Chung Wang, Martin Hsiu-Chu Lin, Wei-Hsun Yang, Chun-Yu Cheng, Kuo-Tai Chen, Wei-Chao Huang, Ming-Hsueh Lee
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Rashmi R. Shah, Peter D. Stonier
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Valproic Acid Sensitizes Hepatocellular Carcinoma Cells to Proton Therapy by Suppressing NRF2 Activation
Jeong Il Yu, Changhoon Choi, Sung-Won Shin, Arang Son, Ga-Haeng Lee, Shin-Yeong Kim, Hee Chul Park
Scientific Reports.2017;[Epub] CrossRef
Histone deacetylase inhibitors stimulate the susceptibility of A549 cells to a plasma-activated medium treatment
Tetsuo Adachi, Ayame Kano, Saho Nonomura, Tetsuro Kamiya, Hirokazu Hara
Archives of Biochemistry and Biophysics.2016; 606: 120. CrossRef
Does Valproic Acid or Levetiracetam Improve Survival in Glioblastoma? A Pooled Analysis of Prospective Clinical Trials in Newly Diagnosed Glioblastoma
Caroline Happold, Thierry Gorlia, Olivier Chinot, Mark R. Gilbert, L. Burt Nabors, Wolfgang Wick, Stephanie L. Pugh, Monika Hegi, Timothy Cloughesy, Patrick Roth, David A. Reardon, James R. Perry, Minesh P. Mehta, Roger Stupp, Michael Weller
Journal of Clinical Oncology.2016; 34(7): 731. CrossRef

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Constitutive Expression of MAP Kinase Phosphatase-1 Confers Multi-drug Resistance in Human Glioblastoma Cells: Hana Yu, Junseong Park, Jungsul Lee, Kyungsun Choi, Chulhee Choi; Cancer Res Treat. 2012;44(3):195-201. Published online September 30, 2012; DOI: https://doi.org/10.4143/crt.2012.44.3.195

Abstract PDF PubReader ePub

PURPOSE
Current treatment of glioblastoma after surgery consists of a combination of fractionated radiotherapy and temozolomide. However, it is difficult to completely remove glioblastoma because it has uncertain boundaries with surrounding tissues. Moreover, combination therapy is not always successful because glioblastoma has diverse resistances. To overcome these limitations, we examined the combined effects of chemotherapy and knockdown of mitogen-activated protein kinase phosphatase-1 (MKP-1).
MATERIALS AND METHODS
We used ten different anti-cancer drugs (cisplatin, cyclophosphoamide, doxorubicin, epirubicin, etoposide, 5-fluorouracil, gemcitabine, irinotecan, mitomycin C, and vincristine) to treat glioblastoma multiforme (GBM) cells. Knockdown of MKP-1 was performed using siRNA and lipofectamine. The basal level of MKP-1 in GBM was analyzed based on cDNA microarray data obtained from the Gene Expression Omnibus (GEO) databases.
RESULTS
Anti-cancer drug-induced cell death was significantly enhanced by knockdown of MKP-1, and this effect was most prominent in cells treated with irinotecan and etoposide. Treatment with these two drugs led to significantly increased phosphorylation of c-Jun N-terminal kinase (JNK) in a time-dependent manner, while pharmacological inhibition of JNK partially inhibited drug-induced cell death. Knockdown of MKP-1 also enhanced drug-induced phosphorylation of JNK.
CONCLUSION
Increased MKP-1 expression levels could be the cause of the high resistance to conventional chemotherapeutics in human GBM. Therefore, MKP-1 is an attractive target for overcoming drug resistance in this highly refractory malignancy.

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Case Report

Second Primary Glioblastoma Multiforme Following Autologous Hematopoietic Stem Cell Transplantation in a Patient with Acute Myelogenous Leukemia: Eun-Oh Kim, Hee-Je Kim, Ki-Seong Eom, Byung-Sik Cho, Sung-Eun Lee, Seung-Ah Yahng, Jong-Wook Lee, Woo-Sung Min; Cancer Res Treat. 2011;43(3):195-198. Published online September 30, 2011; DOI: https://doi.org/10.4143/crt.2011.43.3.195

Abstract PDF PubReader ePub

Glioblastoma multiforme (GM) is one of the most aggressive primary brain tumors, and has a poor prognosis despite intensive treatment. GM is also the most malignant astrocytoma, with histopathological features that include cellular polymorphism, rapid mitotic activity, microvascular proliferation, and necrosis. The causes of GM remain obscure, but several reports have shown associations between GM and genetic alterations and radiation exposure. Furthermore, high-dose chemotherapy/radiotherapy with autologous stem cell transplantation is increasingly being used to treat patients with leukemia, and patients who undergo stem cell transplantation have a higher risk of solid tumor cancer development later in life. Based on these associations, we discuss GM development in a patient who underwent chemoradiotherapy conditioning prior to stem cell transplantation.

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Glioblastoma Multiforme in a Post Allogeneic Stem Cell Transplant Patient. A Case Report and Literature Review of Post Transplant Neurological Tumors
Abhijeet P. Ganapule, Sunita Susan Varghese, Geeta Chacko, I. Aparna, Auro Viswabandya
Indian Journal of Hematology and Blood Transfusion.2016; 32(S1): 192. CrossRef

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Original Article

Expression of Cell Surface Receptors on Human Glioblastoma Xenograft Model in NOD/SCID Mouse: Kyung Seung Oh, Ki Uk Kim, Na Hee Park, Su Yeong Seo, Sun Seob Choi, Gi Yeong Huh; Cancer Res Treat. 2002;34(1):52-57. Published online February 28, 2002; DOI: https://doi.org/10.4143/crt.2002.34.1.52

Abstract PDF: PURPOSE
To obtain basic data for development of a glioblastoma-specific immunotoxin, the expression of variable cell surface receptors on a human glioblastoma xenograft model was evaluated, using NOD/SCID mice.
MATERIALS AND METHODS
We developed a xenograft model in NOD/SCID mice implanted with a human glioblastoma cell line (U-87MG). Immunohistochemical studies were performed on implanted tumor nodules (n=8) using antibodies against CD71, EGFR, IGF-IRalpha, CXCR4 and IL-4Ralpha.
RESULTS
Expression of IL-4Ralpha, in implanted tumornodules, was the highest of the cell surface receptors evaluated in this study. However, the endothelial cells in, and around, the tumor nodules also revealed immunopositivity against IL-4Ralpha. The immunoreactivity of IL-4Ralpha, and other surface receptors such as CD71, IGF-IRalpha and EGFR, was prominent in tumor nodules associated with tumor necrosis.
CONCLUSION
IL-4Ralpha would be a possible target for the development of glioblastoma-specific immunotoxin, although there are limitations due to its endothelial expression.

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