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1
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Brenner AJ, Patel T, Bao A, Phillips WT, Michalek JE, Youssef M, Weinberg JS, Kamiya Matsuoka C, Hedrick MH, LaFrance N, Moore M, Floyd JR. Convection enhanced delivery of Rhenium ( 186Re) Obisbemeda ( 186RNL) in recurrent glioma: a multicenter, single arm, phase 1 clinical trial. Nat Commun 2025; 16:2079. [PMID: 40055350 PMCID: PMC11889265 DOI: 10.1038/s41467-025-57263-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 02/18/2025] [Indexed: 03/25/2025] Open
Abstract
Rhenium (186Re) Obisbemeda (186RNL), chelated-186Re encapsulated in nanoliposomes and delivered to brain tumors via convection enhanced delivery (CED), was evaluated in a Phase 1 dose escalation trial (NCT01906385). The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included safety and tolerability, dose distribution, the overall response rate (ORR), disease-specific progression-free survival (PFS), and overall survival (OS). 21 patients received up to 22.3 mCi 186RNL over 6 dosing cohorts. Most adverse events (AEs) were unrelated to 186RNL and the MTD was not reached. Although not predefined outcomes, the mOS and mPFS were 11 and 4 months, respectively, and found to correlate with radiation absorbed dose to the tumor and percent tumor treated. When dichotomized by absorbed dose of 100 Gy, the mOS and mPFS were 17 months and 6 months, respectively, for >100 Gy, compared to 6 (mOS) and 2 (mPFS) months, respectively, for <100 Gy. For ORR, 57.1% exhibited stable disease (SD), 4.8% partial response, and 38.1% progressive disease. Overall, patients received radiation absorbed doses without significant toxicity higher than possible with external beam radiation therapy (EBRT) and demonstrated mOS beyond standard of care for recurrent glioblastoma (~8 months).
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Affiliation(s)
- Andrew J Brenner
- Mays Cancer Center at UT Health San Antonio, San Antonio, TX, USA.
| | - Toral Patel
- UT Southwestern Medical Center of Dallas, Dallas, TX, USA
| | - Ande Bao
- Case Western Reserve University, Cleveland, OH, USA
| | | | - Joel E Michalek
- Mays Cancer Center at UT Health San Antonio, San Antonio, TX, USA
| | | | | | | | | | | | | | - John R Floyd
- Mays Cancer Center at UT Health San Antonio, San Antonio, TX, USA
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Kim J, Kim R, Lee W, Kim GH, Jeon S, Lee YJ, Lee JS, Kim KH, Won J, Lee W, Park K, Kim HJ, Im S, Lee KJ, Park C, Kim J, Lee JY. Assembly of glioblastoma tumoroids and cerebral organoids: a 3D in vitro model for tumor cell invasion. Mol Oncol 2025; 19:698-715. [PMID: 39473365 PMCID: PMC11887666 DOI: 10.1002/1878-0261.13740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 08/02/2024] [Accepted: 09/13/2024] [Indexed: 03/08/2025] Open
Abstract
Glioblastoma (GBM) has a fatal prognosis because of its aggressive and invasive characteristics. Understanding the mechanism of invasion necessitates an elucidation of the relationship between tumor cells and the tumor microenvironment. However, there has been a scarcity of suitable models to investigate this. In this study, we established a glioblastoma-cerebral organoid assembloid (GCOA) model by co-culturing patient-derived GBM tumoroids and human cerebral organoids. Tumor cells from the tumoroids infiltrated the cerebral organoids, mimicking the invasive nature of the parental tumors. Using time-lapse imaging, various invasion patterns of cancer cells within cerebral organoids resembling a normal tissue milieu were monitored. Both single- and collective-cell invasion was captured in real-time. We also confirmed the formation of an intercellular tumor network and tumor-normal-cell interactions. Furthermore, the transcriptomic characterization of GCOAs revealed distinct features of invasive tumor cells. Overall, this study established the GCOA as a three-dimensional (3D) in vitro assembloid model to investigate invasion mechanisms and interactions between tumor cells and their microenvironment.
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Affiliation(s)
- Jieun Kim
- Department of Anatomy and Cell BiologySeoul National University College of MedicineSeoulKorea
| | - Rokhyun Kim
- Medical Research CenterGenomic Medicine Institute, Seoul National UniversitySeoulKorea
- Department of Biomedical SciencesSeoul National University College of MedicineSeoulKorea
| | - Wonseok Lee
- Department of Anatomy and Cell BiologySeoul National University College of MedicineSeoulKorea
- Department of Transitional MedicineSeoul National University College of MedicineSeoulKorea
- Department of Neurosurgery, Seoul National University HospitalSeoul National University College of MedicineSeoulKorea
| | - Gyu Hyun Kim
- Laboratory of Synaptic Circuit Plasticity, Neural Circuits Research GroupKorea Brain Research InstituteDaeguKorea
| | - Seeun Jeon
- Department of Anatomy and Cell BiologySeoul National University College of MedicineSeoulKorea
| | - Yun Jin Lee
- Department of Anatomy and Cell BiologySeoul National University College of MedicineSeoulKorea
| | - Jong Seok Lee
- Division of Pediatric NeurosurgerySeoul National University Children's HospitalSeoulKorea
| | - Kyung Hyun Kim
- Department of Anatomy and Cell BiologySeoul National University College of MedicineSeoulKorea
- Division of Pediatric NeurosurgerySeoul National University Children's HospitalSeoulKorea
| | - Jae‐Kyung Won
- Department of Pathology, Seoul National University HospitalSeoul National University College of MedicineSeoulKorea
| | - Woochan Lee
- Medical Research CenterGenomic Medicine Institute, Seoul National UniversitySeoulKorea
- Department of Biomedical SciencesSeoul National University College of MedicineSeoulKorea
| | - Kyunghyuk Park
- Medical Research CenterGenomic Medicine Institute, Seoul National UniversitySeoulKorea
| | - Hyun Je Kim
- Department of Biomedical SciencesSeoul National University College of MedicineSeoulKorea
- Cancer Research Institute, Medical Research CenterSeoul National University College of MedicineSeoulKorea
| | - Sun‐Wha Im
- Department of Biochemistry and Molecular BiologyKangwon National University School of MedicineChuncheonKorea
| | - Kea Joo Lee
- Laboratory of Synaptic Circuit Plasticity, Neural Circuits Research GroupKorea Brain Research InstituteDaeguKorea
| | - Chul‐Kee Park
- Department of Neurosurgery, Seoul National University HospitalSeoul National University College of MedicineSeoulKorea
| | - Jong‐Il Kim
- Medical Research CenterGenomic Medicine Institute, Seoul National UniversitySeoulKorea
- Department of Biomedical SciencesSeoul National University College of MedicineSeoulKorea
- Cancer Research Institute, Medical Research CenterSeoul National University College of MedicineSeoulKorea
- Department of Biochemistry and Molecular BiologySeoul National University College of MedicineSeoulKorea
| | - Ji Yeoun Lee
- Department of Anatomy and Cell BiologySeoul National University College of MedicineSeoulKorea
- Division of Pediatric NeurosurgerySeoul National University Children's HospitalSeoulKorea
- Neuroscience Research Institute, Medical Research CenterSeoul National University College of MedicineSeoulKorea
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Lee Y, Kang S, Thuy LT, Son M, Park JY, Ahn SB, Kang M, Oh J, Choi JS, Lee M. Exosome-membrane and polymer-based hybrid-complex for systemic delivery of plasmid DNA into brains for the treatment of glioblastoma. Asian J Pharm Sci 2025; 20:101006. [PMID: 39931357 PMCID: PMC11808510 DOI: 10.1016/j.ajps.2024.101006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 10/02/2024] [Accepted: 10/12/2024] [Indexed: 02/13/2025] Open
Abstract
Herpes simplex virus thymidine kinase (HSVtk) gene therapy is a promising strategy for glioblastoma therapy. However, delivery of plasmid DNA (pDNA) encoding HSVtk into the brain by systemic administration is a challenge since pDNA can hardly penetrate the blood-brain barrier. In this study, an exosome-membrane (EM) and polymer-based hybrid complex was developed for systemic delivery of pDNA into the brain. Histidine/arginine-linked polyamidoamine (PHR) was used as a carrier. PHR binds to pDNA by electrostatic interaction. The pDNA/PHR complex was mixed with EM and subjected to extrusion to produce pDNA/PHR-EM hybrid complex. For glioblastoma targeting, T7 peptide was attached to the pDNA/PHR-EM complex. Both pDNA/PHR-EM and T7-decorated pDNA/PHR-EM (pDNA/PHR-EM-T7) had a surface charge of -5 mV and a size of 280 nm. Transfection assays indicated that pDNA/PHR-EM-T7 enhanced the transfection to C6 cells compared with pDNA/PHR-EM. Intravenous administration of pHSVtk/PHR-EM-T7 showed that pHSVtk/PHR-EM and pHSVtk/PHR-EM-T7 delivered pHSVtk more efficiently than pHSVtk/lipofectamine and pHSVtk/PHR into glioblastoma in vivo. pHSVtk/PHR-EM-T7 had higher delivery efficiency than pHSVtk/PHR-EM. As a result, the HSVtk expression and apoptosis levels in the tumors of the pHSVtk/PHR-EM-T7 group were higher than those of the other control groups. Therefore, the pDNA/PHR-EM-T7 hybrid complex is a useful carrier for systemic delivery of pHSVtk to glioblastoma.
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Affiliation(s)
- Youngki Lee
- Department of Bioengineering, Hanyang University, Seoul, 04763, Republic of Korea
| | - Subin Kang
- Department of Bioengineering, Hanyang University, Seoul, 04763, Republic of Korea
| | - Le Thi Thuy
- Department of Biochemistry, Chungnam National University, Daejeon, 34134, Republic of Korea
| | - Mincheol Son
- Department of Bioengineering, Hanyang University, Seoul, 04763, Republic of Korea
| | - Jae Young Park
- Department of Bioengineering, Hanyang University, Seoul, 04763, Republic of Korea
| | - Sung Bin Ahn
- Department of Bioengineering, Hanyang University, Seoul, 04763, Republic of Korea
| | - Minji Kang
- Department of Bioengineering, Hanyang University, Seoul, 04763, Republic of Korea
| | - Jihun Oh
- Department of Bioengineering, Hanyang University, Seoul, 04763, Republic of Korea
| | - Joon Sig Choi
- Department of Biochemistry, Chungnam National University, Daejeon, 34134, Republic of Korea
| | - Minhyung Lee
- Department of Bioengineering, Hanyang University, Seoul, 04763, Republic of Korea
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Norollahi SE, Yousefi B, Nejatifar F, Yousefzadeh-Chabok S, Rashidy-Pour A, Samadani AA. Practical immunomodulatory landscape of glioblastoma multiforme (GBM) therapy. J Egypt Natl Canc Inst 2024; 36:33. [PMID: 39465481 DOI: 10.1186/s43046-024-00240-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 09/21/2024] [Indexed: 10/29/2024] Open
Abstract
Glioblastoma multiforme (GBM) is the most common harmful high-grade brain tumor with high mortality and low survival rate. Importantly, besides routine diagnostic and therapeutic methods, modern and useful practical techniques are urgently needed for this serious malignancy. Correspondingly, the translational medicine focusing on genetic and epigenetic profiles of glioblastoma, as well as the immune framework and brain microenvironment, based on these challenging findings, indicates that key clinical interventions include immunotherapy, such as immunoassay, oncolytic viral therapy, and chimeric antigen receptor T (CAR T) cell therapy, which are of great importance in both diagnosis and therapy. Relatively, vaccine therapy reflects the untapped confidence to enhance GBM outcomes. Ongoing advances in immunotherapy, which utilizes different methods to regenerate or modify the resistant body for cancer therapy, have revealed serious results with many different problems and difficulties for patients. Safe checkpoint inhibitors, adoptive cellular treatment, cellular and peptide antibodies, and other innovations give researchers an endless cluster of instruments to plan profoundly in personalized medicine and the potential for combination techniques. In this way, antibodies that block immune checkpoints, particularly those that target the program death 1 (PD-1)/PD-1 (PD-L1) ligand pathway, have improved prognosis in a wide range of diseases. However, its use in combination with chemotherapy, radiation therapy, or monotherapy is ineffective in treating GBM. The purpose of this review is to provide an up-to-date overview of the translational elements concentrating on the immunotherapeutic field of GBM alongside describing the molecular mechanism involved in GBM and related signaling pathways, presenting both historical perspectives and future directions underlying basic and clinical practice.
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Affiliation(s)
- Seyedeh Elham Norollahi
- Cancer Research Center and, Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Bahman Yousefi
- Cancer Research Center and, Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Fatemeh Nejatifar
- Department of Hematology and Oncology, School of Medicine, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran
| | - Shahrokh Yousefzadeh-Chabok
- Guilan Road Trauma Research Center, Trauma Institute, Guilan University of Medical Sciences, Rasht, Iran
- , Rasht, Iran
| | - Ali Rashidy-Pour
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran.
| | - Ali Akbar Samadani
- Guilan Road Trauma Research Center, Trauma Institute, Guilan University of Medical Sciences, Rasht, Iran.
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Hu Y, Zhou L, Wang Z, Ye Z, Liu H, Lu Y, Qi Z, Yang K, Zeng J, Li H, Tang R, Ren J, Guo R, Yao M. Assembled Embedded 3D Hydrogel System for Asynchronous Drug Delivery to Inhibit Postoperative Recurrence of Malignant Glioma and Promote Neurological Recovery. ADVANCED FUNCTIONAL MATERIALS 2024; 34. [DOI: 10.1002/adfm.202401383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Indexed: 01/21/2025]
Abstract
AbstractSurgical resection of glioblastoma multiforme (GBM) often results in tumor recurrence and mild neurologic deficits. Here, a 3D asynchronous drug delivery system is innovatively developed to address the dual challenges of GBM recurrence and postoperative neurological deficit. Based on transcriptome analysis of tumor cells and tumor microenvironment (TME) cells between primary and recurrent mouse GBM tissues, a novel dual‐targeting approach is developed to combine mTOR pathway inhibition with microglia/macrophage repolarization. Then, in situ injectable methacrylated gelatin (GelMA) is constructed to perfectly fit into the tumor resection cavity and achieve direct delivery of dual‐targeted drugs, exhibiting outstanding postoperative GBM inhibitory effects in vivo. At the same time, neurotrophic factor‐saturated 3D‐printed GelMA patches are used to construct a 3D asynchronous drug delivery system, allowing gradual penetration of the neurotrophic factors into the underlying hydrogel to promote axonal sprouting after GBM suppression. Notably, this 3D asynchronous drug delivery system promotes neurological recovery without weakening the efficacy of inhibiting tumor recurrence. Therefore, this study not only proposes a new dual‐targeted GBM treatment strategy but also pioneers the construction of a 3D asynchronous drug delivery system for the comprehensive treatment of GBM. This study is expected to improve the poor prognosis of patients with GBM.
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Affiliation(s)
- Yang Hu
- State Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory Disease National Center for Respiratory Medicine Department of Thoracic Surgery and Oncology Guangzhou Institute of Respiratory Health The First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong 510182 P. R. China
| | - Liming Zhou
- Key Laboratory of Biomaterials of Guangdong Higher Education Institutes Key Laboratory of Regenerative Medicine of Ministry of Education Guangdong Provincial Engineering and Technological Research Centre for Drug Carrier Development Department of Biomedical Engineering Jinan University Guangzhou 510632 P. R. China
| | - Zhenning Wang
- Department of Neurosurgery The Tenth Affiliated Hospital Southern Medical University (Dongguan People's Hospital) Dongguan 523018 P. R. China
| | - Zhiming Ye
- State Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory Disease National Center for Respiratory Medicine Department of Thoracic Surgery and Oncology Guangzhou Institute of Respiratory Health The First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong 510182 P. R. China
| | - Huiling Liu
- Key Laboratory of Biomaterials of Guangdong Higher Education Institutes Key Laboratory of Regenerative Medicine of Ministry of Education Guangdong Provincial Engineering and Technological Research Centre for Drug Carrier Development Department of Biomedical Engineering Jinan University Guangzhou 510632 P. R. China
| | - Yi Lu
- State Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory Disease National Center for Respiratory Medicine Department of Thoracic Surgery and Oncology Guangzhou Institute of Respiratory Health The First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong 510182 P. R. China
| | - Zhihui Qi
- Department of Anesthesia The First Affiliated Hospital of Sun Yat‐sen University Guangzhou Guangdong 510080 P. R. China
| | - Kunhua Yang
- Department of Anesthesia The First Affiliated Hospital of Sun Yat‐sen University Guangzhou Guangdong 510080 P. R. China
| | - Jianhao Zeng
- Department of Microbiology Immunology, and Cancer Biology University of Virginia Health System Charlottesville VA 22908 USA
| | - Huimin Li
- State Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory Disease National Center for Respiratory Medicine Department of Thoracic Surgery and Oncology Guangzhou Institute of Respiratory Health The First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong 510182 P. R. China
| | - Ruizhe Tang
- State Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory Disease National Center for Respiratory Medicine Department of Thoracic Surgery and Oncology Guangzhou Institute of Respiratory Health The First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong 510182 P. R. China
| | - Jiaoyan Ren
- School of Food Sciences and Engineering South China University of Technology Guangzhou 510641 P. R. China
| | - Rui Guo
- Key Laboratory of Biomaterials of Guangdong Higher Education Institutes Key Laboratory of Regenerative Medicine of Ministry of Education Guangdong Provincial Engineering and Technological Research Centre for Drug Carrier Development Department of Biomedical Engineering Jinan University Guangzhou 510632 P. R. China
| | - Maojin Yao
- State Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory Disease National Center for Respiratory Medicine Department of Thoracic Surgery and Oncology Guangzhou Institute of Respiratory Health The First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong 510182 P. R. China
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Onciul R, Brehar FM, Toader C, Covache-Busuioc RA, Glavan LA, Bratu BG, Costin HP, Dumitrascu DI, Serban M, Ciurea AV. Deciphering Glioblastoma: Fundamental and Novel Insights into the Biology and Therapeutic Strategies of Gliomas. Curr Issues Mol Biol 2024; 46:2402-2443. [PMID: 38534769 DOI: 10.3390/cimb46030153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 03/06/2024] [Accepted: 03/09/2024] [Indexed: 03/28/2024] Open
Abstract
Gliomas constitute a diverse and complex array of tumors within the central nervous system (CNS), characterized by a wide range of prognostic outcomes and responses to therapeutic interventions. This literature review endeavors to conduct a thorough investigation of gliomas, with a particular emphasis on glioblastoma (GBM), beginning with their classification and epidemiological characteristics, evaluating their relative importance within the CNS tumor spectrum. We examine the immunological context of gliomas, unveiling the intricate immune environment and its ramifications for disease progression and therapeutic strategies. Moreover, we accentuate critical developments in understanding tumor behavior, focusing on recent research breakthroughs in treatment responses and the elucidation of cellular signaling pathways. Analyzing the most novel transcriptomic studies, we investigate the variations in gene expression patterns in glioma cells, assessing the prognostic and therapeutic implications of these genetic alterations. Furthermore, the role of epigenetic modifications in the pathogenesis of gliomas is underscored, suggesting that such changes are fundamental to tumor evolution and possible therapeutic advancements. In the end, this comparative oncological analysis situates GBM within the wider context of neoplasms, delineating both distinct and shared characteristics with other types of tumors.
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Affiliation(s)
- Razvan Onciul
- Department of Neurosurgery, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Neurosurgery Department, Emergency University Hospital, 050098 Bucharest, Romania
| | - Felix-Mircea Brehar
- Department of Neurosurgery, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Neurosurgery, Clinical Emergency Hospital "Bagdasar-Arseni", 041915 Bucharest, Romania
| | - Corneliu Toader
- Department of Neurosurgery, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Vascular Neurosurgery, National Institute of Neurology and Neurovascular Diseases, 077160 Bucharest, Romania
| | | | - Luca-Andrei Glavan
- Department of Neurosurgery, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Bogdan-Gabriel Bratu
- Department of Neurosurgery, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Horia Petre Costin
- Department of Neurosurgery, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - David-Ioan Dumitrascu
- Department of Neurosurgery, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Matei Serban
- Department of Neurosurgery, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Alexandru Vlad Ciurea
- Department of Neurosurgery, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Neurosurgery Department, Sanador Clinical Hospital, 010991 Bucharest, Romania
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Darwish A, Pammer M, Gallyas F, Vígh L, Balogi Z, Juhász K. Emerging Lipid Targets in Glioblastoma. Cancers (Basel) 2024; 16:397. [PMID: 38254886 PMCID: PMC10814456 DOI: 10.3390/cancers16020397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 01/09/2024] [Accepted: 01/12/2024] [Indexed: 01/24/2024] Open
Abstract
GBM accounts for most of the fatal brain cancer cases, making it one of the deadliest tumor types. GBM is characterized by severe progression and poor prognosis with a short survival upon conventional chemo- and radiotherapy. In order to improve therapeutic efficiency, considerable efforts have been made to target various features of GBM. One of the targetable features of GBM is the rewired lipid metabolism that contributes to the tumor's aggressive growth and penetration into the surrounding brain tissue. Lipid reprogramming allows GBM to acquire survival, proliferation, and invasion benefits as well as supportive modulation of the tumor microenvironment. Several attempts have been made to find novel therapeutic approaches by exploiting the lipid metabolic reprogramming in GBM. In recent studies, various components of de novo lipogenesis, fatty acid oxidation, lipid uptake, and prostaglandin synthesis have been considered promising targets in GBM. Emerging data also suggest a significant role hence therapeutic potential of the endocannabinoid metabolic pathway in GBM. Here we review the lipid-related GBM characteristics in detail and highlight specific targets with their potential therapeutic use in novel antitumor approaches.
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Affiliation(s)
- Ammar Darwish
- Institute of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 7624 Pécs, Hungary
| | - Milán Pammer
- Institute of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 7624 Pécs, Hungary
| | - Ferenc Gallyas
- Institute of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 7624 Pécs, Hungary
| | - László Vígh
- Institute of Biochemistry, HUN-REN Biological Research Center, 6726 Szeged, Hungary
| | - Zsolt Balogi
- Institute of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 7624 Pécs, Hungary
| | - Kata Juhász
- Institute of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 7624 Pécs, Hungary
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8
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Hillen T, Loy N, Painter KJ, Thiessen R. Modelling microtube driven invasion of glioma. J Math Biol 2023; 88:4. [PMID: 38015257 PMCID: PMC10684558 DOI: 10.1007/s00285-023-02025-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 10/20/2023] [Accepted: 10/29/2023] [Indexed: 11/29/2023]
Abstract
Malignant gliomas are notoriously invasive, a major impediment against their successful treatment. This invasive growth has motivated the use of predictive partial differential equation models, formulated at varying levels of detail, and including (i) "proliferation-infiltration" models, (ii) "go-or-grow" models, and (iii) anisotropic diffusion models. Often, these models use macroscopic observations of a diffuse tumour interface to motivate a phenomenological description of invasion, rather than performing a detailed and mechanistic modelling of glioma cell invasion processes. Here we close this gap. Based on experiments that support an important role played by long cellular protrusions, termed tumour microtubes, we formulate a new model for microtube-driven glioma invasion. In particular, we model a population of tumour cells that extend tissue-infiltrating microtubes. Mitosis leads to new nuclei that migrate along the microtubes and settle elsewhere. A combination of steady state analysis and numerical simulation is employed to show that the model can predict an expanding tumour, with travelling wave solutions led by microtube dynamics. A sequence of scaling arguments allows us reduce the detailed model into simpler formulations, including models falling into each of the general classes (i), (ii), and (iii) above. This analysis allows us to clearly identify the assumptions under which these various models can be a posteriori justified in the context of microtube-driven glioma invasion. Numerical simulations are used to compare the various model classes and we discuss their advantages and disadvantages.
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Affiliation(s)
- Thomas Hillen
- Department of Mathematical and Statistical Sciences, University of Alberta, Edmonton, Canada.
| | - Nadia Loy
- Department of Mathematical Sciences (DISMA), Politecnico di Torino, Turin, Italy
| | - Kevin J Painter
- Interuniversity Department of Regional and Urban Studies and Planning (DIST), Politecnico di Torino, Turin, Italy
| | - Ryan Thiessen
- Department of Mathematical and Statistical Sciences, University of Alberta, Edmonton, Canada
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9
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Al-Hawary SIS, Pallathadka H, Hjazi A, Zhumanov ZE, Alazbjee AAA, Imad S, Alsalamy A, Hussien BM, Jaafer NS, Mahmoudi R. ETS transcription factor ELK3 in human cancers: An emerging therapeutic target. Pathol Res Pract 2023; 248:154728. [PMID: 37542863 DOI: 10.1016/j.prp.2023.154728] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 07/26/2023] [Accepted: 07/29/2023] [Indexed: 08/07/2023]
Abstract
Cancer is a genetic and complex disorder, resulting from several events associated with onset, development, and metastasis. Tumor suppressors and oncogenes are among the main regulators of tumor progression, contributing to various cancer-related behaviors like cell proliferation, invasion, migration, epithelial-mesenchymal transition (EMT), cell cycle, and apoptosis. Transcription factors (TFs) could act as tumor suppressors or oncogenes in cancer progression. E-twenty-six/E26 (ETS) family of TFs have a winged helix-turn-helix (HLH) motif, which interacted with specific DNA regions with high levels of purines and GGA core. ETS proteins act as transcriptional repressors or activators to modulate the expression of target genes. ETS transcription factor ELK3 (ELK3), as a type of ETS protein, was shown to enhance in various cancers, suggesting that it may have an oncogenic role. These studies indicated that ELK3 promoted invasion, migration, cell cycle, proliferation, and EMT, and suppressed cell apoptosis. In addition, these studies demonstrated that ELK3 could be a promising diagnostic and prognostic biomarker in human cancer. Moreover, accumulating data proved that ELK3 could be a novel chemoresistance mediator in human cancer. Here, we aimed to explore the overall change of ELK3 and its underlying molecular mechanism in human cancers. Moreover, we aimed to investigate the potential role of ELK3 as a prognostic and diagnostic biomarker as well as its capability as a chemoresistance mediator in cancer.
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Affiliation(s)
| | | | - Ahmed Hjazi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Ziyadulla Eshmamatovich Zhumanov
- Department of Pathological Anatomy, With a Section-biopsy Course, Samarkand State Medical Institute, Amir Temur Street 18, Samarkand, Uzbekistan; Department of Scientific Affairs, Tashkent State Dental Institute, Makhtumkuli Street 103, Tashkent 100047, Uzbekistan
| | | | - Shad Imad
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | - Ali Alsalamy
- College of Technical Engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna 66002, Iraq
| | - Beneen M Hussien
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Noor Sadiq Jaafer
- Department of Medical Laboratory Technologies, Al Rafidain University College, Bagdad, Iraq
| | - Reza Mahmoudi
- Department of Toxicology and Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
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10
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Yang J, Zhang X, Gao X, Wu H, Li X, Yang L, Zhang N. Fiber Density and Structural Brain Connectome in Glioblastoma Are Correlated With Glioma Cell Infiltration. Neurosurgery 2023; 92:1234-1242. [PMID: 36744904 DOI: 10.1227/neu.0000000000002356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 11/08/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Glioblastoma (GBM) preferred to infiltrate into white matter (WM) beyond the recognizable tumor margin. OBJECTIVE To investigate whether fiber density (FD) and structural brain connectome can provide meaningful information about WM destruction and glioma cell infiltration. METHODS GBM cases were collected based on inclusion criteria, and baseline information and preoperative MRI results were obtained. GBM lesions were automatically segmented into necrosis, contrast-enhanced tumor, and edema areas. We obtained the FD map to compute the FD and lnFD values in each subarea and reconstructed the structural brain connectome to obtain the topological metrics in each subarea. We also divided the edema area into a nonenhanced tumor (NET) area and a normal WM area based on the contralesional lnFD value in the edema area, and computed the NET ratio. RESULTS Twenty-five GBM cases were included in this retrospective study. The FD/lnFD value and topological metrics (aCp, aLp, aEg, aEloc, and ar) were significantly correlated with GBM subareas, which represented the extent of WM destruction and glioma cell infiltration. The FD/lnFD values and topological parameters were correlated with the NET ratio. In particular, the lnFD value in the edema area was correlated with the NET ratio (coefficient, 0.92). Therefore, a larger lnFD value indicates more severe glioma infiltration in the edema area and suggests an extended resection for better clinical outcomes. CONCLUSION The FD and structural brain connectome in this study provide a new insight into glioma infiltration and a different consideration of their clinical application in neuro-oncology.
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Affiliation(s)
- Jia Yang
- Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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11
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Foglar M, Aumiller M, Bochmann K, Buchner A, El Fahim M, Quach S, Sroka R, Stepp H, Thon N, Forbrig R, Rühm A. Interstitial Photodynamic Therapy of Glioblastomas: A Long-Term Follow-up Analysis of Survival and Volumetric MRI Data. Cancers (Basel) 2023; 15:cancers15092603. [PMID: 37174068 PMCID: PMC10177153 DOI: 10.3390/cancers15092603] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 03/19/2023] [Accepted: 03/20/2023] [Indexed: 05/15/2023] Open
Abstract
BACKGROUND The treatment of glioblastomas, the most common primary malignant brain tumors, with a devastating survival perspective, remains a major challenge in medicine. Among the recently explored therapeutic approaches, 5-aminolevulinic acid (5-ALA)-mediated interstitial photodynamic therapy (iPDT) has shown promising results. METHODS A total of 16 patients suffering from de novo glioblastomas and undergoing iPDT as their primary treatment were retrospectively analyzed regarding survival and the characteristic tissue regions discernible in the MRI data before treatment and during follow-up. These regions were segmented at different stages and were analyzed, especially regarding their relation to survival. RESULTS In comparison to the reference cohorts treated with other therapies, the iPDT cohort showed a significantly prolonged progression-free survival (PFS) and overall survival (OS). A total of 10 of 16 patients experienced prolonged OS (≥ 24 months). The dominant prognosis-affecting factor was the MGMT promoter methylation status (methylated: median PFS of 35.7 months and median OS of 43.9 months) (unmethylated: median PFS of 8.3 months and median OS of 15.0 months) (combined: median PFS of 16.4 months and median OS of 28.0 months). Several parameters with a known prognostic relevance to survival after standard treatment were not found to be relevant to this iPDT cohort, such as the necrosis-tumor ratio, tumor volume, and posttreatment contrast enhancement. After iPDT, a characteristic structure (iPDT remnant) appeared in the MRI data in the former tumor area. CONCLUSIONS In this study, iPDT showed its potential as a treatment option for glioblastomas, with a large fraction of patients having prolonged OS. Parameters of prognostic relevance could be derived from the patient characteristics and MRI data, but they may partially need to be interpreted differently compared to the standard of care.
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Affiliation(s)
- Marco Foglar
- Laser-Forschungslabor, LIFE Center, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Maximilian Aumiller
- Laser-Forschungslabor, LIFE Center, University Hospital, LMU Munich, 81377 Munich, Germany
- Department of Urology, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Katja Bochmann
- Max Planck Institute for Psychiatry, Max Planck Society, 80804 Munich, Germany
- Institute of Neuroradiology, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Alexander Buchner
- Department of Urology, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Mohamed El Fahim
- Laser-Forschungslabor, LIFE Center, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Stefanie Quach
- Department of Neurosurgery, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Ronald Sroka
- Laser-Forschungslabor, LIFE Center, University Hospital, LMU Munich, 81377 Munich, Germany
- Department of Urology, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Herbert Stepp
- Laser-Forschungslabor, LIFE Center, University Hospital, LMU Munich, 81377 Munich, Germany
- Department of Urology, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Niklas Thon
- Department of Neurosurgery, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Robert Forbrig
- Institute of Neuroradiology, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Adrian Rühm
- Laser-Forschungslabor, LIFE Center, University Hospital, LMU Munich, 81377 Munich, Germany
- Department of Urology, University Hospital, LMU Munich, 81377 Munich, Germany
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12
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Loras A, Gonzalez-Bonet LG, Gutierrez-Arroyo JL, Martinez-Cadenas C, Marques-Torrejon MA. Neural Stem Cells as Potential Glioblastoma Cells of Origin. Life (Basel) 2023; 13:life13040905. [PMID: 37109434 PMCID: PMC10145968 DOI: 10.3390/life13040905] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 03/24/2023] [Accepted: 03/27/2023] [Indexed: 03/31/2023] Open
Abstract
Glioblastoma multiforme (GBM) is the most malignant brain tumor in adults and it remains incurable. These tumors are very heterogeneous, resistant to cytotoxic therapies, and they show high rates of invasiveness. Therefore, patients face poor prognosis, and the survival rates remain very low. Previous research states that GBM contains a cell population with stem cell characteristics called glioma stem cells (GSCs). These cells are able to self-renew and regenerate the tumor and, therefore, they are partly responsible for the observed resistance to therapies and tumor recurrence. Recent data indicate that neural stem cells (NSCs) in the subventricular zone (SVZ) are the cells of origin of GBM, that is, the cell type acquiring the initial tumorigenic mutation. The involvement of SVZ-NSCs is also associated with GBM progression and recurrence. Identifying the cellular origin of GBM is important for the development of early detection techniques and the discovery of early disease markers. In this review, we analyze the SVZ-NSC population as a potential GBM cell of origin, and its potential role for GBM therapies.
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Affiliation(s)
- Alba Loras
- Department of Medicine, University of Valencia, 46010 Valencia, Spain
- Department of Medicine, Jaume I University of Castellon, 12071 Castellon de la Plana, Spain
| | - Luis G. Gonzalez-Bonet
- Department of Neurosurgery, Castellon General University Hospital, 12004 Castellon de la Plana, Spain
| | - Julia L. Gutierrez-Arroyo
- Department of Medicine, Jaume I University of Castellon, 12071 Castellon de la Plana, Spain
- Department of Neurosurgery, Castellon General University Hospital, 12004 Castellon de la Plana, Spain
| | | | - Maria Angeles Marques-Torrejon
- Department of Medicine, Jaume I University of Castellon, 12071 Castellon de la Plana, Spain
- Correspondence: ; Tel.: +34-964-387-478
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13
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Chen D, Xu Y, Gao X, Zhu X, Liu X, Yan D. A novel signature of cuproptosis-related lncRNAs predicts prognosis in glioma: Evidence from bioinformatic analysis and experiments. Front Pharmacol 2023; 14:1158723. [PMID: 37101543 PMCID: PMC10123286 DOI: 10.3389/fphar.2023.1158723] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 03/29/2023] [Indexed: 04/28/2023] Open
Abstract
Background: Glioma patients often experience unfavorable outcomes and elevated mortality rates. Our study established a prognostic signature utilizing cuproptosis-associated long non-coding RNAs (CRLs) and identified novel prognostic biomarkers and therapeutic targets for glioma. Methods: The expression profiles and related data of glioma patients were obtained from The Cancer Genome Atlas, an accessible online database. We then constructed a prognostic signature using CRLs and evaluated the prognosis of glioma patients by means of Kaplan-Meier survival curves and receiver operating characteristic curves. A nomogram based on clinical features was employed to predict the individual survival probability of glioma patients. Functional enrichment analysis was conducted to identify crucial CRL-related enriched biological pathways. The role of LEF1-AS1 in glioma was validated in two glioma cell lines (T98 and U251). Results: We developed and validated a prognostic model for glioma with 9 CRLs. Patients with low-risk had a considerably longer overall survival (OS). The prognostic CRL signature may serve independently as an indicator of prognosis for glioma patients. In addition, functional enrichment analysis revealed significant enrichment of multiple immunological pathways. Notable differences were observed between the two risk groups in terms of immune cell infiltration, function, and immune checkpoints. We further identified four drugs based on their different IC50 values from the two risk groups. Subsequently, we discovered two molecular subtypes of glioma (cluster one and cluster two), with the cluster one subtype exhibiting a remarkably longer OS compared to the cluster two subtype. Finally, we observed that inhibition of LEF1-AS1 curbed the proliferation, migration, and invasion of glioma cells. Conclusion: The CRL signatures were confirmed as a reliable prognostic and therapy response indicator for glioma patients. Inhibition of LEF1-AS1 effectively suppressed the growth, migration, and invasion of gliomas; therefore, LEF1-AS1 presents itself as a promising prognostic biomarker and potential therapeutic target for glioma.
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Affiliation(s)
- Di Chen
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yuan Xu
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Xueping Gao
- Department of Clinical Laboratory Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Xuqiang Zhu
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xianzhi Liu
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Dongming Yan
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- *Correspondence: Dongming Yan,
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14
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Wang LM, Englander ZK, Miller ML, Bruce JN. Malignant Glioma. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1405:1-30. [PMID: 37452933 DOI: 10.1007/978-3-031-23705-8_1] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/18/2023]
Abstract
This chapter provides a comprehensive overview of malignant gliomas, the most common primary brain tumor in adults. These tumors are varied in their cellular origin, genetic profile, and morphology under the microscope, but together they share some of the most dismal prognoses of all neoplasms in the body. Although there is currently no cure for malignant glioma, persistent efforts to improve outcomes in patients with these tumors have led to modest increases in survival, and researchers worldwide continue to strive toward a deeper understanding of the factors that influence glioma development and response to treatment. In addition to well-established epidemiology, clinical manifestations, and common histopathologic and radiologic features of malignant gliomas, this section considers recent advances in molecular biology that have led to a more nuanced understanding of the genetic changes that characterize the different types of malignant glioma, as well as their implications for treatment. Beyond the traditional classification of malignant gliomas based on histopathological features, this chapter incorporates the World Health Organization's 2016 criteria for the classification of brain tumors, with special focus on disease-defining genetic alterations and newly established subcategories of malignant glioma that were previously unidentifiable based on microscopic examination alone. Traditional therapeutic modalities that form the cornerstone of treatment for malignant glioma, such as aggressive surgical resection followed by adjuvant chemotherapy and radiation therapy, and the studies that support their efficacy are reviewed in detail. This provides a foundation for additional discussion of novel therapeutic methods such as immunotherapy and convection-enhanced delivery, as well as new techniques for enhancing extent of resection such as fluorescence-guided surgery.
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Affiliation(s)
- Linda M Wang
- Columbia University Irving Medical Center, New York, NY, 10032, USA
| | | | - Michael L Miller
- Columbia University Irving Medical Center, New York, NY, 10032, USA
| | - Jeffrey N Bruce
- Department of Neurosurgery, Columbia University Irving Medical Center, New York, NY, 10032, USA.
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15
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McCarthy L, Verma G, Hangel G, Neal A, Moffat BA, Stockmann JP, Andronesi OC, Balchandani P, Hadjipanayis CG. Application of 7T MRS to High-Grade Gliomas. AJNR Am J Neuroradiol 2022; 43:1378-1395. [PMID: 35618424 PMCID: PMC9575545 DOI: 10.3174/ajnr.a7502] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 02/11/2022] [Indexed: 01/26/2023]
Abstract
MRS, including single-voxel spectroscopy and MR spectroscopic imaging, captures metabolites in high-grade gliomas. Emerging evidence indicates that 7T MRS may be more sensitive to aberrant metabolic activity than lower-field strength MRS. However, the literature on the use of 7T MRS to visualize high-grade gliomas has not been summarized. We aimed to identify metabolic information provided by 7T MRS, optimal spectroscopic sequences, and areas for improvement in and new applications for 7T MRS. Literature was found on PubMed using "high-grade glioma," "malignant glioma," "glioblastoma," "anaplastic astrocytoma," "7T," "MR spectroscopy," and "MR spectroscopic imaging." 7T MRS offers higher SNR, modestly improved spatial resolution, and better resolution of overlapping resonances. 7T MRS also yields reduced Cramér-Rao lower bound values. These features help to quantify D-2-hydroxyglutarate in isocitrate dehydrogenase 1 and 2 gliomas and to isolate variable glutamate, increased glutamine, and increased glycine with higher sensitivity and specificity. 7T MRS may better characterize tumor infiltration and treatment effect in high-grade gliomas, though further study is necessary. 7T MRS will benefit from increased sample size; reductions in field inhomogeneity, specific absorption rate, and acquisition time; and advanced editing techniques. These findings suggest that 7T MRS may advance understanding of high-grade glioma metabolism, with reduced Cramér-Rao lower bound values and better measurement of smaller metabolite signals. Nevertheless, 7T is not widely used clinically, and technical improvements are necessary. 7T MRS isolates metabolites that may be valuable therapeutic targets in high-grade gliomas, potentially resulting in wider ranging neuro-oncologic applications.
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Affiliation(s)
- L McCarthy
- From the Department of Neurosurgery (L.M., C.G.H.), Icahn School of Medicine at Mount Sinai, Mount Sinai Health System, New York, New York
| | - G Verma
- BioMedical Engineering and Imaging Institute (G.V., P.B.), Icahn School of Medicine at Mount Sinai, New York, New York
| | - G Hangel
- Department of Neurosurgery (G.H.)
- High-field MR Center (G.H.), Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria
| | - A Neal
- Department of Medicine (A.N.), Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia
- Department of Neurology (A.N.), Royal Melbourne Hospital, Melbourne, Australia
| | - B A Moffat
- The Melbourne Brain Centre Imaging Unit (B.A.M.), Department of Radiology, The University of Melbourne, Melbourne, Australia
| | - J P Stockmann
- A. A. Martinos Center for Biomedical Imaging (J.P.S., O.C.A.), Massachusetts General Hospital, Charlestown, Massachusetts
- Harvard Medical School (J.P.S., O.C.A.), Boston, Massachusetts
| | - O C Andronesi
- A. A. Martinos Center for Biomedical Imaging (J.P.S., O.C.A.), Massachusetts General Hospital, Charlestown, Massachusetts
- Harvard Medical School (J.P.S., O.C.A.), Boston, Massachusetts
| | - P Balchandani
- BioMedical Engineering and Imaging Institute (G.V., P.B.), Icahn School of Medicine at Mount Sinai, New York, New York
| | - C G Hadjipanayis
- From the Department of Neurosurgery (L.M., C.G.H.), Icahn School of Medicine at Mount Sinai, Mount Sinai Health System, New York, New York
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16
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Ascorbate content of clinical glioma tissues is related to tumour grade and to global levels of 5-hydroxymethyl cytosine. Sci Rep 2022; 12:14845. [PMID: 36050369 PMCID: PMC9436949 DOI: 10.1038/s41598-022-19032-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 08/23/2022] [Indexed: 11/23/2022] Open
Abstract
Gliomas are incurable brain cancers with poor prognosis, with epigenetic dysregulation being a distinctive feature. 5-hydroxymethylcytosine (5-hmC), an intermediate generated in the demethylation of 5-methylcytosine, is present at reduced levels in glioma tissue compared with normal brain, and that higher levels of 5-hmC are associated with improved patient survival. DNA demethylation is enzymatically driven by the ten–eleven translocation (TET) dioxygenases that require ascorbate as an essential cofactor. There is limited data on ascorbate in gliomas and the relationship between ascorbate and 5-hmC in gliomas has never been reported. Clinical glioma samples (11 low-grade, 26 high-grade) were analysed for ascorbate, global DNA methylation and hydroxymethylation, and methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter. Low-grade gliomas contained significantly higher levels of ascorbate than high-grade gliomas (p = 0.026). Levels of 5-hmC were significantly higher in low-grade than high-grade glioma (p = 0.0013). There was a strong association between higher ascorbate and higher 5-hmC (p = 0.004). Gliomas with unmethylated and methylated MGMT promoters had similar ascorbate levels (p = 0.96). One mechanism by which epigenetic modifications could occur is through ascorbate-mediated optimisation of TET activity in gliomas. These findings open the door to clinical intervention trials in patients with glioma to provide both mechanistic information and potential avenues for adjuvant ascorbate therapy.
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17
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A consensus definition of supratotal resection for anatomically distinct primary glioblastoma: an AANS/CNS Section on Tumors survey of neurosurgical oncologists. J Neurooncol 2022; 159:233-242. [PMID: 35913556 DOI: 10.1007/s11060-022-04048-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Accepted: 05/26/2022] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Supratotal resection (SpTR) of glioblastoma may be associated with improved survival, but published results have varied in part from lack of consensus on the definition and appropriate use of SpTR. A previous small survey of neurosurgical oncologists with expertise performing SpTR found resection 1-2 cm beyond contrast enhancement was an acceptable definition and glioblastoma involving the right frontal and bilateral anterior temporal lobes were considered most amenable to SpTR. The general neurosurgical oncology community has not yet confirmed the practicality of this definition. METHODS Seventy-six neurosurgical oncology members of the AANS/CNS Tumor Section were surveyed, representing 34.0% of the 223 members who were administered the survey. Participants were presented with 11 definitions of SpTR and rated each definition's appropriateness. Participants additionally reviewed magnetic resonance imaging for 10 anatomically distinct glioblastomas and assessed the tumor location's eloquence, perceived equipoise of enrolling patients in a randomized trial comparing gross total to SpTR, and their personal treatment plans. RESULTS Most neurosurgeons surveyed agree that gross total plus resection of some non-contrast enhancement (n = 57, 80.3%) or resection 1-2 cm beyond contrast enhancement (n = 52, 73.2%) are appropriate definitions for SpTR. Cases were divided into three anatomically distinct groups by perceived equipoise between gross total and SpTR. The best clinical trial candidates were thought to be right anterior temporal (n = 58, 76.3%) and right frontal (n = 55, 73.3%) glioblastomas. CONCLUSION Support exists among neurosurgical oncologists with varying familiarity performing SpTR to adopt the proposed consensus definition of SpTR of glioblastoma and to potentially investigate the utility of SpTR to treat right anterior temporal and right frontal glioblastomas in a clinical trial. A smaller proportion of general neurosurgical oncologists than SpTR experts would personally treat a left anterior temporal glioblastoma with SpTR.
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Dana P, Pimpha N, Chaipuang A, Thumrongsiri N, Tanyapanyachon P, Taweechaipaisankul A, Chonniyom W, Watcharadulyarat N, Sathornsumetee S, Saengkrit N. Inhibiting Metastasis and Improving Chemosensitivity via Chitosan-Coated Selenium Nanoparticles for Brain Cancer Therapy. NANOMATERIALS 2022; 12:nano12152606. [PMID: 35957037 PMCID: PMC9370598 DOI: 10.3390/nano12152606] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 07/20/2022] [Accepted: 07/25/2022] [Indexed: 02/05/2023]
Abstract
Selenium nanoparticles (SeNPs) were synthesized to overcome the limitations of selenium, such as its narrow safe range and low water solubility. SeNPs reduce the toxicity and improve the bioavailability of selenium. Chitosan-coated SeNPs (Cs-SeNPs) were developed to further stabilize SeNPs and to test their effects against glioma cells. The effects of Cs-SeNPs on cell growth were evaluated in monolayer and 3D-tumor spheroid culture. Cell migration and cell invasion were determined using a trans-well assay. The effect of Cs-SeNPs on chemotherapeutic drug 5-fluorouracil (5-FU) sensitivity of glioma cells was determined in tumor spheroids. An in vitro blood–brain barrier (BBB) model was established to test the permeability of Cs-SeNPs. SeNPs and Cs-SeNPs can reduce the cell viability of glioma cells in a dose-dependent manner. Compared with SeNPs, Cs-SeNPs more strongly inhibited 3D-tumor spheroid growth. Cs-SeNPs exhibited stronger effects in inhibiting cell migration and cell invasion than SeNPs. Improved 5-FU sensitivity was observed in Cs-SeNP-treated cells. Cellular uptake in glioma cells indicated a higher uptake rate of coumarin-6-labeled Cs-SeNPs than SeNPs. The capability of coumarin-6 associated Cs-SeNPs to pass through the BBB was confirmed. Taken together, Cs-SeNPs provide exceptional performance and are a potential alternative therapeutic strategy for future glioma treatment.
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Affiliation(s)
- Paweena Dana
- National Nanotechnology Center (NANOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani 12120, Thailand; (P.D.); (N.P.); (A.C.); (N.T.); (P.T.); (A.T.); (W.C.); (N.W.)
| | - Nuttaporn Pimpha
- National Nanotechnology Center (NANOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani 12120, Thailand; (P.D.); (N.P.); (A.C.); (N.T.); (P.T.); (A.T.); (W.C.); (N.W.)
| | - Angkana Chaipuang
- National Nanotechnology Center (NANOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani 12120, Thailand; (P.D.); (N.P.); (A.C.); (N.T.); (P.T.); (A.T.); (W.C.); (N.W.)
| | - Nutthanit Thumrongsiri
- National Nanotechnology Center (NANOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani 12120, Thailand; (P.D.); (N.P.); (A.C.); (N.T.); (P.T.); (A.T.); (W.C.); (N.W.)
| | - Prattana Tanyapanyachon
- National Nanotechnology Center (NANOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani 12120, Thailand; (P.D.); (N.P.); (A.C.); (N.T.); (P.T.); (A.T.); (W.C.); (N.W.)
| | - Anukul Taweechaipaisankul
- National Nanotechnology Center (NANOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani 12120, Thailand; (P.D.); (N.P.); (A.C.); (N.T.); (P.T.); (A.T.); (W.C.); (N.W.)
| | - Walailuk Chonniyom
- National Nanotechnology Center (NANOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani 12120, Thailand; (P.D.); (N.P.); (A.C.); (N.T.); (P.T.); (A.T.); (W.C.); (N.W.)
| | - Natsorn Watcharadulyarat
- National Nanotechnology Center (NANOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani 12120, Thailand; (P.D.); (N.P.); (A.C.); (N.T.); (P.T.); (A.T.); (W.C.); (N.W.)
| | - Sith Sathornsumetee
- Research Network NANOTEC-Mahidol University in Theranostic Nanomedicine, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok 10700, Thailand;
- Department of Medicine (Neurology), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok 10700, Thailand
| | - Nattika Saengkrit
- National Nanotechnology Center (NANOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani 12120, Thailand; (P.D.); (N.P.); (A.C.); (N.T.); (P.T.); (A.T.); (W.C.); (N.W.)
- Correspondence: ; Tel.: +66-2117-6558
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Boccellato C, Rehm M. Glioblastoma, from disease understanding towards optimal cell-based in vitro models. Cell Oncol (Dordr) 2022; 45:527-541. [PMID: 35763242 PMCID: PMC9424171 DOI: 10.1007/s13402-022-00684-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/01/2022] [Indexed: 11/24/2022] Open
Abstract
Abstract
Background
Glioblastoma (GBM) patients are notoriously difficult to treat and ultimately all succumb to disease. This unfortunate scenario motivates research into better characterizing and understanding this disease, and into developing novel research tools by which potential novel therapeutics and treatment options initially can be evaluated pre-clinically. Here, we provide a concise overview of glioblastoma epidemiology, disease classification, the challenges faced in the treatment of glioblastoma and current novel treatment strategies. From this, we lead into a description and assessment of advanced cell-based models that aim to narrow the gap between pre-clinical and clinical studies. Such invitro models are required to deliver reliable and meaningful data for the development and pre-validation of novel therapeutics and treatments.
Conclusions
The toolbox for GBM cell-based models has expanded substantially, with the possibility of 3D printing tumour tissues and thereby replicating invivo tissue architectures now looming on the horizon. A comparison of experimental cell-based model systems and techniques highlights advantages and drawbacks of the various tools available, based on which cell-based models and experimental approaches best suited to address a diversity of research questions in the glioblastoma research field can be selected.
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Affiliation(s)
- Chiara Boccellato
- Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany.
| | - Markus Rehm
- Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany.
- Stuttgart Research Center Systems Biology, University of Stuttgart, 70569, Stuttgart, Germany.
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20
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Ghosh S, Huda P, Fletcher NL, Howard CB, Walsh B, Campbell D, Pinkham MB, Thurecht KJ. Antibody-Based Formats to Target Glioblastoma: Overcoming Barriers to Protein Drug Delivery. Mol Pharm 2022; 19:1233-1247. [PMID: 35438509 DOI: 10.1021/acs.molpharmaceut.1c00996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Glioblastoma (GB) is recognized as the most aggressive form of primary brain cancer. Despite advances in treatment strategies that include surgery, radiation, and chemotherapy, the median survival time (∼15 months) of patients with GB has not significantly improved. The poor prognosis of GB is also associated with a very high chance of tumor recurrence (∼90%), and current treatment measures have failed to address the complications associated with this disease. However, targeted therapies enabled through antibody engineering have shown promise in countering GB when used in combination with conventional approaches. Here, we discuss the challenges in conventional as well as future GB therapeutics and highlight some of the known advantages of using targeted biologics to overcome these impediments. We also review a broad range of potential alternative routes that could be used clinically to administer anti-GB biologics to the brain through evasion of its natural barriers.
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Affiliation(s)
- Saikat Ghosh
- Centre for Advanced Imaging (CAI), Australian Institute for Bioengineering and Nanotechnology (AIBN) and ARC Training Centre for Innovation in Biomedical Imaging Technology, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Pie Huda
- Centre for Advanced Imaging (CAI), Australian Institute for Bioengineering and Nanotechnology (AIBN) and ARC Training Centre for Innovation in Biomedical Imaging Technology, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Nicholas L Fletcher
- Centre for Advanced Imaging (CAI), Australian Institute for Bioengineering and Nanotechnology (AIBN) and ARC Training Centre for Innovation in Biomedical Imaging Technology, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Christopher B Howard
- Centre for Advanced Imaging (CAI), Australian Institute for Bioengineering and Nanotechnology (AIBN) and ARC Training Centre for Innovation in Biomedical Imaging Technology, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Bradley Walsh
- GlyTherix, Ltd., Sydney, New South Wales 2113, Australia
| | | | - Mark B Pinkham
- Department of Radiation Oncology, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia
| | - Kristofer J Thurecht
- Centre for Advanced Imaging (CAI), Australian Institute for Bioengineering and Nanotechnology (AIBN) and ARC Training Centre for Innovation in Biomedical Imaging Technology, The University of Queensland, Brisbane, Queensland 4072, Australia
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21
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Sandbhor P, Goda J, Mohanty B, Chaudhari P, Dutt S, Banerjee R. Non-invasive transferrin targeted nanovesicles sensitize resistant glioblastoma multiforme tumors and improve survival in orthotopic mouse models. NANOSCALE 2021; 14:108-126. [PMID: 34897360 DOI: 10.1039/d1nr05460k] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The blood-brain barrier (BBB) and tumor heterogeneity have resulted in abysmally poor clinical outcomes in glioblastoma (GBM) with the standard therapeutic regimen. Despite several anti-glioma drug delivery strategies, the lack of adequate chemotherapeutic bioavailability in gliomas has led to a suboptimal therapeutic gain in terms of improvement in survival and increased systemic toxicities. This has paved the way for designing highly specific and non-invasive drug delivery approaches for treating GBM. The intranasal (IN) route is one such delivery strategy that has the potential to reach the brain parenchyma by circumventing the BBB. We recently showed that in situ hydrogel embedded with miltefosine (HePc, proapoptotic anti-tumor agent) and temozolomide (TMZ, DNA methylating agent) loaded targeted nanovesicles prevented tumor relapses in orthotopic GBM mouse models. In this study, we specifically investigated the potential of a non-invasive IN route of TMZ delivered from lipid nanovesicles (LNs) decorated with surface transferrin (Tf) and co-encapsulated with HePc to reach the brain by circumventing the BBB in glioma bearing mice. The targeted nanovesicles (228.3 ± 10 nm, -41.7 ± 4 mV) exhibited mucoadhesiveness with 2% w/v mucin suggesting their potential to increase brain drug bioavailability after IN administration. The optimized TLNs had controlled, tunable and significantly different release kinetics in simulated cerebrospinal fluid and simulated nasal fluid demonstrating efficient release of the payload upon reaching the brain. Drug synergy (combination index, 0.7) showed a 6.4-fold enhanced cytotoxicity against resistant U87MG cells compared to free drugs. In vivo gamma scintigraphy of 99mTc labeled LNs showed 500- and 280-fold increased brain concentration post 18 h of treatment. The efficacy of the TLNs increased by 1.8-fold in terms of survival of tumor-bearing mice compared to free drugs. These findings suggested that targeted drug synergy has the potential to intranasally deliver a high therapeutic dose of the chemotherapy agent (TMZ) and could serve as a platform for future clinical application.
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Affiliation(s)
- Puja Sandbhor
- Department of Biosciences and Bioengineering, Indian Institute of Technology, Bombay, Powai, Mumbai, India.
| | - Jayant Goda
- Department of Radiation Oncology ACTREC, Tata Memorial Center, Kharghar Navi-Mumbai, India.
| | - Bhabani Mohanty
- Department of Comparative Oncology and Small Animal Imaging Facility, ACTREC, Tata Memorial Center, Kharghar Navi-Mumbai, India
- Department of Biosciences and Bioengineering, Indian Institute of Technology, Bombay, Powai, Mumbai, India.
| | - Pradip Chaudhari
- Department of Radiation Oncology ACTREC, Tata Memorial Center, Kharghar Navi-Mumbai, India.
- Department of Comparative Oncology and Small Animal Imaging Facility, ACTREC, Tata Memorial Center, Kharghar Navi-Mumbai, India
| | - Shilpee Dutt
- Department Shilpee Lab/DNA Repair and Cellular Oncology Lab, ACTREC, Tata Memorial Center, Kharghar Navi-Mumbai, India
| | - Rinti Banerjee
- Department of Biosciences and Bioengineering, Indian Institute of Technology, Bombay, Powai, Mumbai, India.
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22
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Chato L, Latifi S. Machine Learning and Radiomic Features to Predict Overall Survival Time for Glioblastoma Patients. J Pers Med 2021; 11:jpm11121336. [PMID: 34945808 PMCID: PMC8705288 DOI: 10.3390/jpm11121336] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 11/24/2021] [Accepted: 12/07/2021] [Indexed: 01/11/2023] Open
Abstract
Glioblastoma is an aggressive brain tumor with a low survival rate. Understanding tumor behavior by predicting prognosis outcomes is a crucial factor in deciding a proper treatment plan. In this paper, an automatic overall survival time prediction system (OST) for glioblastoma patients is developed on the basis of radiomic features and machine learning (ML). This system is designed to predict prognosis outcomes by classifying a glioblastoma patient into one of three survival groups: short-term, mid-term, and long-term. To develop the prediction system, a medical dataset based on imaging information from magnetic resonance imaging (MRI) and non-imaging information is used. A novel radiomic feature extraction method is proposed and developed on the basis of volumetric and location information of brain tumor subregions extracted from MRI scans. This method is based on calculating the volumetric features from two brain sub-volumes obtained from the whole brain volume in MRI images using brain sectional planes (sagittal, coronal, and horizontal). Many experiments are conducted on the basis of various ML methods and combinations of feature extraction methods to develop the best OST system. In addition, the feature fusions of both radiomic and non-imaging features are examined to improve the accuracy of the prediction system. The best performance was achieved by the neural network and feature fusions.
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23
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El-Abtah ME, Wenke MR, Talati P, Fu M, Kim D, Weerasekera A, He J, Vaynrub A, Vangel M, Rapalino O, Andronesi O, Arrillaga-Romany I, Forst DA, Yen YF, Rosen B, Batchelor TT, Gonzalez RG, Dietrich J, Gerstner ER, Ratai EM. Myo-Inositol Levels Measured with MR Spectroscopy Can Help Predict Failure of Antiangiogenic Treatment in Recurrent Glioblastoma. Radiology 2021; 302:410-418. [PMID: 34751617 PMCID: PMC8805659 DOI: 10.1148/radiol.2021210826] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Background Patients with recurrent glioblastoma (GBM) are often treated with antiangiogenic agents, such as bevacizumab (BEV). Despite therapeutic promise, conventional MRI methods fail to help determine which patients may not benefit from this treatment. Purpose To use MR spectroscopic imaging (MRSI) with intermediate and short echo time to measure corrected myo-inositol (mI)normalized by contralateral creatine (hereafter, mI/c-Cr) in participants with recurrent GBM treated with BEV and to investigate whether such measurements can help predict survivorship before BEV initiation (baseline) and at 1 day, 4 weeks, and 8 weeks thereafter. Materials and Methods In this prospective longitudinal study (2016-2020), spectroscopic data on mI-a glial marker and osmoregulator within the brain-normalized by contralateral creatine in the intratumoral, contralateral, and peritumoral volumes of patients with recurrent GBM were evaluated. Area under the receiver operating characteristic curve (AUC) was calculated for all volumes at baseline and 1 day, 4 weeks, and 8 weeks after treatment to determine the ability of mI/c-Cr to help predict survivorship. Results Twenty-one participants (median age ± standard deviation, 62 years ± 12; 15 men) were evaluated. Lower mI/c-Cr in the tumor before and during BEV treatment was predictive of poor survivorship, with receiver operating characteristic analyses showing an AUC of 0.75 at baseline, 0.87 at 1 day after treatment, and 1 at 8 weeks after. A similar result was observed in contralateral normal-appearing tissue and the peritumoral volume, with shorter-term survivors having lower levels of mI/c-Cr. In the contralateral volume, a lower ratio of mI to creatine (hereafter, mI/Cr) predicted shorter-term survival at baseline and all other time points. Within the peritumoral volume, lower mI/c-Cr levels were predictive of shorter-term survival at baseline (AUC, 0.80), at 1 day after treatment (AUC, 0.93), and at 4 weeks after treatment (AUC, 0.68). Conclusion Lower levels of myo-inositol normalized by contralateral creatine within intratumoral, contralateral, and peritumoral volumes were predictive of poor survivorship and antiangiogenic treatment failure as early as before bevacizumab treatment. Adapting MR spectroscopic imaging alongside conventional MRI modalities conveys critical information regarding the biologic characteristics of tumors to help better treat individuals with recurrent glioblastoma. Clinical trial registration no. NCT02843230 © RSNA, 2021 Online supplemental material is available for this article.
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24
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Puca F, Yu F, Bartolacci C, Pettazzoni P, Carugo A, Huang-Hobbs E, Liu J, Zanca C, Carbone F, Del Poggetto E, Gumin J, Dasgupta P, Seth S, Srinivasan S, Lang FF, Sulman EP, Lorenzi PL, Tan L, Shan M, Tolstyka ZP, Kachman M, Zhang L, Gao S, Deem AK, Genovese G, Scaglioni PP, Lyssiotis CA, Viale A, Draetta GF. Medium-Chain Acyl-CoA Dehydrogenase Protects Mitochondria from Lipid Peroxidation in Glioblastoma. Cancer Discov 2021; 11:2904-2923. [PMID: 34039636 PMCID: PMC8711129 DOI: 10.1158/2159-8290.cd-20-1437] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 03/25/2021] [Accepted: 05/18/2021] [Indexed: 11/16/2022]
Abstract
Glioblastoma (GBM) is highly resistant to chemotherapies, immune-based therapies, and targeted inhibitors. To identify novel drug targets, we screened orthotopically implanted, patient-derived glioblastoma sphere-forming cells using an RNAi library to probe essential tumor cell metabolic programs. This identified high dependence on mitochondrial fatty acid metabolism. We focused on medium-chain acyl-CoA dehydrogenase (MCAD), which oxidizes medium-chain fatty acids (MCFA), due to its consistently high score and high expression among models and upregulation in GBM compared with normal brain. Beyond the expected energetics impairment, MCAD depletion in primary GBM models induced an irreversible cascade of detrimental metabolic effects characterized by accumulation of unmetabolized MCFAs, which induced lipid peroxidation and oxidative stress, irreversible mitochondrial damage, and apoptosis. Our data uncover a novel protective role for MCAD to clear lipid molecules that may cause lethal cell damage, suggesting that therapeutic targeting of MCFA catabolism may exploit a key metabolic feature of GBM. SIGNIFICANCE: MCAD exerts a protective role to prevent accumulation of toxic metabolic by-products in glioma cells, actively catabolizing lipid species that would otherwise affect mitochondrial integrity and induce cell death. This work represents a first demonstration of a nonenergetic role for dependence on fatty acid metabolism in cancer.This article is highlighted in the In This Issue feature, p. 2659.
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Affiliation(s)
- Francesca Puca
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Fei Yu
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Caterina Bartolacci
- Department of Internal Medicine Division of Hematology & Oncology, University of Cincinnati, Cincinnati, Ohio
| | - Piergiorgio Pettazzoni
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Alessandro Carugo
- The Translational Research to Advance Therapeutics and Innovation in Oncology Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Emmet Huang-Hobbs
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jintan Liu
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ciro Zanca
- The Translational Research to Advance Therapeutics and Innovation in Oncology Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Federica Carbone
- Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Edoardo Del Poggetto
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Joy Gumin
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Pushan Dasgupta
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sahil Seth
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
- The Translational Research to Advance Therapeutics and Innovation in Oncology Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sanjana Srinivasan
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Frederick F Lang
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Erik P Sulman
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Philip L Lorenzi
- Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Lin Tan
- Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mengrou Shan
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Zachary P Tolstyka
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Maureen Kachman
- Michigan Regional Comprehensive Metabolomics Resource Core, University of Michigan, Ann Arbor, Michigan
| | - Li Zhang
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Sisi Gao
- Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Angela K Deem
- The Translational Research to Advance Therapeutics and Innovation in Oncology Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Giannicola Genovese
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Pier Paolo Scaglioni
- Department of Internal Medicine Division of Hematology & Oncology, University of Cincinnati, Cincinnati, Ohio
| | - Costas A Lyssiotis
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan.
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan
- University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan
| | - Andrea Viale
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Giulio F Draetta
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Discovery of novel ID2 antagonists from pharmacophore-based virtual screening as potential therapeutics for glioma. Bioorg Med Chem 2021; 49:116427. [PMID: 34600240 DOI: 10.1016/j.bmc.2021.116427] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/16/2021] [Accepted: 09/17/2021] [Indexed: 12/29/2022]
Abstract
Glioma, especially the most aggressive type glioblastoma multiforme, is a malignant cancer of the central nervous system with a poor prognosis. Traditional treatments are mainly surgery combined with radiotherapy and chemotherapy, which is still far from satisfactory. Therefore, it is of great clinical significance to find new therapeutic agents. Serving as an inhibitor of differentiation, protein ID2 (inhibitor of DNA binding 2) plays an important role in neurogenesis, neovascularization and malignant development of gliomas. It has been shown that ID2 affects the malignant progression of gliomas through different mechanisms. In this study, a pharmacophore-based virtual screening was carried out and 16 hit compounds were purchased for pharmacological evaluations on their ID2 inhibitory activities. Based on the cytotoxicity of these small-molecule compounds, two compounds were shown to effectively inhibit the viability of glioma cells in the micromolar range. Among them, AK-778-XXMU was chosen for further study due to its better solubility in water. A SPR (Surface Plasma Resonance) assay proved the high affinity between AK-778-XXMU and ID2 protein with the KD value as 129 nM. The plausible binding mode of ID2 was studied by molecular docking and it was found to match AGX51 very well in the same binding site. Subsequently, the cancer-suppressing potency of the compound was characterized both in vitro and in vivo. The data demonstrated that compound AK-778-XXMU is a potent ID2 antagonist which has the potential to be developed as a therapeutic agent against glioma.
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Lipatova AV, Soboleva AV, Gorshkov VA, Bubis JA, Solovyeva EM, Krasnov GS, Kochetkov DV, Vorobyev PO, Ilina IY, Moshkovskii SA, Kjeldsen F, Gorshkov MV, Chumakov PM, Tarasova IA. Multi-Omics Analysis of Glioblastoma Cells' Sensitivity to Oncolytic Viruses. Cancers (Basel) 2021; 13:cancers13215268. [PMID: 34771433 PMCID: PMC8582528 DOI: 10.3390/cancers13215268] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/11/2021] [Accepted: 10/15/2021] [Indexed: 12/28/2022] Open
Abstract
Simple Summary This study aims to uncover the contribution of interferon-dependent antiviral mechanisms preserved in tumor cells to the resistance of glioblastoma multiforme cells to oncolytic viruses. To characterize the functionality of interferon signaling, we used omics profiling and titration-based measurements of cell sensitivity to a panel of viruses of diverse oncolytic potential. This study shows why patient-derived glioblastoma cultures can acquire increased resistance to oncolytic viruses in the presence of interferons and suggests an approach to ranking glioblastoma cells by the acquired resistance. Our findings are important for monitoring the oncolytic potential of viruses to overcome IFN-induced resistance of tumor cells and contribute to successful therapy. Abstract Oncolytic viruses have gained momentum in the last decades as a promising tool for cancer treatment. Despite the progress, only a fraction of patients show a positive response to viral therapy. One of the key variable factors contributing to therapy outcomes is interferon-dependent antiviral mechanisms in tumor cells. Here, we evaluated this factor using patient-derived glioblastoma multiforme (GBM) cultures. Cell response to the type I interferons’ (IFNs) stimulation was characterized at mRNA and protein levels. Omics analysis revealed that GBM cells overexpress interferon-stimulated genes (ISGs) and upregulate their proteins, similar to the normal cells. A conserved molecular pattern unambiguously differentiates between the preserved and defective responses. Comparing ISGs’ portraits with titration-based measurements of cell sensitivity to a panel of viruses, the “strength” of IFN-induced resistance acquired by GBM cells was ranked. The study demonstrates that suppressing a single ISG and encoding an essential antiviral protein, does not necessarily increase sensitivity to viruses. Conversely, silencing IFIT3 and PLSCR1 genes in tumor cells can negatively affect the internalization of vesicular stomatitis and Newcastle disease viruses. We present evidence of a complex relationship between the interferon response genes and other factors affecting the sensitivity of tumor cells to viruses.
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Affiliation(s)
- Anastasiya V. Lipatova
- V. A. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (A.V.L.); (A.V.S.); (G.S.K.); (D.V.K.); (P.O.V.)
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Alesya V. Soboleva
- V. A. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (A.V.L.); (A.V.S.); (G.S.K.); (D.V.K.); (P.O.V.)
| | - Vladimir A. Gorshkov
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, Denmark; (V.A.G.); (F.K.)
| | - Julia A. Bubis
- V. L. Talrose Institute for Energy Problems of Chemical Physics, N.N. Semenov Federal Research Center for Chemical Physics, Russian Academy of Sciences, 119334 Moscow, Russia; (J.A.B.); (E.M.S.); (M.V.G.)
| | - Elizaveta M. Solovyeva
- V. L. Talrose Institute for Energy Problems of Chemical Physics, N.N. Semenov Federal Research Center for Chemical Physics, Russian Academy of Sciences, 119334 Moscow, Russia; (J.A.B.); (E.M.S.); (M.V.G.)
| | - George S. Krasnov
- V. A. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (A.V.L.); (A.V.S.); (G.S.K.); (D.V.K.); (P.O.V.)
| | - Dmitry V. Kochetkov
- V. A. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (A.V.L.); (A.V.S.); (G.S.K.); (D.V.K.); (P.O.V.)
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Pavel O. Vorobyev
- V. A. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (A.V.L.); (A.V.S.); (G.S.K.); (D.V.K.); (P.O.V.)
| | - Irina Y. Ilina
- Federal Research and Clinical Center of Physical-Chemical Medicine, 119435 Moscow, Russia; (I.Y.I.); (S.A.M.)
| | - Sergei A. Moshkovskii
- Federal Research and Clinical Center of Physical-Chemical Medicine, 119435 Moscow, Russia; (I.Y.I.); (S.A.M.)
- Department of Biochemistry, Medico-Biological Faculty, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
| | - Frank Kjeldsen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, Denmark; (V.A.G.); (F.K.)
| | - Mikhail V. Gorshkov
- V. L. Talrose Institute for Energy Problems of Chemical Physics, N.N. Semenov Federal Research Center for Chemical Physics, Russian Academy of Sciences, 119334 Moscow, Russia; (J.A.B.); (E.M.S.); (M.V.G.)
| | - Peter M. Chumakov
- V. A. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (A.V.L.); (A.V.S.); (G.S.K.); (D.V.K.); (P.O.V.)
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
- Correspondence: (P.M.C.); (I.A.T.)
| | - Irina A. Tarasova
- V. L. Talrose Institute for Energy Problems of Chemical Physics, N.N. Semenov Federal Research Center for Chemical Physics, Russian Academy of Sciences, 119334 Moscow, Russia; (J.A.B.); (E.M.S.); (M.V.G.)
- Correspondence: (P.M.C.); (I.A.T.)
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K-RAS Acts as a Critical Regulator of CD44 to Promote the Invasiveness and Stemness of GBM in Response to Ionizing Radiation. Int J Mol Sci 2021; 22:ijms222010923. [PMID: 34681583 PMCID: PMC8539357 DOI: 10.3390/ijms222010923] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 10/04/2021] [Accepted: 10/05/2021] [Indexed: 12/21/2022] Open
Abstract
Radiation therapy is a current standard-of-care treatment and is used widely for GBM patients. However, radiation therapy still remains a significant barrier to getting a successful outcome due to the therapeutic resistance and tumor recurrence. Understanding the underlying mechanisms of this resistance and recurrence would provide an efficient approach for improving the therapy for GBM treatment. Here, we identified a regulatory mechanism of CD44 which induces infiltration and mesenchymal shift of GBM. Ionizing radiation (IR)-induced K-RAS/ERK signaling activation elevates CD44 expression through downregulation of miR-202 and miR-185 expression. High expression of CD44 promotes SRC activation to induce cancer stemness and EMT features of GBM cells. In this study, we demonstrate that the K-RAS/ERK/CD44 axis is a key mechanism in regulating mesenchymal shift of GBM cells after irradiation. These findings suggest that blocking the K-RAS activation or CD44 expression could provide an efficient way for GBM treatment.
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García-Cabezas S, Rivin del Campo E, Solivera-Vela J, Palacios-Eito A. Re-irradiation for high-grade gliomas: Has anything changed? World J Clin Oncol 2021; 12:767-786. [PMID: 34631441 PMCID: PMC8479348 DOI: 10.5306/wjco.v12.i9.767] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/21/2021] [Accepted: 07/30/2021] [Indexed: 02/06/2023] Open
Abstract
Optimal management after recurrence or progression of high-grade gliomas is still undefined and remains a challenge for neuro-oncology multidisciplinary teams. Improved radiation therapy techniques, new imaging methods, published experience, and a better radiobiological knowledge of brain tissue have positioned re-irradiation (re-RT) as an option for many of these patients. Decisions must be individualized, taking into account the pattern of relapse, previous treatment, and functional status, as well as the patient’s preferences and expected quality of life. Many questions remain unanswered with respect to re-RT: Who is the most appropriate candidate, which dose and fractionation are most effective, how to define the target volume, which imaging technique is best for planning, and what is the optimal timing? This review will focus on describing the most relevant studies that include re-RT as salvage therapy, with the aim of simplifying decision-making and designing the best available therapeutic strategy.
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Affiliation(s)
- Sonia García-Cabezas
- Department of Radiation Oncology, Reina Sofia University Hospital, Cordoba 14004, Spain
| | | | - Juan Solivera-Vela
- Department of Neurosurgery, Reina Sofia University Hospital, Cordoba 14004, Spain
| | - Amalia Palacios-Eito
- Department of Radiation Oncology, Reina Sofia University Hospital, Cordoba 14004, Spain
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29
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Han S, Lee Y, Lee M. Biomimetic cell membrane-coated DNA nanoparticles for gene delivery to glioblastoma. J Control Release 2021; 338:22-32. [PMID: 34391836 DOI: 10.1016/j.jconrel.2021.08.021] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 08/10/2021] [Accepted: 08/11/2021] [Indexed: 01/29/2023]
Abstract
Gene therapy has been introduced as an alternative to radiation and chemical therapy for glioblastoma. Biomimetic nanoparticles coated with cell membranes (CM) have advantages such as high biocompatibility and prolong half-life. To apply CM coated nanoparticles to gene delivery, the polyethylenimine (PEI25k)/plasmid DNA (pDNA) complexes were coated with CM from C6 rat glioblastoma cells. With the CM covering, the PEI25k/pDNA complexes formed stable nanoparticles with negative surface charge. The PEI25k/pDNA/CM nanoparticles had high colloidal stability and could be stored for approximately 20 days without aggregation. The transfection efficiency of the PEI25k/pDNA/CM nanoparticles was higher than that of the PEI25k/pDNA complex in serum-containing medium. This suggests that serum does not interfere with transfection efficiency of the nanoparticles. Moreover, the PEI25k/pDNA/CM nanoparticles had lower toxicity than the PEI25k/DNA complex in vitro and in vivo. The PEI25k/pDNA/CM nanoparticles prepared with CMs of different types of cells were transfected into cells. The results showed that the PEI25k/pDNA/CM nanoparticles with the C6 CM had the highest transfection efficiency to C6 cells, suggesting the homotypic targeting effect. The therapeutic effects of the nanoparticles were evaluated in intracranial C6 transplanted glioblastoma animal models. The PEI25k/pDNA/CM nanoparticles were prepared with herpes simplex virus thymidine kinase plasmid (pHSVtk) and injected into the tumor locally. The results showed that the PEI25k/pHSVtk/CM nanoparticles induced higher HSVtk expression compared with the PEI25k/pHSVtk complex. Furthermore, tumor size was reduced more efficiently by the PEI25k/pHSVtk/CM nanoparticles than by the PEI25k/pHSVtk complex. Overall results indicate that PEI25k/pDNA/CM nanoparticles are suitable for pDNA delivery to glioblastoma.
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Affiliation(s)
- Sangrok Han
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul 04763, Republic of Korea
| | - Youngki Lee
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul 04763, Republic of Korea
| | - Minhyung Lee
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul 04763, Republic of Korea.
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Kynurenine Monooxygenase Expression and Activity in Human Astrocytomas. Cells 2021; 10:cells10082028. [PMID: 34440798 PMCID: PMC8393384 DOI: 10.3390/cells10082028] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 08/03/2021] [Accepted: 08/05/2021] [Indexed: 12/24/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. The enzyme indoleamine-2,3-dioxygenase (IDO), which participates in the rate-limiting step of tryptophan catabolism through the kynurenine pathway (KP), is associated with poor prognosis in patients with GBM. The metabolites produced after tryptophan oxidation have immunomodulatory properties that can support the immunosuppressor environment. In this study, mRNA expression, protein expression, and activity of the enzyme kynurenine monooxygenase (KMO) were analyzed in GBM cell lines (A172, LN-18, U87, U373) and patient-derived astrocytoma samples. KMO mRNA expression was assessed by real-time RT-qPCR, KMO protein expression was evaluated by flow cytometry and immunofluorescence, and KMO activity was determined by quantifying 3-hydroxykynurenine by HPLC. Heterogenous patterns of both KMO expression and activity were observed among the GBM cell lines, with the A172 cell line showing the highest KMO expression and activity. Higher KMO mRNA expression was observed in glioma samples than in patients diagnosed with only a neurological disease; high KMO mRNA expression was also observed when using samples from patients with GBM in the TCGA program. The KMO protein expression was localized in GFAP+ cells in tumor tissue. These results suggest that KMO is a relevant target to be explored in glioma since it might play a role in supporting tumor metabolism and immune suppression.
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Intratumour heterogeneity in microRNAs expression regulates glioblastoma metabolism. Sci Rep 2021; 11:15908. [PMID: 34354095 PMCID: PMC8342598 DOI: 10.1038/s41598-021-95289-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Accepted: 07/16/2021] [Indexed: 02/07/2023] Open
Abstract
While specific microRNA (miRNA) signatures have been identified in glioblastoma (GBM), the intratumour heterogeneity in miRNA expression has not yet been characterised. In this study, we reveal significant alterations in miRNA expression across three GBM tumour regions: the core, rim, and invasive margin. Our miRNA profiling analysis showed that miR-330-5p and miR-215-5p were upregulated in the invasive margin relative to the core and the rim regions, while miR-619-5p, miR-4440 and miR-4793-3p were downregulated. Functional analysis of newly identified miRNAs suggests their involvement in regulating lipid metabolic pathways. Subsequent liquid chromatography-mass spectrometry (LC-MS) and tandem mass spectroscopy (LC-MS/MS) profiling of the intracellular metabolome and the lipidome of GBM cells with dysregulated miRNA expression confirmed the alteration in the metabolite levels associated with lipid metabolism. The identification of regional miRNA expression signatures may underlie the metabolic heterogeneity within the GBM tumour and understanding this relationship may open new avenues for the GBM treatment.
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Nanostructured lipid base carrier for specific delivery of garlic oil through blood brain barrier against aggressiveness of glioma. J Drug Deliv Sci Technol 2021. [DOI: 10.1016/j.jddst.2021.102651] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Khalafallah AM, Rakovec M, Bettegowda C, Jackson CM, Gallia GL, Weingart JD, Lim M, Esquenazi Y, Zacharia BE, Goldschmidt E, Ziu M, Ivan ME, Venteicher AS, Nduom EK, Mamelak AN, Chu RM, Yu JS, Sheehan JP, Nahed BV, Carter BS, Berger MS, Sawaya R, Mukherjee D. A Crowdsourced Consensus on Supratotal Resection Versus Gross Total Resection for Anatomically Distinct Primary Glioblastoma. Neurosurgery 2021; 89:712-719. [PMID: 34320218 DOI: 10.1093/neuros/nyab257] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 06/16/2021] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Gross total resection (GTR) of contrast-enhancing tumor is associated with increased survival in primary glioblastoma. Recently, there has been increasing interest in performing supratotal resections (SpTRs) for glioblastoma. OBJECTIVE To address the published results, which have varied in part due to lack of consensus on the definition and appropriate use of SpTR. METHODS A crowdsourcing approach was used to survey 21 neurosurgical oncologists representing 14 health systems nationwide. Participants were presented with 11 definitions of SpTR and asked to rate the appropriateness of each definition. Participants reviewed T1-weighed postcontrast and fluid-attenuated inversion-recovery magnetic resonance imaging for 22 anatomically distinct glioblastomas. Participants were asked to assess the tumor location's eloquence, the perceived equipoise of enrolling patients in a randomized trial comparing gross total to SpTR, and their personal treatment plans. RESULTS Most neurosurgeons surveyed (n = 18, 85.7%) agree that GTR plus resection of some noncontrast enhancement is an appropriate definition for SpTR. Overall, moderate inter-rater agreement existed regarding eloquence, equipoise, and personal treatment plans. The 4 neurosurgeons who had performed >10 SpTRs for glioblastomas in the past year were more likely to recommend it as their treatment plan (P < .005). Cases were divided into 3 anatomically distinct groups based upon perceived eloquence. Anterior temporal and right frontal glioblastomas were considered the best randomization candidates. CONCLUSION We established a consensus definition for SpTR of glioblastoma and identified anatomically distinct locations deemed most amenable to SpTR. These results may be used to plan prospective trials investigating the potential clinical utility of SpTR for glioblastoma.
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Affiliation(s)
- Adham M Khalafallah
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Maureen Rakovec
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Chetan Bettegowda
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Christopher M Jackson
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Gary L Gallia
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jon D Weingart
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Michael Lim
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA
| | - Yoshua Esquenazi
- Vivian L. Smith Department of Neurosurgery, University of Texas Health Science Center, Houston, Texas, USA
| | - Brad E Zacharia
- Department of Neurosurgery, Penn State Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - Ezequiel Goldschmidt
- Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Mateo Ziu
- Inova Neuroscience and Spine Institute, University of Virginia Medical School-Inova Campus, Falls Church, Virginia, USA
| | - Michael E Ivan
- Sylvester Comprehensive Cancer Center, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Andrew S Venteicher
- Center for Skull Base and Pituitary Surgery, Department of Neurosurgery, University of Minnesota, Minneapolis, Minnesota, USA
| | - Edjah K Nduom
- Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Adam N Mamelak
- Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Ray M Chu
- Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - John S Yu
- Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Jason P Sheehan
- Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia, USA
| | - Brian V Nahed
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Bob S Carter
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Mitchel S Berger
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA
| | - Raymond Sawaya
- Division of Surgery, Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Debraj Mukherjee
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
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Oh JH, Choi W, Ko E, Kang M, Tannenbaum A, Deasy JO. PathCNN: interpretable convolutional neural networks for survival prediction and pathway analysis applied to glioblastoma. Bioinformatics 2021; 37:i443-i450. [PMID: 34252964 PMCID: PMC8336441 DOI: 10.1093/bioinformatics/btab285] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
MOTIVATION Convolutional neural networks (CNNs) have achieved great success in the areas of image processing and computer vision, handling grid-structured inputs and efficiently capturing local dependencies through multiple levels of abstraction. However, a lack of interpretability remains a key barrier to the adoption of deep neural networks, particularly in predictive modeling of disease outcomes. Moreover, because biological array data are generally represented in a non-grid structured format, CNNs cannot be applied directly. RESULTS To address these issues, we propose a novel method, called PathCNN, that constructs an interpretable CNN model on integrated multi-omics data using a newly defined pathway image. PathCNN showed promising predictive performance in differentiating between long-term survival (LTS) and non-LTS when applied to glioblastoma multiforme (GBM). The adoption of a visualization tool coupled with statistical analysis enabled the identification of plausible pathways associated with survival in GBM. In summary, PathCNN demonstrates that CNNs can be effectively applied to multi-omics data in an interpretable manner, resulting in promising predictive power while identifying key biological correlates of disease. AVAILABILITY AND IMPLEMENTATION The source code is freely available at: https://github.com/mskspi/PathCNN.
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Affiliation(s)
- Jung Hun Oh
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Wookjin Choi
- Department of Computer Science, Virginia State University, Petersburg, VA 23806, USA
| | - Euiseong Ko
- Department of Computer Science, University of Nevada, Las Vegas, NV 89154, USA
| | - Mingon Kang
- Department of Computer Science, University of Nevada, Las Vegas, NV 89154, USA
| | - Allen Tannenbaum
- Departments of Computer Science and Applied Mathematics & Statistics, Stony Brook University, New York, NY 11794, USA
| | - Joseph O Deasy
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
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Tampakaki M, Oraiopoulou ME, Tzamali E, Tzedakis G, Makatounakis T, Zacharakis G, Papamatheakis J, Sakkalis V. PML Differentially Regulates Growth and Invasion in Brain Cancer. Int J Mol Sci 2021; 22:ijms22126289. [PMID: 34208139 PMCID: PMC8230868 DOI: 10.3390/ijms22126289] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 06/08/2021] [Accepted: 06/09/2021] [Indexed: 12/20/2022] Open
Abstract
Glioblastoma is the most malignant brain tumor among adults. Despite multimodality treatment, it remains incurable, mainly because of its extensive heterogeneity and infiltration in the brain parenchyma. Recent evidence indicates dysregulation of the expression of the Promyelocytic Leukemia Protein (PML) in primary Glioblastoma samples. PML is implicated in various ways in cancer biology. In the brain, PML participates in the physiological migration of the neural progenitor cells, which have been hypothesized to serve as the cell of origin of Glioblastoma. The role of PML in Glioblastoma progression has recently gained attention due to its controversial effects in overall Glioblastoma evolution. In this work, we studied the role of PML in Glioblastoma pathophysiology using the U87MG cell line. We genetically modified the cells to conditionally overexpress the PML isoform IV and we focused on its dual role in tumor growth and invasive capacity. Furthermore, we targeted a PML action mediator, the Enhancer of Zeste Homolog 2 (EZH2), via the inhibitory drug DZNeP. We present a combined in vitro–in silico approach, that utilizes both 2D and 3D cultures and cancer-predictive computational algorithms, in order to differentiate and interpret the observed biological results. Our overall findings indicate that PML regulates growth and invasion through distinct cellular mechanisms. In particular, PML overexpression suppresses cell proliferation, while it maintains the invasive capacity of the U87MG Glioblastoma cells and, upon inhibition of the PML-EZH2 pathway, the invasion is drastically eliminated. Our in silico simulations suggest that the underlying mechanism of PML-driven Glioblastoma physiology regulates invasion by differential modulation of the cell-to-cell adhesive and diffusive capacity of the cells. Elucidating further the role of PML in Glioblastoma biology could set PML as a potential molecular biomarker of the tumor progression and its mediated pathway as a therapeutic target, aiming at inhibiting cell growth and potentially clonal evolution regarding their proliferative and/or invasive phenotype within the heterogeneous tumor mass.
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Affiliation(s)
- Maria Tampakaki
- Institute of Computer Science, Foundation for Research and Technology-Hellas, 70013 Heraklion, Greece; (M.T.); (M.-E.O.); (E.T.); (G.T.)
- School of Medicine, University of Crete, 71003 Heraklion, Greece
- Institute of Electronic Structure and Laser, Foundation for Research and Technology-Hellas, 70013 Heraklion, Greece
| | - Mariam-Eleni Oraiopoulou
- Institute of Computer Science, Foundation for Research and Technology-Hellas, 70013 Heraklion, Greece; (M.T.); (M.-E.O.); (E.T.); (G.T.)
| | - Eleftheria Tzamali
- Institute of Computer Science, Foundation for Research and Technology-Hellas, 70013 Heraklion, Greece; (M.T.); (M.-E.O.); (E.T.); (G.T.)
| | - Giorgos Tzedakis
- Institute of Computer Science, Foundation for Research and Technology-Hellas, 70013 Heraklion, Greece; (M.T.); (M.-E.O.); (E.T.); (G.T.)
| | - Takis Makatounakis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, 70013 Heraklion, Greece;
| | - Giannis Zacharakis
- Institute of Electronic Structure and Laser, Foundation for Research and Technology-Hellas, 70013 Heraklion, Greece
- Correspondence: (G.Z.); (J.P.); (V.S.)
| | - Joseph Papamatheakis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, 70013 Heraklion, Greece;
- Department of Biology, University of Crete, 70013 Heraklion, Greece
- Correspondence: (G.Z.); (J.P.); (V.S.)
| | - Vangelis Sakkalis
- Institute of Computer Science, Foundation for Research and Technology-Hellas, 70013 Heraklion, Greece; (M.T.); (M.-E.O.); (E.T.); (G.T.)
- Correspondence: (G.Z.); (J.P.); (V.S.)
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Zheng W, Chen Q, Liu H, Hu S, Zhou Y, Bai Y, Zhang J, Pan Y, Shao C. CD81 Enhances Radioresistance of Glioblastoma by Promoting Nuclear Translocation of Rad51. Cancers (Basel) 2021; 13:cancers13091998. [PMID: 33919192 PMCID: PMC8122253 DOI: 10.3390/cancers13091998] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 04/15/2021] [Indexed: 11/20/2022] Open
Abstract
Simple Summary CD81 is highly expressed in glioblastoma (GBM) as a transmembrane protein. The functional study demonstrated that CD81 contributed to radioresistance of GBM. Further evidence showed that CD81 expression was closely related to DNA damage response and homologous recombination repair (HRR) was responsible for the CD81 mediated radioresistance. Particularly, nuclear membrane protein CD81 assisted the nuclear transport of Rad51, a key protein involved in HRR process after irradiation. Overall, CD81 may be utility as a predictive biomarker and therapeutic target of radioresistant GBM. Abstract Glioblastoma (GBM) is the most common type of primary tumor in central nervous system in adult with a 5-year survival rate of ≤5%. Despite of recent advances in tumor radiotherapy, the prognosis of GBM remains to be dismal due to radioresistance. In this study, we identified CD81 as a potential biomarker of GBM radioresistance with the analysis of upregulated genes in human glioma radioresistant cell lines U251R and T98G in comparison with U251 cells. In vitro and in vivo experiments demonstrated that suppressing CD81 by siRNA/shRNA enhanced radiation-induced cell killing and DNA damage of γ-H2AX formation, and delayed tumor xenograft growth of GBM. Mechanistically, we found that knockdown of CD81 significantly decreased radiation-induced expression of nuclear Rad51, a key protein involved in homologous recombination repair (HRR) of DNA, suggesting that CD81 is essential for DNA damage response. Meanwhile, when the cells were treated with B02, a Rad51 inhibitor, silencing CD81 would not sensitize GBM cells to radiation, which further illustrates that Rad51 acts as an effector protein of CD81 in tumor radioresistance. Dual immunofluorescence staining of CD81 and Rad51 illustrated that nuclear membrane CD81 contributed to the nuclear transport of Rad51 after irradiation. In conclusion, we demonstrated for the first time that CD81 not only played a vital role in DNA repair through regulating Rad51 nuclear transport, but also might serve as a potential target of GBM radiotherapy.
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Rogers JL, Vera E, Acquaye A, Briceno N, Jammula V, King AL, Leeper H, Quezado MM, Gonzalez Alarcon J, Boris L, Burton E, Celiku O, Choi A, Christ A, Crandon S, Grajkowska E, Leggiero N, Lollo N, Penas-Prado M, Reyes J, Siegel C, Theeler BJ, Timmer M, Wall K, Wu J, Aldape K, Gilbert MR, Armstrong TS. Living with a central nervous system (CNS) tumor: findings on long-term survivorship from the NIH Natural History Study. Neurooncol Pract 2021; 8:460-474. [PMID: 34277024 DOI: 10.1093/nop/npab022] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Background Primary central nervous system (CNS) tumors are often associated with high symptom burden and a poor prognosis from the time of diagnosis. The purpose of this study is to describe patient-reported outcomes (PRO) data from long-term survivors (LTS; ≥5-year survival post-diagnosis). Methods Clinical/treatment/molecular characteristics and PROs (symptom burden/interference (MDASI-BT/SP), perceived cognition (Neuro-QoL), anxiety/depression (PROMIS), and general health status (EQ-5D-3L)) were collected on 248 adult LTS between 9/2016 and 8/2019. Descriptive statistics and regression analysis were used to report results. Results Participants had a median age of 47 years (19-82) and were primarily White (83%) males (51%) with high-grade tumors (59%) and few mutations. Forty-two percent of the 222 brain tumor LTS reported no moderate-to-severe symptoms, whereas 45% reported three or more; most common symptoms were fatigue (40%), difficulty remembering (29%), and drowsiness (28%). Among spine tumor LTS (n = 42), nearly half reported moderate-to-severe weakness, pain, fatigue, and numbness/tingling, with 72% experiencing activity-related interference. Severe anxiety, depression, and cognitive symptoms were reported in up to 23% of the sample. Brain tumor LTS at higher risk for severe symptoms were more likely to be young, unemployed, and have poor KPS (Karnofsky Performance Status), whereas high symptom-risk spinal cord tumor LTS had poor KPS and received any tumor treatment. Conclusions Findings indicate LTS fall into distinct cohorts with no significant symptoms or very high symptom burden, regardless of tumor grade or mutational profile. These LTS data demonstrate the need for survivorship care programs and future studies to explore the symptom trajectory of all CNS tumor patients for prevention and early interventions.
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Affiliation(s)
- James L Rogers
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Elizabeth Vera
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Alvina Acquaye
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Nicole Briceno
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Varna Jammula
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Amanda L King
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Heather Leeper
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Martha M Quezado
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Javier Gonzalez Alarcon
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Lisa Boris
- Leidos Biomedical Research, Frederick National Laboratory for Cancer Research Sponsored by the National Cancer Institute, Frederick, Maryland, USA
| | - Eric Burton
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Orieta Celiku
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Anna Choi
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Alexa Christ
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Sonja Crandon
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Ewa Grajkowska
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | | | - Nicole Lollo
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Marta Penas-Prado
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Jennifer Reyes
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Christine Siegel
- Leidos Biomedical Research, Frederick National Laboratory for Cancer Research Sponsored by the National Cancer Institute, Frederick, Maryland, USA
| | - Brett J Theeler
- Department of Neurology, Walter Reed National Military Medical Center, Bethesda, Maryland, USA
| | - Michael Timmer
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Kathleen Wall
- Leidos Biomedical Research, Frederick National Laboratory for Cancer Research Sponsored by the National Cancer Institute, Frederick, Maryland, USA
| | - Jing Wu
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Kenneth Aldape
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Mark R Gilbert
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Terri S Armstrong
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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Janjua TI, Rewatkar P, Ahmed-Cox A, Saeed I, Mansfeld FM, Kulshreshtha R, Kumeria T, Ziegler DS, Kavallaris M, Mazzieri R, Popat A. Frontiers in the treatment of glioblastoma: Past, present and emerging. Adv Drug Deliv Rev 2021; 171:108-138. [PMID: 33486006 DOI: 10.1016/j.addr.2021.01.012] [Citation(s) in RCA: 142] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 12/13/2020] [Accepted: 01/09/2021] [Indexed: 12/13/2022]
Abstract
Glioblastoma (GBM) is one of the most aggressive cancers of the brain. Despite extensive research over the last several decades, the survival rates for GBM have not improved and prognosis remains poor. To date, only a few therapies are approved for the treatment of GBM with the main reasons being: 1) significant tumour heterogeneity which promotes the selection of resistant subpopulations 2) GBM induced immunosuppression and 3) fortified location of the tumour in the brain which hinders the delivery of therapeutics. Existing therapies for GBM such as radiotherapy, surgery and chemotherapy have been unable to reach the clinical efficacy necessary to prolong patient survival more than a few months. This comprehensive review evaluates the current and emerging therapies including those in clinical trials that may potentially improve both targeted delivery of therapeutics directly to the tumour site and the development of agents that may specifically target GBM. Particular focus has also been given to emerging delivery technologies such as focused ultrasound, cellular delivery systems nanomedicines and immunotherapy. Finally, we discuss the importance of developing novel materials for improved delivery efficacy of nanoparticles and therapeutics to reduce the suffering of GBM patients.
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Lv F, Du Q, Li L, Xi X, Liu Q, Li W, Liu S. Eriodictyol inhibits glioblastoma migration and invasion by reversing EMT via downregulation of the P38 MAPK/GSK-3β/ZEB1 pathway. Eur J Pharmacol 2021; 900:174069. [PMID: 33811837 DOI: 10.1016/j.ejphar.2021.174069] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 03/25/2021] [Accepted: 03/26/2021] [Indexed: 12/12/2022]
Abstract
Eriodictyol (ERD) is a natural flavonoid that exists in many vegetables and fruits, especially citrus fruits. It has been proven to have many pharmacological effects, such as antioxidative, anti-inflammatory and neuroprotective effects. Our previous study showed that eriodictyol could inhibit the proliferation and induce the apoptosis of glioblastoma cells by downregulating the PI3K/Akt/NF-κB pathway and restraining its migration and invasion. However, the mechanism by which eriodictyol prevents glioblastoma metastasis is still unknown. Epithelial-mesenchymal transition (EMT) is a key process for many cancer metastases; it also confers locomotivity to tumor cells, including glioblastoma. In this study, we found that eriodictyol can suppress the migration and invasion of glioblastoma A172 and U87 MG cell lines by suppressing the EMT markers - N-cadherin and E-cadherin through Wound healing and Transwell assays, Western blot, RT-qPCR, immunofluorescence and immunohistochemistry. Further research revealed that the mechanism could be connected with downregulation of the P38 MAPK/GSK-3β/ZEB1 signaling pathway. These findings can provide a new idea for the treatment of glioblastoma.
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Affiliation(s)
- Feng Lv
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University (Gener Hospital), Chongqing, 401120, PR China
| | - Qian Du
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University (Gener Hospital), Chongqing, 401120, PR China
| | - Lin Li
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University (Gener Hospital), Chongqing, 401120, PR China
| | - Xin Xi
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University (Gener Hospital), Chongqing, 401120, PR China
| | - Qinglong Liu
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University (Gener Hospital), Chongqing, 401120, PR China
| | - Wenjun Li
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University (Gener Hospital), Chongqing, 401120, PR China.
| | - Songqing Liu
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University (Gener Hospital), Chongqing, 401120, PR China.
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40
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Estimating Glioblastoma Biophysical Growth Parameters Using Deep Learning Regression. BRAINLESION : GLIOMA, MULTIPLE SCLEROSIS, STROKE AND TRAUMATIC BRAIN INJURIES. BRAINLES (WORKSHOP) 2021; 12658:157-167. [PMID: 34514469 DOI: 10.1007/978-3-030-72084-1_15] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Glioblastoma ( GBM ) is arguably the most aggressive, infiltrative, and heterogeneous type of adult brain tumor. Biophysical modeling of GBM growth has contributed to more informed clinical decision-making. However, deploying a biophysical model to a clinical environment is challenging since underlying computations are quite expensive and can take several hours using existing technologies. Here we present a scheme to accelerate the computation. In particular, we present a deep learning ( DL )-based logistic regression model to estimate the GBM's biophysical growth in seconds. This growth is defined by three tumor-specific parameters: 1) a diffusion coefficient in white matter ( Dw ), which prescribes the rate of infiltration of tumor cells in white matter, 2) a mass-effect parameter ( Mp ), which defines the average tumor expansion, and 3) the estimated time ( T ) in number of days that the tumor has been growing. Preoperative structural multi-parametric MRI ( mpMRI ) scans from n = 135 subjects of the TCGA-GBM imaging collection are used to quantitatively evaluate our approach. We consider the mpMRI intensities within the region defined by the abnormal FLAIR signal envelope for training one DL model for each of the tumor-specific growth parameters. We train and validate the DL-based predictions against parameters derived from biophysical inversion models. The average Pearson correlation coefficients between our DL-based estimations and the biophysical parameters are 0.85 for Dw, 0.90 for Mp, and 0.94 for T, respectively. This study unlocks the power of tumor-specific parameters from biophysical tumor growth estimation. It paves the way towards their clinical translation and opens the door for leveraging advanced radiomic descriptors in future studies by means of a significantly faster parameter reconstruction compared to biophysical growth modeling approaches.
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41
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Crake RLI, Burgess ER, Royds JA, Phillips E, Vissers MCM, Dachs GU. The Role of 2-Oxoglutarate Dependent Dioxygenases in Gliomas and Glioblastomas: A Review of Epigenetic Reprogramming and Hypoxic Response. Front Oncol 2021; 11:619300. [PMID: 33842321 PMCID: PMC8027507 DOI: 10.3389/fonc.2021.619300] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 01/25/2021] [Indexed: 12/30/2022] Open
Abstract
Gliomas are a heterogeneous group of cancers that predominantly arise from glial cells in the brain, but may also arise from neural stem cells, encompassing low-grade glioma and high-grade glioblastoma. Whereas better diagnosis and new treatments have improved patient survival for many cancers, glioblastomas remain challenging with a highly unfavorable prognosis. This review discusses a super-family of enzymes, the 2-oxoglutarate dependent dioxygenase enzymes (2-OGDD) that control numerous processes including epigenetic modifications and oxygen sensing, and considers their many roles in the pathology of gliomas. We specifically describe in more detail the DNA and histone demethylases, and the hypoxia-inducible factor hydroxylases in the context of glioma, and discuss the substrate and cofactor requirements of the 2-OGDD enzymes. Better understanding of how these enzymes contribute to gliomas could lead to the development of new treatment strategies.
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Affiliation(s)
- Rebekah L. I. Crake
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
| | - Eleanor R. Burgess
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
| | - Janice A. Royds
- Department of Pathology, University of Otago, Dunedin, New Zealand
| | - Elisabeth Phillips
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
| | - Margreet C. M. Vissers
- Centre for Free Radical Research, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
| | - Gabi U. Dachs
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
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42
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Yekula A, Taylor A, Beecroft A, Kang KM, Small JL, Muralidharan K, Rosh Z, Carter BS, Balaj L. The role of extracellular vesicles in acquisition of resistance to therapy in glioblastomas. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2021; 4:1-16. [PMID: 35582008 PMCID: PMC9019190 DOI: 10.20517/cdr.2020.61] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 10/05/2020] [Accepted: 10/21/2020] [Indexed: 12/26/2022]
Abstract
Glioblastoma (GBM) is the most aggressive primary brain tumor with a median survival of 15 months despite standard care therapy consisting of maximal surgical debulking, followed by radiation therapy with concurrent and adjuvant temozolomide treatment. The natural history of GBM is characterized by inevitable recurrence with patients dying from increasingly resistant tumor regrowth after therapy. Several mechanisms including inter- and intratumoral heterogeneity, the evolution of therapy-resistant clonal subpopulations, reacquisition of stemness in glioblastoma stem cells, multiple drug efflux mechanisms, the tumor-promoting microenvironment, metabolic adaptations, and enhanced repair of drug-induced DNA damage have been implicated in therapy failure. Extracellular vesicles (EVs) have emerged as crucial mediators in the maintenance and establishment of GBM. Multiple seminal studies have uncovered the multi-dynamic role of EVs in the acquisition of drug resistance. Mechanisms include EV-mediated cargo transfer and EVs functioning as drug efflux channels and decoys for antibody-based therapies. In this review, we discuss the various mechanisms of therapy resistance in GBM, highlighting the emerging role of EV-orchestrated drug resistance. Understanding the landscape of GBM resistance is critical in devising novel therapeutic approaches to fight this deadly disease.
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Affiliation(s)
- Anudeep Yekula
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, USA
| | | | | | - Keiko M. Kang
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Julia L. Small
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Koushik Muralidharan
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Zachary Rosh
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Bob S. Carter
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Leonora Balaj
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, USA
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Yao J, Wang Z, Cheng Y, Ma C, Zhong Y, Xiao Y, Gao X, Li Z. M2 macrophage-derived exosomal microRNAs inhibit cell migration and invasion in gliomas through PI3K/AKT/mTOR signaling pathway. J Transl Med 2021; 19:99. [PMID: 33676540 PMCID: PMC7937290 DOI: 10.1186/s12967-021-02766-w] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 02/22/2021] [Indexed: 12/14/2022] Open
Abstract
Background Glioma, the most common primary brain tumor, account Preparing figures for 30 to 40% of all intracranial tumors. Herein, we aimed to study the effects of M2 macrophage-derived exosomal microRNAs (miRNAs) on glioma cells. Methods First, we identified seven differentially expressed miRNAs in infiltrating macrophages and detected the expression of these seven miRNAs in M2 macrophages. We then selected hsa-miR-15a-5p (miR-15a) and hsa-miR-92a-3p (miR-92a) for follow-up studies, and confirmed that miR-15a and miR-92a were under-expressed in M2 macrophage exosomes. Subsequently, we demonstrated that M2 macrophage-derived exosomes promoted migration and invasion of glioma cells, while exosomal miR-15a and miR-92a had the opposite effects on glioma cells. Next, we performed the target gene prediction in four databases and conducted target gene validation by qRT-PCR, western blot and dual luciferase reporter gene assays. Results The results revealed that miR-15a and miR-92a were bound to CCND1 and RAP1B, respectively. Western blot assays demonstrated that interference with the expression of CCND1 or RAP1B reduced the phosphorylation level of AKT and mTOR, indicating that both CCND1 and RAP1B can activate the PI3K/AKT/mTOR signaling pathway. Conclusion Collectively, these findings indicate that M2 macrophage-derived exosomal miR-15a and miR-92a inhibit cell migration and invasion of glioma cells through PI3K/AKT/mTOR signaling pathway. Supplementary information The online version contains supplementary material available at 10.1186/s12967-021-02766-w.
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Affiliation(s)
- Jie Yao
- Human Genetic Resources Conservation Center of Hubei Province, Wuhan, 430071, China.,Tumor Precision Diagnosis and Treatment Technology and Translation Medicine, Hubei Engineering Research Center, Wuhan, 430071, China
| | - Zefen Wang
- Department of Physiology, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, China
| | - Yong Cheng
- Department of Neurology, Hankou Hospital, General Hospital of Central Theater Command of Chinese People's Liberation Army, Wuhan, 430014, China
| | - Chao Ma
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, No 169 Donghu Road, Wuhan, 430071, Hubei, China
| | - Yahua Zhong
- Department of Oncology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Yilei Xiao
- Department of Neurosurgery, Liaocheng People's Hospital, Liaocheng, 252000, China
| | - Xu Gao
- Department of Neurosurgery, General Hospital of Northern Theater Command of People's Liberation Army, Shenyang, 110000, China
| | - Zhiqiang Li
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, No 169 Donghu Road, Wuhan, 430071, Hubei, China.
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Giammalva GR, Brunasso L, Costanzo R, Paolini F, Umana GE, Scalia G, Gagliardo C, Gerardi RM, Basile L, Graziano F, Gulì C, Messina D, Pino MA, Feraco P, Tumbiolo S, Midiri M, Iacopino DG, Maugeri R. Brain Mapping-Aided SupraTotal Resection (SpTR) of Brain Tumors: The Role of Brain Connectivity. Front Oncol 2021; 11:645854. [PMID: 33738262 PMCID: PMC7960910 DOI: 10.3389/fonc.2021.645854] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 01/18/2021] [Indexed: 11/13/2022] Open
Abstract
Brain gliomas require a deep knowledge of their effects on brain connectivity. Understanding the complex relationship between tumor and functional brain is the preliminary and fundamental step for the subsequent surgery. The extent of resection (EOR) is an independent variable of surgical effectiveness and it correlates with the overall survival. Until now, great efforts have been made to achieve gross total resection (GTR) as the standard of care of brain tumor patients. However, high and low-grade gliomas have an infiltrative behavior and peritumoral white matter is often infiltrated by tumoral cells. According to these evidences, many efforts have been made to push the boundary of the resection beyond the contrast-enhanced lesion core on T1w MRI, in the so called supratotal resection (SpTR). SpTR is aimed to maximize the extent of resection and thus the overall survival. SpTR of primary brain tumors is a feasible technique and its safety is improved by intraoperative neuromonitoring and advanced neuroimaging. Only transient cognitive impairments have been reported in SpTR patients compared to GTR patients. Moreover, SpTR is related to a longer overall and progression-free survival along with preserving neuro-cognitive functions and quality of life.
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Affiliation(s)
- Giuseppe Roberto Giammalva
- Unit of Neurosurgery, Department of Biomedicine, Neuroscience and Advanced Diagnostics, Post Graduate Residency Program in Neurosurgery, University of Palermo, Palermo, Italy
| | - Lara Brunasso
- Unit of Neurosurgery, Department of Biomedicine, Neuroscience and Advanced Diagnostics, Post Graduate Residency Program in Neurosurgery, University of Palermo, Palermo, Italy
| | - Roberta Costanzo
- Unit of Neurosurgery, Department of Biomedicine, Neuroscience and Advanced Diagnostics, Post Graduate Residency Program in Neurosurgery, University of Palermo, Palermo, Italy
| | - Federica Paolini
- Unit of Neurosurgery, Department of Biomedicine, Neuroscience and Advanced Diagnostics, Post Graduate Residency Program in Neurosurgery, University of Palermo, Palermo, Italy
| | | | | | - Cesare Gagliardo
- Section of Radiological Sciences, Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Rosa Maria Gerardi
- Unit of Neurosurgery, Department of Biomedicine, Neuroscience and Advanced Diagnostics, Post Graduate Residency Program in Neurosurgery, University of Palermo, Palermo, Italy
| | - Luigi Basile
- Unit of Neurosurgery, Department of Biomedicine, Neuroscience and Advanced Diagnostics, Post Graduate Residency Program in Neurosurgery, University of Palermo, Palermo, Italy
| | | | - Carlo Gulì
- Unit of Neurosurgery, Department of Biomedicine, Neuroscience and Advanced Diagnostics, Post Graduate Residency Program in Neurosurgery, University of Palermo, Palermo, Italy
| | - Domenico Messina
- Unit of Neurosurgery, Department of Biomedicine, Neuroscience and Advanced Diagnostics, Post Graduate Residency Program in Neurosurgery, University of Palermo, Palermo, Italy
| | - Maria Angela Pino
- Unit of Neurosurgery, Department of Biomedicine, Neuroscience and Advanced Diagnostics, Post Graduate Residency Program in Neurosurgery, University of Palermo, Palermo, Italy
| | - Paola Feraco
- Neuroradiology Unit, S. Chiara Hospital, Trento, Italy
| | - Silvana Tumbiolo
- Department of Neurosurgery, Villa Sofia Hospital, Palermo, Italy
| | - Massimo Midiri
- Unit of Neurosurgery, Department of Biomedicine, Neuroscience and Advanced Diagnostics, Post Graduate Residency Program in Neurosurgery, University of Palermo, Palermo, Italy
| | - Domenico Gerardo Iacopino
- Unit of Neurosurgery, Department of Biomedicine, Neuroscience and Advanced Diagnostics, Post Graduate Residency Program in Neurosurgery, University of Palermo, Palermo, Italy
| | - Rosario Maugeri
- Unit of Neurosurgery, Department of Biomedicine, Neuroscience and Advanced Diagnostics, Post Graduate Residency Program in Neurosurgery, University of Palermo, Palermo, Italy
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Sacko O, Benouaich-Amiel A, Brandicourt P, Niaré M, Charni S, Cavandoli C, Brauge D, Catalaa I, Brenner A, Moyal ECJ, Roux FE. The Impact of Surgery on the Survival of Patients with Recurrent Glioblastoma. Asian J Neurosurg 2021; 16:1-7. [PMID: 34211860 PMCID: PMC8202372 DOI: 10.4103/ajns.ajns_180_20] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/06/2020] [Accepted: 09/16/2020] [Indexed: 11/24/2022] Open
Abstract
Objective: The purpose of this study was to investigate the possible benefit of repeat surgery on overall survival for patients with recurrent glioblastoma multiforme (GBM). Methods: We performed a retrospective analysis of data from patients who presented with recurrent GBM over a 5-year period (n = 157), comparing baseline characteristics and survival for patients who had at least 1 new tumor resection followed by chemotherapy (reoperation group, n = 59) and those who received medical treatment only (no-reoperation group, n = 98) for recurrence. Results: The baseline characteristics of the two groups differed in terms of WHO performance status (better in the reoperation group), mean age (60 years in the reoperation group vs. 65 years in the no-reoperation group), mean interval to recurrence (3 months later in the reoperation group than in the no-reoperation group) and more gross total resections in the reoperation group. Nevertheless, the patients in the reoperation group had a higher rate [32.8%] of sensorimotor deficits than those of the no-reoperation group [14.2]. There was no significant difference in sex; tumor localization, side, or extent; MGMT status; MIB-1 labeling index; or Karnofsky Performance Status [KPS] score. After adjustment for age, the WHO performance status, interval of recurrence, and extent of resection at the first operation, multivariate analysis showed that median survival was significantly better in the reoperation group than in the no-reoperation group (22.9 vs. 14.61 months, P < 0.05). After a total of 69 repeat operations in 59 patients (10 had 2 repeat surgeries), we noted 13 temporary and 20 permanent adverse postoperative events, yielding a permanent complication rate of 28.99% (20/69). There was also a statistically significant (P = 0.029, Student's t-test) decrease in the mean KPS score after reoperation (mean preoperative KPS score of 89.34 vs. mean postoperative score of 84.91). Conclusion: Our retrospective study suggests that repeat surgery may be beneficial for patients with GBM recurrence who have good functional status (WHO performance status 0 and 1), although the potential benefits must be weighed against the risk of permanent complications, which occurred in almost 30% of the patients who underwent repeat resection in this series.
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Affiliation(s)
- Oumar Sacko
- Pôle Neurosciences, Neurochirurgie, PPR, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France.,Université Paul-Sabatier, Toulouse, France
| | - Alexandra Benouaich-Amiel
- Pôle Neurosciences, Neurochirurgie, PPR, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France.,Université Paul-Sabatier, Toulouse, France
| | - Pierre Brandicourt
- Pôle Neurosciences, Neurochirurgie, PPR, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France.,Université Paul-Sabatier, Toulouse, France
| | - Mahamadou Niaré
- Pôle Neurosciences, Neurochirurgie, PPR, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France.,Université Paul-Sabatier, Toulouse, France.,CNRS (Centre Recherche et Cognition), Toulouse, France
| | - Saloua Charni
- Pôle Neurosciences, Neurochirurgie, PPR, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France.,Université Paul-Sabatier, Toulouse, France.,CNRS (Centre Recherche et Cognition), Toulouse, France
| | - Clarissa Cavandoli
- Pôle Neurosciences, Neurochirurgie, PPR, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France.,Université Paul-Sabatier, Toulouse, France
| | - David Brauge
- Pôle Neurosciences, Neurochirurgie, PPR, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France.,Université Paul-Sabatier, Toulouse, France
| | - Isabelle Catalaa
- Neuroradiologie, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France.,Université Paul-Sabatier, Toulouse, France
| | - Adam Brenner
- Western University of Health Sciences, Pomona, USA
| | | | - Franck-Emmanuel Roux
- Pôle Neurosciences, Neurochirurgie, PPR, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France.,Université Paul-Sabatier, Toulouse, France.,CNRS (Centre Recherche et Cognition), Toulouse, France
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Oronsky B, Reid TR, Oronsky A, Sandhu N, Knox SJ. A Review of Newly Diagnosed Glioblastoma. Front Oncol 2021; 10:574012. [PMID: 33614476 PMCID: PMC7892469 DOI: 10.3389/fonc.2020.574012] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 09/28/2020] [Indexed: 12/19/2022] Open
Abstract
Glioblastoma is an aggressive and inevitably recurrent primary intra-axial brain tumor with a dismal prognosis. The current mainstay of treatment involves maximally safe surgical resection followed by radiotherapy over a 6-week period with concomitant temozolomide chemotherapy followed by temozolomide maintenance. This review provides a summary of the epidemiological, clinical, histologic and genetic characteristics of newly diagnosed disease as well as the current standard of care and potential future therapeutic prospects.
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Affiliation(s)
- Bryan Oronsky
- Department of Clinical Research, EpicentRx, San Diego, CA, United States
| | - Tony R. Reid
- Department of Medical Oncology, UC San Diego School of Medicine, San Diego, CA, United States
| | - Arnold Oronsky
- Department of Clinical Research, InterWest Partners, Menlo Park, CA, United States
| | - Navjot Sandhu
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, United States
| | - Susan J. Knox
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, United States
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Stadlbauer A, Kinfe TM, Eyüpoglu I, Zimmermann M, Kitzwögerer M, Podar K, Buchfelder M, Heinz G, Oberndorfer S, Marhold F. Tissue Hypoxia and Alterations in Microvascular Architecture Predict Glioblastoma Recurrence in Humans. Clin Cancer Res 2020; 27:1641-1649. [PMID: 33293375 DOI: 10.1158/1078-0432.ccr-20-3580] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 11/03/2020] [Accepted: 12/04/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE Insufficient control of infiltrative glioblastoma (GBM) cells is a major cause of treatment failure and tumor recurrence. Hence, detailed insights into pathophysiologic changes that precede GBM recurrence are needed to develop more precise neuroimaging modalities for tailored diagnostic monitoring and therapeutic approaches. EXPERIMENTAL DESIGN Overall, 168 physiologic MRI follow-up examinations of 56 patients with GBM who developed recurrence after standard therapy were retrospectively evaluated, that is, two post-standard-therapeutic follow-ups before and one at radiological recurrence. MRI biomarkers for microvascular architecture and perfusion, neovascularization activity, oxygen metabolism, and hypoxia were determined for brain areas that developed in the further course into recurrence and for the recurrent GBM itself. The temporal pattern of biomarker changes was fitted with locally estimated scatterplot smoothing functions and analyzed for pathophysiologic changes preceding radiological GBM recurrence. RESULTS Our MRI approach demonstrated early pathophysiologic changes prior to radiological GBM recurrence in all patients. Analysis of the time courses revealed a model for the pathophysiology of GBM recurrence: 190 days prior to radiological recurrence, vascular cooption by GBM cells induced vessel regression, detected as decreasing vessel density/perfusion and increasing hypoxia. Seventy days later, neovascularization activity was upregulated, which reincreased vessel density and perfusion. Hypoxia, however, continued to intensify for 30 days and peaked 90 days before radiological recurrence. CONCLUSIONS Hypoxia may represent an early sign for GBM recurrence. This might become useful in the development of new combined diagnostic-therapeutic approaches for tailored clinical management of recurrent GBM. Further preclinical and in-human studies are required for validation and evaluation.
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Affiliation(s)
- Andreas Stadlbauer
- Department of Neurosurgery, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany.
- Institute of Medical Radiology, University Clinic St. Pölten, Karl Landsteiner University of Health Sciences, St. Pölten, Austria
| | - Thomas M Kinfe
- Department of Neurosurgery, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany
- Division of Functional Neurosurgery and Stereotaxy, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Ilker Eyüpoglu
- Department of Neurosurgery, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Max Zimmermann
- Department of Neurosurgery, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany
- Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, Tübingen, Germany
| | - Melitta Kitzwögerer
- Department of Pathology, University Clinic of St. Pölten, St. Pölten, Austria
| | - Klaus Podar
- Department of Internal Medicine 2, University Hospital Krems, Karl Landsteiner University of Health Sciences, Krems, Austria
| | - Michael Buchfelder
- Department of Neurosurgery, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Gertraud Heinz
- Institute of Medical Radiology, University Clinic St. Pölten, Karl Landsteiner University of Health Sciences, St. Pölten, Austria
| | - Stefan Oberndorfer
- Department of Neurology, University Clinic of St. Pölten, Karl Landsteiner University of Health Sciences, St. Pölten, Austria
| | - Franz Marhold
- Department of Neurosurgery, University Clinic of St. Pölten, Karl Landsteiner University of Health Sciences, St. Pölten, Austria
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Zhang J, Deng M, Tong H, Xue W, Guo Y, Wang J, Chen L, Wang S. A novel miR-7156-3p-HOXD13 axis modulates glioma progression by regulating tumor cell stemness. Int J Biol Sci 2020; 16:3200-3209. [PMID: 33162825 PMCID: PMC7645993 DOI: 10.7150/ijbs.51293] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 10/03/2020] [Indexed: 12/28/2022] Open
Abstract
Malignant glioma is the most common brain tumor in adults. Despite the great advances in anti-glioma treatments which have led to significant improvement in clinical outcomes, tumor recurrence remains the major cause of mortality. Increased cancer cell stemness and invasiveness are correlated with glioma progression. By searching the Cancer Genome Atlas, we showed that the expression of miR-7156-3p is significantly decreased in glioma tissues compared to the normal brain, and the decreased level of miR-7156-3p is closely correlated with glioma grade and patient survival. Clinical study consistently confirmed that miR-7156-3p is negatively correlated with glioma grade. Cell culture and animal experiments revealed that inhibition of miR-7156-3p effectively stimulates glioma cell stemness, invasion, and growth. In contrast, the augmentation of miR-7156-3p inhibits these phenotypes. Using Next-generation sequencing combined with target prediction approach, Homeobox D13 (HOXD13) is identified as the target gene of miR-7156-3p and further validated by luciferase reporter assay and cell transfection experiments. Additional in vitro and animal experiments demonstrated that miR-7156-3p regulates glioma cell stemness, invasion, and growth by mediating HOXD13. In conclusion, our findings provide new insight into the regulation of glioma stemness and invasiveness and may propose a potential strategy for anti-glioma treatment. Moreover, miR-7156-3p may serve as a candidate biomarker for predicting glioma progression in clinical practice.
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Affiliation(s)
- Junfeng Zhang
- Department of Radiology, Daping Hospital, Army Medical University, Chongqing 400042, China.,Chongqing Clinical Research Center of Imaging and Nuclear Medicine, Chongqing 400042, China
| | - Mengsheng Deng
- State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Haipeng Tong
- Department of Radiology, Daping Hospital, Army Medical University, Chongqing 400042, China.,Chongqing Clinical Research Center of Imaging and Nuclear Medicine, Chongqing 400042, China
| | - Wei Xue
- Department of Radiology, Daping Hospital, Army Medical University, Chongqing 400042, China.,Chongqing Clinical Research Center of Imaging and Nuclear Medicine, Chongqing 400042, China
| | - Yu Guo
- Department of Radiology, Daping Hospital, Army Medical University, Chongqing 400042, China.,Chongqing Clinical Research Center of Imaging and Nuclear Medicine, Chongqing 400042, China
| | - Jianmin Wang
- State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Lizhao Chen
- Department of Neurosurgery, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Shunan Wang
- Department of Radiology, Daping Hospital, Army Medical University, Chongqing 400042, China.,Chongqing Clinical Research Center of Imaging and Nuclear Medicine, Chongqing 400042, China
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Kraboth Z, Kalman B. Longitudinal Characteristics of Glioblastoma in Genome-Wide Studies. Pathol Oncol Res 2020; 26:2035-2047. [PMID: 31376079 PMCID: PMC7471193 DOI: 10.1007/s12253-019-00705-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 07/25/2019] [Indexed: 01/20/2023]
Abstract
Glioblastoma is one of the deadliest tumors with barely over one-year median survival despite intensive efforts in defining its molecular characteristics and searching for innovative treatment strategies. While major progress has been made in cataloging cross-sectional genomic, transcriptomic and epigenomic features of the tumor, and inferring its main molecular pathways and niches for potential targeted intervention, we still do not have sufficient knowledge concerning evolutionary patterns and dynamics of molecular changes or the treatment-induced effects affecting glioblastoma biology. In this review, we summarize the results of recent longitudinal genomic, transcriptomic and epigenomic studies that brought us closer to a better understanding of this lethal disease. Evidence suggests that neuronal / glioma stem cells with accumulating mutations initiate glioblastoma development and recurrence, but the hypothetical models describing the courses that lead to established tumors have not been fully proven. Moving from the histopathological phenotype to the results of high resolution OMICS studies, we try to synthesize the currently available information from sequential glioblastoma analyses in order to highlight its multifaceted features and heterogenetity, as well as the expected complexity of potential treatment strategies that might once succeed.
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Affiliation(s)
- Zoltan Kraboth
- Graduate School in Neurosciences, University of Pecs, 12. Szigeti street, Pecs, 7624, Hungary
- Institute of Laboratory Medicine, University of Pecs, 13. Ifjusag street, Pecs, 7624, Hungary
- Szentagothai Research Center, University of Pecs, 20. Ifjusag street, Pecs, 7624, Hungary
| | - Bernadette Kalman
- Graduate School in Neurosciences, University of Pecs, 12. Szigeti street, Pecs, 7624, Hungary.
- Institute of Laboratory Medicine, University of Pecs, 13. Ifjusag street, Pecs, 7624, Hungary.
- Szentagothai Research Center, University of Pecs, 20. Ifjusag street, Pecs, 7624, Hungary.
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Palpan Flores A, Vivancos Sanchez C, Roda JM, Cerdán S, Barrios AJ, Utrilla C, Royo A, Gandía González ML. Assessment of Pre-operative Measurements of Tumor Size by MRI Methods as Survival Predictors in Wild Type IDH Glioblastoma. Front Oncol 2020; 10:1662. [PMID: 32984040 PMCID: PMC7492614 DOI: 10.3389/fonc.2020.01662] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Accepted: 07/28/2020] [Indexed: 11/16/2022] Open
Abstract
Objective: We evaluate the performance of three MRI methods to determine non-invasively tumor size, as overall survival (OS) and Progression Free Survival (PFS) predictors, in a cohort of wild type, IDH negative, glioblastoma patients. Investigated protocols included bidimensional (2D) diameter measurements, and three-dimensional (3D) estimations by the ellipsoid or semi-automatic segmentation methods. Methods: We investigated OS in a cohort of 44 patients diagnosed with wild type IDH glioblastoma (58.2 ± 11.4 years, 1.9/1 male/female) treated with neurosurgical resection followed by adjuvant chemo and radiotherapy. Pre-operative MRI images were evaluated to determine tumor mass area and volume, gadolinium enhancement volume, necrosis volume, and FLAIR-T2 hyper-intensity area and volume. We implemented then multivariate Cox statistical analysis to select optimal predictors for OS and PFS. Results: Median OS was 16 months (1–42 months), ranging from 9 ± 2.4 months in patients over 65 years, to 18 ± 1.6 months in younger ones. Patients with tumors carrying O6-methylguanin-DNA-methyltransferase (MGMT) methylation survived 30 ± 5.2 vs. 13 ± 2.5 months in non-methylated. Our study evidenced high and positive correlations among the results of the three methods to determine tumor size. FLAIR-T2 hyper-intensity areas (2D) and volumes (3D) were also similar as determined by the three methods. Cox proportional hazards analysis with the 2D and 3D methods indicated that OS was associated to age ≥ 65 years (HR 2.70, 2.94, and 3.16), MGMT methylation (HR 2.98, 3.07, and 2.90), and FLAIR-T2 ≥ 2,000 mm2 or ≥60 cm3 (HR 4.16, 3.93, and 3.72), respectively. Other variables including necrosis, tumor mass, necrosis/tumor ratio, and FLAIR/tumor ratio were not significantly correlated with OS. Conclusion: Our results reveal a high correlation among measurements of tumor size performed with the three methods. Pre-operative FLAIR-T2 hyperintensity area and volumes provided, independently of the measurement method, the optimal neuroimaging features predicting OS in primary glioblastoma patients, followed by age ≥ 65 years and MGMT methylation.
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Affiliation(s)
| | | | - José M Roda
- Department of Neurosurgery, University Hospital La Paz, Madrid, Spain
| | - Sebastian Cerdán
- Institute of Biomedical Research "Alberto Sols" CSIC/UAM, Madrid, Spain
| | | | - Cristina Utrilla
- Department of Neuroradiology, University Hospital La Paz, Madrid, Spain
| | - Aranzazu Royo
- Department of Neuroradiology, University Hospital La Paz, Madrid, Spain
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