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1
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Garcia-Moure M, Laspidea V, Gupta S, Gillard AG, Khatua S, Parthasarathy A, He J, Lang FF, Fueyo J, Alonso MM, Gomez-Manzano C. The emerging field of viroimmunotherapy for pediatric brain tumors. Neuro Oncol 2024; 26:1981-1993. [PMID: 39148489 PMCID: PMC11534321 DOI: 10.1093/neuonc/noae160] [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: 05/05/2024] [Indexed: 08/17/2024] Open
Abstract
Pediatric brain tumors are the most common solid tumors in children. Even to date, with the advances in multimodality therapeutic management, survival outcomes remain dismal in some types of tumors, such as pediatric-type diffuse high-grade gliomas or central nervous system embryonal tumors. Failure to understand the complex molecular heterogeneity and the elusive tumor and microenvironment interplay continues to undermine therapeutic efficacy. Developing a strategy that would improve survival for these fatal tumors remains unmet in pediatric neuro-oncology. Oncolytic viruses (OVs) are emerging as a feasible, safe, and promising therapy for brain tumors. The new paradigm in virotherapy implies that the direct cytopathic effect is followed, under certain circumstances, by an antitumor immune response responsible for the partial or complete debulking of the tumor mass. OVs alone or combined with other therapeutic modalities have been primarily used in adult neuro-oncology. A surge in encouraging preclinical studies in pediatric brain tumor models recently led to the clinical translation of OVs with encouraging results in these tumors. In this review, we summarize the different virotherapy tested in preclinical and clinical studies in pediatric brain tumors, and we discuss the limitations and future avenues necessary to improve the response of these tumors to this type of therapy.
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Affiliation(s)
- Marc Garcia-Moure
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Virginia Laspidea
- Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain
| | - Sumit Gupta
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Andrew G Gillard
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Soumen Khatua
- Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Akhila Parthasarathy
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jiasen He
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Frederick F Lang
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Juan Fueyo
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Marta M Alonso
- Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain
- Program of Solid Tumors, Center for the Applied Medical Research, Pamplona, Spain
| | - Candelaria Gomez-Manzano
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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2
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Nazam N, Erwin MH, Julson JR, Quinn CH, Beierle AM, Bownes LV, Stewart JE, Kang KD, Butey S, Mroczek-Musulman E, Ohlmeyer M, Beierle EA. PP2A activation overcomes leptomeningeal dissemination in group 3 medulloblastoma. J Biol Chem 2024; 300:107892. [PMID: 39419284 DOI: 10.1016/j.jbc.2024.107892] [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: 03/27/2024] [Revised: 10/01/2024] [Accepted: 10/05/2024] [Indexed: 10/19/2024] Open
Abstract
Leptomeningeal dissemination (LMD) is the primary cause of treatment failure in children with group 3 medulloblastoma (MB). Building on our previous work on protein phosphatase 2A (PP2A) activation in MB, here we present preclinical and molecular data on the effects of two novel classes of PP2A activators on disease processes of LMD in group 3 MB. The PP2A activators used in this study are ATUX-6156 and ATUX-6954 (diarylmethylcycloamine sulfonylureas), and ATUX-1215 and ATUX-5800 (diarylmethyl-4-aminotetrahydropyran-sulfonamides). Treatment with these compounds led to suppression of the endogenous PP2A inhibitor, cancerous inhibitor of PP2A (CIP2A), enhanced phosphatase activity (10-60%), and reduced MB viability, migration, and invasion, prerequisites for MB cells to access the cerebrospinal fluid, affecting the initiation stage of LMD. PP2A activator treatment of MB cells led to apoptosis mediated via caspase 9/PARP signaling due to decreased phosphorylation of Bad, impeding the dispersal stage of LMD. Cell proliferation and LMD-driving cellular traits and molecules pertinent to the third stage, colonization, were also affected. Treatment with ATUX-1215 or ATUX-5800 prevented LMD in an intraventricular murine model of MB, possibly mediated by disruption of the CCL2-CCR2 axis by altered NF-kB phosphorylation via disrupted AKT signaling. The present investigation offers proof-of-principle data for PP2A-based reactivation therapy for Group 3 MB and provides the first indications that PP2A reactivation may challenge the current paradigm in targeting the 3-stage process of MB LMD. Further investigations of PP2A activators are warranted as these compounds may prove beneficial as therapeutics for MB.
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Affiliation(s)
- Nazia Nazam
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Michael H Erwin
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Janet R Julson
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Colin H Quinn
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Andee M Beierle
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Laura V Bownes
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Jerry E Stewart
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Kyung-Don Kang
- Division of Hematology Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Swatika Butey
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | | | | | - Elizabeth A Beierle
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA.
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3
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Vazaios K, Stavrakaki Ε, Vogelezang LB, Ju J, Waranecki P, Metselaar DS, Meel MH, Kemp V, van den Hoogen BG, Hoeben RC, Chiocca EA, Goins WF, Stubbs A, Li Y, Alonso MM, Calkoen FG, Hulleman E, van der Lugt J, Lamfers ML. The heterogeneous sensitivity of pediatric brain tumors to different oncolytic viruses is predicted by unique gene expression profiles. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200804. [PMID: 38694569 PMCID: PMC11060958 DOI: 10.1016/j.omton.2024.200804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 04/11/2024] [Indexed: 05/04/2024]
Abstract
Despite decades of research, the prognosis of high-grade pediatric brain tumors (PBTs) remains dismal; however, recent cases of favorable clinical responses were documented in clinical trials using oncolytic viruses (OVs). In the current study, we employed four different species of OVs: adenovirus Delta24-RGD, herpes simplex virus rQNestin34.5v1, reovirus R124, and the non-virulent Newcastle disease virus rNDV-F0-GFP against three entities of PBTs (high-grade gliomas, atypical teratoid/rhabdoid tumors, and ependymomas) to determine their in vitro efficacy. These four OVs were screened on 14 patient-derived PBT cell cultures and the degree of oncolysis was assessed using an ATP-based assay. Subsequently, the observed viral efficacies were correlated to whole transcriptome data and Gene Ontology analysis was performed. Although no significant tumor type-specific OV efficacy was observed, the analysis revealed the intrinsic biological processes that associated with OV efficacy. The predictive power of the identified expression profiles was further validated in vitro by screening additional PBTs. In summary, our results demonstrate OV susceptibility of multiple patient-derived PBT entities and the ability to predict in vitro responses to OVs using unique expression profiles. Such profiles may hold promise for future OV preselection with effective oncolytic potency in a specific tumor, therewith potentially improving OV responses.
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Affiliation(s)
- Konstantinos Vazaios
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands
- Department of Neurosurgery, Brain Tumor Center, Erasmus Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
- Center for Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
| | - Εftychia Stavrakaki
- Department of Neurosurgery, Brain Tumor Center, Erasmus Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
| | - Lisette B. Vogelezang
- Department of Neurosurgery, Brain Tumor Center, Erasmus Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
| | - Jie Ju
- Department of Pathology and Clinical Bioinformatics, Erasmus Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
| | - Piotr Waranecki
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands
| | - Dennis S. Metselaar
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands
| | - Michaël H. Meel
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands
- Department of Pediatrics, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands
| | - Vera Kemp
- Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, the Netherlands
| | | | - Rob C. Hoeben
- Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, the Netherlands
| | - E. Antonio Chiocca
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - William F. Goins
- Department of Microbiology & Molecular Genetics, University of Pittsburgh School of Medicine, 450 Technology Dr, Pittsburgh, PA 15219, USA
| | - Andrew Stubbs
- Department of Pathology and Clinical Bioinformatics, Erasmus Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
| | - Yunlei Li
- Department of Pathology and Clinical Bioinformatics, Erasmus Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
| | - Marta M. Alonso
- Program in Solid Tumors, Center for Applied Medical Research (CIMA), Avda. de Pío XII, 55, 31008 Pamplona, Spain
- Department of Pediatrics, Clínica Universidad de Navarra, Av. de Pío XII, 36, 31008 Pamplona, Spain
- Health Research Institute of Navarra (IDISNA), Av. de Pío XII, 36, 31008 Pamplona, Spain
| | - Friso G. Calkoen
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands
| | - Esther Hulleman
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands
| | - Jasper van der Lugt
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands
| | - Martine L.M. Lamfers
- Department of Neurosurgery, Brain Tumor Center, Erasmus Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
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4
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Yang H, Li M, Deng Y, Wen H, Luo M, Zhang W. Roles and interactions of tumor microenvironment components in medulloblastoma with implications for novel therapeutics. Genes Chromosomes Cancer 2024; 63:e23233. [PMID: 38607297 DOI: 10.1002/gcc.23233] [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: 03/08/2024] [Accepted: 03/16/2024] [Indexed: 04/13/2024] Open
Abstract
Medulloblastomas, the most common malignant pediatric brain tumors, can be classified into the wingless, sonic hedgehog (SHH), group 3, and group 4 subgroups. Among them, the SHH subgroup with the TP53 mutation and group 3 generally present with the worst patient outcomes due to their high rates of recurrence and metastasis. A novel and effective treatment for refractory medulloblastomas is urgently needed. To date, the tumor microenvironment (TME) has been shown to influence tumor growth, recurrence, and metastasis through immunosuppression, angiogenesis, and chronic inflammation. Treatments targeting TME components have emerged as promising approaches to the treatment of solid tumors. In this review, we summarize progress in research on medulloblastoma microenvironment components and their interactions. We also discuss challenges and future research directions for TME-targeting medulloblastoma therapy.
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Affiliation(s)
- Hanjie Yang
- Department of Pediatric Neurosurgery, Neurosurgery Center, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Min Li
- Department of Pediatric Neurosurgery, Neurosurgery Center, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yuhao Deng
- Department of Pediatric Neurosurgery, Neurosurgery Center, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Huantao Wen
- Department of Pediatric Neurosurgery, Neurosurgery Center, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Minjie Luo
- Department of Pediatric Neurosurgery, Neurosurgery Center, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Wangming Zhang
- Department of Pediatric Neurosurgery, Neurosurgery Center, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Zhujiang Hospital, Southern Medical University, Guangzhou, China
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Rechberger JS, Toll SA, Vanbilloen WJF, Daniels DJ, Khatua S. Exploring the Molecular Complexity of Medulloblastoma: Implications for Diagnosis and Treatment. Diagnostics (Basel) 2023; 13:2398. [PMID: 37510143 PMCID: PMC10378552 DOI: 10.3390/diagnostics13142398] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/07/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
Medulloblastoma is the most common malignant brain tumor in children. Over the last few decades, significant progress has been made in revealing the key molecular underpinnings of this disease, leading to the identification of distinct molecular subgroups with different clinical outcomes. In this review, we provide an update on the molecular landscape of medulloblastoma and treatment strategies. We discuss the four main molecular subgroups (WNT-activated, SHH-activated, and non-WNT/non-SHH groups 3 and 4), highlighting the key genetic alterations and signaling pathways associated with each entity. Furthermore, we explore the emerging role of epigenetic regulation in medulloblastoma and the mechanism of resistance to therapy. We also delve into the latest developments in targeted therapies and immunotherapies. Continuing collaborative efforts are needed to further unravel the complex molecular mechanisms and profile optimal treatment for this devastating disease.
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Affiliation(s)
- Julian S Rechberger
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Stephanie A Toll
- Department of Pediatrics, Division of Hematology/Oncology, Children's Hospital of Michigan, Detroit, MI 48201, USA
| | - Wouter J F Vanbilloen
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA
- Department of Neurology, Elisabeth-Tweesteden Hospital, 5022 Tilburg, The Netherlands
| | - David J Daniels
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Soumen Khatua
- Department of Pediatric Hematology/Oncology, Section of Neuro-Oncology, Mayo Clinic, Rochester, MN 55905, USA
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6
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Gross EG, Hamo MA, Estevez-Ordonez D, Laskay NMB, Atchley TJ, Johnston JM, Markert JM. Oncolytic virotherapies for pediatric tumors. Expert Opin Biol Ther 2023; 23:987-1003. [PMID: 37749907 PMCID: PMC11309584 DOI: 10.1080/14712598.2023.2245326] [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: 05/02/2023] [Accepted: 08/03/2023] [Indexed: 09/27/2023]
Abstract
INTRODUCTION Many pediatric patients with malignant tumors continue to suffer poor outcomes. The current standard of care includes maximum safe surgical resection followed by chemotherapy and radiation which may be associated with considerable long-term morbidity. The emergence of oncolytic virotherapy (OVT) may provide an alternative or adjuvant treatment for pediatric oncology patients. AREAS COVERED We reviewed seven virus types that have been investigated in past or ongoing pediatric tumor clinical trials: adenovirus (AdV-tk, Celyvir, DNX-2401, VCN-01, Ad-TD-nsIL-12), herpes simplex virus (G207, HSV-1716), vaccinia (JX-594), reovirus (pelareorep), poliovirus (PVSRIPO), measles virus (MV-NIS), and Senecavirus A (SVV-001). For each virus, we discuss the mechanism of tumor-specific replication and cytotoxicity as well as key findings of preclinical and clinical studies. EXPERT OPINION Substantial progress has been made in the past 10 years regarding the clinical use of OVT. From our review, OVT has favorable safety profiles compared to chemotherapy and radiation treatment. However, the antitumor effects of OVT remain variable depending on tumor type and viral agent used. Although the widespread adoption of OVT faces many challenges, we are optimistic that OVT will play an important role alongside standard chemotherapy and radiotherapy for the treatment of malignant pediatric solid tumors in the future.
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Affiliation(s)
- Evan G Gross
- Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Mohammad A Hamo
- Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | | | - Nicholas MB Laskay
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Travis J Atchley
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - James M Johnston
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
- Division of Pediatric Neurosurgery, Children’s of Alabama, Birmingham, AL, USA
| | - James M Markert
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
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7
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Kardani K, Sanchez Gil J, Rabkin SD. Oncolytic herpes simplex viruses for the treatment of glioma and targeting glioblastoma stem-like cells. Front Cell Infect Microbiol 2023; 13:1206111. [PMID: 37325516 PMCID: PMC10264819 DOI: 10.3389/fcimb.2023.1206111] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 05/15/2023] [Indexed: 06/17/2023] Open
Abstract
Glioblastoma (GBM) is one of the most lethal cancers, having a poor prognosis and a median survival of only about 15 months with standard treatment (surgery, radiation, and chemotherapy), which has not been significantly extended in decades. GBM demonstrates remarkable cellular heterogeneity, with glioblastoma stem-like cells (GSCs) at the apex. GSCs are a subpopulation of GBM cells that possess the ability to self-renew, differentiate, initiate tumor formation, and manipulate the tumor microenvironment (TME). GSCs are no longer considered a static population of cells with specific markers but are quite flexible phenotypically and in driving tumor heterogeneity and therapeutic resistance. In light of these features, they are a critical target for successful GBM therapy. Oncolytic viruses, in particular oncolytic herpes simplex viruses (oHSVs), have many attributes for therapy and are promising agents to target GSCs. oHSVs are genetically-engineered to selectively replicate in and kill cancer cells, including GSCs, but not normal cells. Moreover, oHSV can induce anti-tumor immune responses and synergize with other therapies, such as chemotherapy, DNA repair inhibitors, and immune checkpoint inhibitors, to potentiate treatment effects and reduce GSC populations that are partly responsible for chemo- and radio-resistance. Herein, we present an overview of GSCs, activity of different oHSVs, clinical trial results, and combination strategies to enhance efficacy, including therapeutic arming of oHSV. Throughout, the therapeutic focus will be on GSCs and studies specifically targeting these cells. Recent clinical trials and approval of oHSV G47Δ in Japan for patients with recurrent glioma demonstrate the efficacy and promise of oHSV therapy.
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Affiliation(s)
| | | | - Samuel D. Rabkin
- Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
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8
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Grigore FN, Yang SJ, Chen CC, Koga T. Pioneering models of pediatric brain tumors. Neoplasia 2023; 36:100859. [PMID: 36599191 PMCID: PMC9823239 DOI: 10.1016/j.neo.2022.100859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 11/16/2022] [Accepted: 11/28/2022] [Indexed: 01/04/2023]
Abstract
Among children and adolescents in the United States (0 to 19 years old), brain and other central nervous system tumors are the second most common types of cancers, surpassed in incidence only by leukemias. Despite significant progress in the diagnosis and treatment modalities, brain cancer remains the leading cause of death in the pediatric population. There is an obvious unfulfilled need to streamline the therapeutic strategies and improve survival for these patients. For that purpose, preclinical models play a pivotal role. Numerous models are currently used in pediatric brain tumor research, including genetically engineered mouse models, patient-derived xenografts and cell lines, and newer models that utilize novel technologies such as genome engineering and organoids. Furthermore, extensive studies by the Children's Brain Tumor Network (CBTN) researchers and others have revealed multiomic landscapes of variable pediatric brain tumors. Combined with such integrative data, these novel technologies have enabled numerous applicable models. Genome engineering, including CRISPR/Cas9, expanded the flexibility of modeling. Models generated through genome engineering enabled studying particular genetic alterations in clean isogenic backgrounds, facilitating the dissection of functional mechanisms of those mutations in tumor biology. Organoids have been applied to study tumor-to-tumor-microenvironment interactions and to address developmental aspects of tumorigenesis, which is essential in some pediatric brain tumors. Other modalities, such as humanized mouse models, could potentially be applied to pediatric brain tumors. In addition to current valuable models, such novel models are anticipated to expedite functional tumor biology study and establish effective therapeutics for pediatric brain tumors.
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Affiliation(s)
- Florina-Nicoleta Grigore
- Department of Neurosurgery, University of Minnesota, MMC96, Room D-429, 420 Delaware St SE, Minneapolis, MN 55455, USA
| | - Serena Johanna Yang
- Department of Neurosurgery, University of Minnesota, MMC96, Room D-429, 420 Delaware St SE, Minneapolis, MN 55455, USA
| | - Clark C Chen
- Department of Neurosurgery, University of Minnesota, MMC96, Room D-429, 420 Delaware St SE, Minneapolis, MN 55455, USA
| | - Tomoyuki Koga
- Department of Neurosurgery, University of Minnesota, MMC96, Room D-429, 420 Delaware St SE, Minneapolis, MN 55455, USA.
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9
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Kang KD, Bernstock JD, Totsch SK, Gary SE, Rocco A, Nan L, Li R, Etminan T, Han X, Beierle EA, Eisemann T, Wechsler-Reya RJ, Bae S, Whitley R, Yancey Gillespie G, Markert JM, Friedman GK. Safety and Efficacy of Intraventricular Immunovirotherapy with Oncolytic HSV-1 for CNS Cancers. Clin Cancer Res 2022; 28:5419-5430. [PMID: 36239623 PMCID: PMC9771977 DOI: 10.1158/1078-0432.ccr-22-1382] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 09/12/2022] [Accepted: 10/12/2022] [Indexed: 01/24/2023]
Abstract
PURPOSE Oncolytic virotherapy with herpes simplex virus-1 (HSV) has shown promise for the treatment of pediatric and adult brain tumors; however, completed and ongoing clinical trials have utilized intratumoral/peritumoral oncolytic HSV (oHSV) inoculation due to intraventricular/intrathecal toxicity concerns. Intratumoral delivery requires an invasive neurosurgical procedure, limits repeat injections, and precludes direct targeting of metastatic and leptomeningeal disease. To address these limitations, we determined causes of toxicity from intraventricular oHSV and established methods for mitigating toxicity to treat disseminated brain tumors in mice. EXPERIMENTAL DESIGN HSV-sensitive CBA/J mice received intraventricular vehicle, inactivated oHSV, or treatment doses (1×107 plaque-forming units) of oHSV, and toxicity was assessed by weight loss and IHC. Protective strategies to reduce oHSV toxicity, including intraventricular low-dose oHSV or interferon inducer polyinosinic-polycytidylic acid (poly I:C) prior to oHSV treatment dose, were evaluated and then utilized to assess intraventricular oHSV treatment of multiple models of disseminated CNS disease. RESULTS A standard treatment dose of intraventricular oHSV damaged ependymal cells via virus replication and induction of CD8+ T cells, whereas vehicle or inactivated virus resulted in no toxicity. Subsequent doses of intraventricular oHSV caused little additional toxicity. Interferon induction with phosphorylation of eukaryotic initiation factor-2α (eIF2α) via intraventricular pretreatment with low-dose oHSV or poly I:C mitigated ependyma toxicity. This approach enabled the safe delivery of multiple treatment doses of clinically relevant oHSV G207 and prolonged survival in disseminated brain tumor models. CONCLUSIONS Toxicity from intraventricular oHSV can be mitigated, resulting in therapeutic benefit. These data support the clinical translation of intraventricular G207.
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Affiliation(s)
- Kyung-Don Kang
- Department of Pediatrics, Division of Pediatric Hematology
and Oncology, University of Alabama at Birmingham; Birmingham, AL, USA
| | - Joshua D. Bernstock
- Department of Pediatrics, Division of Pediatric Hematology
and Oncology, University of Alabama at Birmingham; Birmingham, AL, USA,Department of Neurosurgery, Brigham and Women’s
Hospital, Harvard University; Boston, MA, USA,Corresponding authors: Joshua D.
Bernstock MD, PhD, MPH, Department of Neurosurgery
- Harvard Medical School,
Brigham and Women’s Hospital
- Boston Children’s Hospital, Hale
Building
- 60 Fenwood Road
- Boston, MA 02115, USA, P: 914.419.7749
- F:
617.713.3050
- ; Gregory K. Friedman,
MD, Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Ave
S, Lowder 512, Birmingham, AL 35233, USA, P: 205.638.9285
- F: 205.975.1941
| | - Stacie K. Totsch
- Department of Pediatrics, Division of Pediatric Hematology
and Oncology, University of Alabama at Birmingham; Birmingham, AL, USA
| | - Sam E. Gary
- Department of Pediatrics, Division of Pediatric Hematology
and Oncology, University of Alabama at Birmingham; Birmingham, AL, USA,Medical Scientist Training Program, University of Alabama
at Birmingham, Birmingham, AL, USA
| | - Abbey Rocco
- Department of Pediatrics, Division of Pediatric Hematology
and Oncology, University of Alabama at Birmingham; Birmingham, AL, USA
| | - Li Nan
- Department of Pediatrics, Division of Pediatric Hematology
and Oncology, University of Alabama at Birmingham; Birmingham, AL, USA
| | - Rong Li
- Department of Pathology, Children’s of Alabama;
Birmingham, AL, USA
| | - Tina Etminan
- Department of Pediatrics, Division of Pediatric Hematology
and Oncology, University of Alabama at Birmingham; Birmingham, AL, USA
| | - Xiaosi Han
- Department of Neurology, Division of Neuro-Oncology,
University of Alabama at Birmingham; Birmingham, AL, USA
| | | | - Tanja Eisemann
- Sanford Burnham Prebys Medical Discovery Institute; La
Jolla, CA, USA
| | | | - Sejong Bae
- Department of Medicine, Division of Preventative Medicine,
University of Alabama at Birmingham; Birmingham, AL, USA
| | - Richard Whitley
- Department of Pediatrics, Division of Infectious Diseases,
University of Alabama at Birmingham; Birmingham, AL, USA
| | - G. Yancey Gillespie
- Department of Neurosurgery, University of Alabama at
Birmingham; Birmingham, AL, USA
| | - James M. Markert
- Department of Neurosurgery, University of Alabama at
Birmingham; Birmingham, AL, USA
| | - Gregory K. Friedman
- Department of Pediatrics, Division of Pediatric Hematology
and Oncology, University of Alabama at Birmingham; Birmingham, AL, USA,Department of Neurosurgery, University of Alabama at
Birmingham; Birmingham, AL, USA,Corresponding authors: Joshua D.
Bernstock MD, PhD, MPH, Department of Neurosurgery
- Harvard Medical School,
Brigham and Women’s Hospital
- Boston Children’s Hospital, Hale
Building
- 60 Fenwood Road
- Boston, MA 02115, USA, P: 914.419.7749
- F:
617.713.3050
- ; Gregory K. Friedman,
MD, Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Ave
S, Lowder 512, Birmingham, AL 35233, USA, P: 205.638.9285
- F: 205.975.1941
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10
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Omole RK, Oluwatola O, Akere MT, Eniafe J, Agboluaje EO, Daramola OB, Ayantunji YJ, Omotade TI, Torimiro N, Ayilara MS, Adeyemi OI, Salinsile OS. Comprehensive assessment on the applications of oncolytic viruses for cancer immunotherapy. Front Pharmacol 2022; 13:1082797. [PMID: 36569326 PMCID: PMC9772532 DOI: 10.3389/fphar.2022.1082797] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 11/24/2022] [Indexed: 12/13/2022] Open
Abstract
The worldwide burden of cancers is increasing at a very high rate, including the aggressive and resistant forms of cancers. Certain levels of breakthrough have been achieved with the conventional treatment methods being used to treat different forms of cancers, but with some limitations. These limitations include hazardous side effects, destruction of non-tumor healthy cells that are rapidly dividing and developing, tumor resistance to anti-cancer drugs, damage to tissues and organs, and so on. However, oncolytic viruses have emerged as a worthwhile immunotherapeutic option for the treatment of different types of cancers. In this treatment approach, oncolytic viruses are being modeled to target cancer cells with optimum cytotoxicity and spare normal cells with optimal safety, without the oncolytic viruses themselves being killed by the host immune defense system. Oncolytic viral infection of the cancer cells are also being genetically manipulated (either by removal or addition of certain genes into the oncolytic virus genome) to make the tumor more visible and available for attack by the host immune cells. Hence, different variants of these viruses are being developed to optimize their antitumor effects. In this review, we examined how grave the burden of cancer is on a global level, particularly in sub-Saharan Africa, major conventional therapeutic approaches to the treatment of cancer and their individual drawbacks. We discussed the mechanisms of action employed by these oncolytic viruses and different viruses that have found their relevance in the fight against various forms of cancers. Some pre-clinical and clinical trials that involve oncolytic viruses in cancer management were reported. This review also examined the toxicity and safety concerns surrounding the adoption of oncolytic viro-immunotherapy for the treatment of cancers and the likely future directions for researchers and general audience who wants updated information.
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Affiliation(s)
- Richard Kolade Omole
- Department of Microbiology, Obafemi Awolowo University, Ile-Ife, Nigeria,Microbiology Unit, Department of Applied Sciences, Osun State College of Technology, Esa-Oke, Nigeria,*Correspondence: Richard Kolade Omole,
| | - Oluwaseyi Oluwatola
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United States,Department of Immunology, Moffit Cancer Center, Tampa, FL, United States
| | - Millicent Tambari Akere
- Department of Medicinal and Biological Chemistry, University of Toledo, Toledo, OH, United States
| | - Joseph Eniafe
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA, United States
| | | | | | - Yemisi Juliet Ayantunji
- Department of Microbiology, Obafemi Awolowo University, Ile-Ife, Nigeria,Advanced Space Technology Applications Laboratory, Cooperative Information Network, National Space Research and Development Agency, Ile-Ife, Nigeria
| | | | - Nkem Torimiro
- Department of Microbiology, Obafemi Awolowo University, Ile-Ife, Nigeria
| | - Modupe Stella Ayilara
- Food Security and Safety Focus Area, Faculty of Natural and Agricultural Sciences, North-West University, Mmabatho, South Africa
| | - Oluwole Isaac Adeyemi
- Department of Pharmacology, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria
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11
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D’Amico M, De Amicis F. Aberrant Notch signaling in gliomas: a potential landscape of actionable converging targets for combination approach in therapies resistance. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2022; 5:939-953. [PMID: 36627893 PMCID: PMC9771760 DOI: 10.20517/cdr.2022.46] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 06/06/2022] [Accepted: 09/02/2022] [Indexed: 11/06/2022]
Abstract
The current therapeutic protocols and prognosis of gliomas still depend on clinicopathologic and radiographic characteristics. For high-grade gliomas, the standard of care is resection followed by radiotherapy plus temozolomide chemotherapy. However, treatment resistance develops due to different mechanisms, among which is the dynamic interplay between the tumor and its microenvironment. Different signaling pathways cause the proliferation of so-called glioma stem cells, a minor cancer cell population with stem cell-like characteristics and aggressive phenotype. In the last decades, numerous studies have indicated that Notch is a crucial pathway that maintains the characteristics of resistant glioma stem cells. Data obtained from preclinical models indicate that downregulation of the Notch pathway could induce multifaceted drug sensitivity, acting on the expression of drug-transporter proteins, inducing epithelial-mesenchymal transition, and shaping the tumor microenvironment. This review provides a brief overview of the published data supporting the roles of Notch in drug resistance and demonstrates how potential novel strategies targeting Notch could become an efficacious action to improve the therapy of high-grade glioma to overcome drug resistance.
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Affiliation(s)
- Maria D’Amico
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, Rende 87036, Italy
| | - Francesca De Amicis
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, Rende 87036, Italy.,Health Center, University of Calabria, Via P. Bucci, Rende 87036, Italy.,Correspondence to: Prof. Francesca De Amicis, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, Rende 87036, Italy. E-mail:
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12
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van Bree NFHN, Wilhelm M. The Tumor Microenvironment of Medulloblastoma: An Intricate Multicellular Network with Therapeutic Potential. Cancers (Basel) 2022; 14:5009. [PMID: 36291792 PMCID: PMC9599673 DOI: 10.3390/cancers14205009] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 10/08/2022] [Accepted: 10/10/2022] [Indexed: 11/25/2022] Open
Abstract
Medulloblastoma (MB) is a heterogeneous disease in which survival is highly affected by the underlying subgroup-specific characteristics. Although the current treatment modalities have increased the overall survival rates of MB up to 70-80%, MB remains a major cause of cancer-related mortality among children. This indicates that novel therapeutic approaches against MB are needed. New promising treatment options comprise the targeting of cells and components of the tumor microenvironment (TME). The TME of MB consists of an intricate multicellular network of tumor cells, progenitor cells, astrocytes, neurons, supporting stromal cells, microglia, immune cells, extracellular matrix components, and vasculature systems. In this review, we will discuss all the different components of the MB TME and their role in MB initiation, progression, metastasis, and relapse. Additionally, we briefly introduce the effect that age plays on the TME of brain malignancies and discuss the MB subgroup-specific differences in TME components and how all of these variations could affect the progression of MB. Finally, we highlight the TME-directed treatments, in which we will focus on therapies that are being evaluated in clinical trials.
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Affiliation(s)
| | - Margareta Wilhelm
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institute, 17165 Stockholm, Sweden
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13
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Martín-Rubio P, Espiau-Romera P, Royo-García A, Caja L, Sancho P. Metabolic determinants of stemness in medulloblastoma. World J Stem Cells 2022; 14:587-598. [PMID: 36157911 PMCID: PMC9453267 DOI: 10.4252/wjsc.v14.i8.587] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/26/2022] [Accepted: 08/01/2022] [Indexed: 02/07/2023] Open
Abstract
Medulloblastomas (MBs) are the most prevalent brain tumours in children. They are classified as grade IV, the highest in malignancy, with about 30% metastatic tumours at the time of diagnosis. Cancer stem cells (CSCs) are a small subset of tumour cells that can initiate and support tumour growth. In MB, CSCs contribute to tumour initiation, metastasis, and therapy resistance. Metabolic differences among the different MB groups have started to emerge. Sonic hedgehog tumours show enriched lipid and nucleic acid metabolism pathways, whereas Group 3 MBs upregulate glycolysis, gluconeogenesis, glutamine anabolism, and glutathione-mediated anti-oxidant pathways. Such differences impact the clinical behaviour of MB tumours and can be exploited therapeutically. In this review, we summarise the existing knowledge about metabolic rewiring in MB, with a particular focus on MB-CSCs. Finally, we highlight some of the emerging metabolism-based therapeutic strategies for MB.
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Affiliation(s)
| | | | - Alba Royo-García
- Hospital Universitario Miguel Servet, IIS Aragón, Zaragoza 50009, Spain
| | - Laia Caja
- Department of Medical Biochemistry and Microbiology, Biomedical Center, Uppsala University, Uppsala SE-751, Sweden
| | - Patricia Sancho
- Hospital Universitario Miguel Servet, IIS Aragón, Zaragoza 50009, Spain
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14
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Ghajar-Rahimi G, Kang KD, Totsch SK, Gary S, Rocco A, Blitz S, Kachurak K, Chambers MR, Li R, Beierle EA, Bag A, Johnston JM, Markert JM, Bernstock JD, Friedman GK. Clinical advances in oncolytic virotherapy for pediatric brain tumors. Pharmacol Ther 2022; 239:108193. [PMID: 35487285 DOI: 10.1016/j.pharmthera.2022.108193] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 04/10/2022] [Accepted: 04/21/2022] [Indexed: 10/18/2022]
Abstract
Malignant brain tumors constitute nearly one-third of cancer diagnoses in children and have recently surpassed hematologic malignancies as the most lethal neoplasm in the pediatric population. Outcomes for children with brain tumors are unacceptably poor and current standards of care-surgical resection, chemotherapy, and radiation-are associated with significant long-term morbidity. Oncolytic virotherapy has emerged as a promising immunotherapy for the treatment of brain tumors. While the majority of brain tumor clinical trials utilizing oncolytic virotherapy have been in adults, five viruses are being tested in pediatric brain tumor clinical trials: herpes simplex virus (G207), reovirus (pelareorep/Reolysin), measles virus (MV-NIS), poliovirus (PVSRIPO), and adenovirus (DNX-2401, AloCELYVIR). Herein, we review past and current pediatric immunovirotherapy brain tumor trials including the relevant preclinical and clinical research that contributed to their development. We describe mechanisms by which the viruses may overcome barriers in treating pediatric brain tumors, examine challenges associated with achieving effective, durable responses, highlight unique aspects and successes of the trials, and discuss future directions of immunovirotherapy research for the treatment of pediatric brain tumors.
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Affiliation(s)
- Gelare Ghajar-Rahimi
- Medical Scientist Training Program, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Kyung-Don Kang
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Stacie K Totsch
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Sam Gary
- Medical Scientist Training Program, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Abbey Rocco
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA
| | | | - Kara Kachurak
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - M R Chambers
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Rong Li
- Department of Pathology, University of Alabama at Birmingham, and Children's of Alabama, Birmingham, AL, USA
| | - Elizabeth A Beierle
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Asim Bag
- Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - James M Johnston
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - James M Markert
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Joshua D Bernstock
- Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard University, Boston, MA, USA.
| | - Gregory K Friedman
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA.
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15
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Gospel of malignant Glioma: Oncolytic virus therapy. Gene 2022; 818:146217. [PMID: 35093451 DOI: 10.1016/j.gene.2022.146217] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 12/09/2021] [Accepted: 01/13/2022] [Indexed: 12/12/2022]
Abstract
Glioma accounts for nearly 80% of all intracranial malignant tumors. It is a major challenge to society as it is causes to impaired brain function in many patients. Currently, gliomas are mainly treated with surgery, postoperative radiotherapy, and chemotherapy. However, the curative effects of these treatments are not satisfactory. Oncolytic virus (OV) is a novel treatment which works by activating the immune functions and inducing apoptosis of tumor cells. The OV propagates indefinitely in the host cell, eventually leading to the death of host cell. Subsequently, a large number of antigens and signal molecules are released which exert antitumor immunity. Several preclinical and clinical studies have shown that G207, DNX2401, Zika and other viruses have important roles in malignant tumors. For example, these viruses can reduce the growth of tumor cells without causing severe complications. However, the known OVs have not been clearly classified. Herein, we divided OVs into neurotropic and non-neurophilic OVs based on whether the OVs are naturally neurotropic or not. The therapeutic effects of each group were compared. Finally, challenges encountered in the clinical application of OVs in the treatment of malignant gliomas were summarized.
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16
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de la Nava D, Selvi KM, Alonso MM. Immunovirotherapy for Pediatric Solid Tumors: A Promising Treatment That is Becoming a Reality. Front Immunol 2022; 13:866892. [PMID: 35493490 PMCID: PMC9043602 DOI: 10.3389/fimmu.2022.866892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 03/23/2022] [Indexed: 11/13/2022] Open
Abstract
Immunotherapy has seen tremendous strides in the last decade, acquiring a prominent position at the forefront of cancer treatment since it has been proven to be efficacious for a wide variety of tumors. Nevertheless, while immunotherapy has changed the paradigm of adult tumor treatment, this progress has not yet been translated to the pediatric solid tumor population. For this reason, alternative curative therapies are urgently needed for the most aggressive pediatric tumors. In recent years, oncolytic virotherapy has consolidated as a feasible strategy for cancer treatment, not only for its tumor-specific effects and safety profile but also for its capacity to trigger an antitumor immune response. This review will summarize the current status of immunovirotherapy to treat cancer, focusing on pediatric solid malignancies. We will revisit previous basic, translational, and clinical research and discuss advances in overcoming the existing barriers and limitations to translate this promising therapeutic as an every-day cancer treatment for the pediatric and young adult populations.
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Affiliation(s)
- Daniel de la Nava
- Health Research Institute of Navarra (IdiSNA), Pamplona, Spain
- Programs in Solid Tumors and Neuroscience, Foundation for the Applied Medical Research, Pamplona, Spain
- Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain
| | - Kadir Mert Selvi
- Health Research Institute of Navarra (IdiSNA), Pamplona, Spain
- Programs in Solid Tumors and Neuroscience, Foundation for the Applied Medical Research, Pamplona, Spain
- Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain
| | - Marta M. Alonso
- Health Research Institute of Navarra (IdiSNA), Pamplona, Spain
- Programs in Solid Tumors and Neuroscience, Foundation for the Applied Medical Research, Pamplona, Spain
- Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain
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17
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Quinn CH, Beierle AM, Hutchins SC, Marayati R, Bownes LV, Stewart JE, Markert HR, Erwin MH, Aye JM, Yoon KJ, Friedman GK, Willey CD, Markert JM, Beierle EA. Targeting High-Risk Neuroblastoma Patient-Derived Xenografts with Oncolytic Virotherapy. Cancers (Basel) 2022; 14:cancers14030762. [PMID: 35159029 PMCID: PMC8834037 DOI: 10.3390/cancers14030762] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/25/2022] [Accepted: 01/28/2022] [Indexed: 12/14/2022] Open
Abstract
Cancer is the leading cause of death by disease in children, and over 15% of pediatric cancer-related mortalities are due to neuroblastoma. Current treatment options for neuroblastoma remain suboptimal as they often have significant toxicities, are associated with long-term side effects, and result in disease relapse in over half of children with high-risk disease. There is a dire need for new therapies, and oncolytic viruses may represent an effective solution. Oncolytic viruses attack tumor cells in two ways: direct infection of tumor cells leading to cytolysis, and production of a debris field that stimulates an anti-tumor immune response. Our group has previously shown that M002, an oncolytic herpes simplex virus (oHSV), genetically engineered to express murine interleukin-12 (mIL-12), was effective at targeting and killing long term passage tumor cell lines. In the current study, we investigated M002 in three neuroblastoma patient-derived xenografts (PDXs). PDXs better recapitulate the human condition, and these studies were designed to gather robust data for translation to a clinical trial. We found that all three PDXs expressed viral entry receptors, and that the virus actively replicated in the cells. M002 caused significant tumor cell death in 2D culture and 3D bioprinted tumor models. Finally, the PDXs displayed variable susceptibility to M002, with a more profound effect on high-risk neuroblastoma PDXs compared to low-risk PDX. These findings validate the importance of incorporating PDXs for preclinical testing of oncolytic viral therapeutics and showcase a novel technique, 3D bioprinting, to test therapies in PDXs. Collectively, our data indicate that oHSVs effectively target high-risk neuroblastoma, and support the advancement of this therapy to the clinical setting.
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Affiliation(s)
- Colin H. Quinn
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35205, USA; (C.H.Q.); (R.M.); (L.V.B.); (J.E.S.); (H.R.M.); (M.H.E.)
| | - Andee M. Beierle
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL 35233, USA; (A.M.B.); (C.D.W.)
| | - Sara Claire Hutchins
- Division of Pediatric Hematology Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, USA; (S.C.H.); (J.M.A.); (G.K.F.)
| | - Raoud Marayati
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35205, USA; (C.H.Q.); (R.M.); (L.V.B.); (J.E.S.); (H.R.M.); (M.H.E.)
| | - Laura V. Bownes
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35205, USA; (C.H.Q.); (R.M.); (L.V.B.); (J.E.S.); (H.R.M.); (M.H.E.)
| | - Jerry E. Stewart
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35205, USA; (C.H.Q.); (R.M.); (L.V.B.); (J.E.S.); (H.R.M.); (M.H.E.)
| | - Hooper R. Markert
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35205, USA; (C.H.Q.); (R.M.); (L.V.B.); (J.E.S.); (H.R.M.); (M.H.E.)
| | - Michael H. Erwin
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35205, USA; (C.H.Q.); (R.M.); (L.V.B.); (J.E.S.); (H.R.M.); (M.H.E.)
| | - Jamie M. Aye
- Division of Pediatric Hematology Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, USA; (S.C.H.); (J.M.A.); (G.K.F.)
| | - Karina J. Yoon
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35233, USA;
| | - Gregory K. Friedman
- Division of Pediatric Hematology Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, USA; (S.C.H.); (J.M.A.); (G.K.F.)
| | - Christopher D. Willey
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL 35233, USA; (A.M.B.); (C.D.W.)
| | - James M. Markert
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA;
| | - Elizabeth A. Beierle
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35205, USA; (C.H.Q.); (R.M.); (L.V.B.); (J.E.S.); (H.R.M.); (M.H.E.)
- Correspondence: ; Tel.: +1-205-638-9688
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18
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The Current Landscape of Targeted Clinical Trials in Non-WNT/Non-SHH Medulloblastoma. Cancers (Basel) 2022; 14:cancers14030679. [PMID: 35158947 PMCID: PMC8833659 DOI: 10.3390/cancers14030679] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/23/2022] [Accepted: 01/24/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Medulloblastoma is a form of malignant brain tumor that arises predominantly in infants and young children and can be divided into different groups based on molecular markers. The group of non-WNT/non-SHH medulloblastoma includes a spectrum of heterogeneous subgroups that differ in their biological characteristics, genetic underpinnings, and clinical course of disease. Non-WNT/non-SHH medulloblastoma is currently treated with surgery, chemotherapy, and radiotherapy; however, new drugs are needed to treat patients who are not yet curable and to reduce treatment-related toxicity and side effects. We here review which new treatment options for non-WNT/non-SHH medulloblastoma are currently clinically tested. Furthermore, we illustrate the challenges that have to be overcome to reach a new therapeutic standard for non-WNT/non-SHH medulloblastoma, for instance the current lack of good preclinical models, and the necessity to conduct trials in a comparably small patient collective. Abstract Medulloblastoma is an embryonal pediatric brain tumor and can be divided into at least four molecularly defined groups. The category non-WNT/non-SHH medulloblastoma summarizes medulloblastoma groups 3 and 4 and is characterized by considerable genetic and clinical heterogeneity. New therapeutic strategies are needed to increase survival rates and to reduce treatment-related toxicity. We performed a noncomprehensive targeted review of the current clinical trial landscape and literature to summarize innovative treatment options for non-WNT/non-SHH medulloblastoma. A multitude of new drugs is currently evaluated in trials for which non-WNT/non-SHH patients are eligible, for instance immunotherapy, kinase inhibitors, and drugs targeting the epigenome. However, the majority of these trials is not restricted to medulloblastoma and lacks molecular classification. Whereas many new molecular targets have been identified in the last decade, which are currently tested in clinical trials, several challenges remain on the way to reach a new therapeutic strategy for non-WNT/non-SHH medulloblastoma. These include the severe lack of faithful preclinical models and predictive biomarkers, the question on how to stratify patients for clinical trials, and the relative lack of studies that recruit large, homogeneous patient collectives. Innovative trial designs and international collaboration will be a key to eventually overcome these obstacles.
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19
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Audi ZF, Saker Z, Rizk M, Harati H, Fares Y, Bahmad HF, Nabha SM. Immunosuppression in Medulloblastoma: Insights into Cancer Immunity and Immunotherapy. Curr Treat Options Oncol 2021; 22:83. [PMID: 34328587 DOI: 10.1007/s11864-021-00874-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/20/2021] [Indexed: 12/13/2022]
Abstract
OPINION STATEMENT Medulloblastoma (MB) is the most common pediatric brain malignancy, with a 5-year overall survival (OS) rate of around 65%. The conventional MB treatment, comprising surgical resection followed by irradiation and adjuvant chemotherapy, often leads to impairment in normal body functions and poor quality of life, especially with the increased risk of recurrence and subsequent development of secondary malignancies. The development and progression of MB are facilitated by a variety of immune-evading mechanisms such as the secretion of immunosuppressive molecules, activation of immunosuppressive cells, inhibition of immune checkpoint molecules, impairment of adhesive molecules, downregulation of the major histocompatibility complex (MHC) molecules, protection against apoptosis, and activation of immunosuppressive pathways. Understanding the tumor-immune relationship in MB is crucial for effective development of immune-based therapeutic strategies. In this comprehensive review, we discuss the immunological aspect of the brain, focusing on the current knowledge tackling the mechanisms of MB immune suppression and evasion. We also highlight several key immunotherapeutic approaches developed to date for the treatment of MB.
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Affiliation(s)
- Zahraa F Audi
- Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon
| | - Zahraa Saker
- Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon
| | - Mahdi Rizk
- Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon
| | - Hayat Harati
- Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon
| | - Youssef Fares
- Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon.,Department of Neurosurgery, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon
| | - Hisham F Bahmad
- Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, 4300 Alton Rd, Miami Beach, FL, USA.
| | - Sanaa M Nabha
- Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon.
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20
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Paul MR, Zage PE. Overview and recent advances in the targeting of medulloblastoma cancer stem cells. Expert Rev Anticancer Ther 2021; 21:957-974. [PMID: 34047251 DOI: 10.1080/14737140.2021.1932472] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Introduction: Medulloblastoma, an embryonal small round blue cell tumor primarily arising in the posterior fossa, is the most common malignancy of the central nervous system in children and requires intensive multi-modality therapy for cure. Overall 5-year survival is approximately 75% in children with primary disease, but outcomes for relapsed disease are very poor. Recent advances have identified molecular subgroups with excellent prognosis, with 5-year overall survival rates >90%, and subgroups with very poor prognosis with overall survival rates <50%. Molecular subtyping has allowed for more sophisticated risk stratification of patients, but new treatments for the highest risk patients have not yet improved outcomes. Targeting cancer stem cells may improve outcomes, and several candidate targets and novel drugs are under investigation.Areas covered: We discuss medulloblastoma epidemiology, biology, treatment modalities, risk stratification, and molecular subgroup analysis, links between subgroup and developmental biology, cancer stem cell biology in medulloblastoma including previously described cancer stem cell markers and proposed targeted treatments in the current literature.Expert opinion: The understanding of cancer stem cells in medulloblastoma will advance therapies targeting the most treatment-resistant cells within the tumor and therefore reduce the incidence of treatment refractory and relapsed disease.
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Affiliation(s)
- Megan Rose Paul
- Department of Pediatrics, Division of Hematology-Oncology, University of California San Diego, La Jolla, California, USA (M.R.P., P.E.Z.); Peckham Center for Cancer and Blood Disorders, Rady Children's Hospital-San Diego, San Diego, California, USA
| | - Peter E Zage
- Department of Pediatrics, Division of Hematology-Oncology, University of California San Diego, La Jolla, California, USA (M.R.P., P.E.Z.); Peckham Center for Cancer and Blood Disorders, Rady Children's Hospital-San Diego, San Diego, California, USA
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Friedman GK, Johnston JM, Bag AK, Bernstock JD, Li R, Aban I, Kachurak K, Nan L, Kang KD, Totsch S, Schlappi C, Martin AM, Pastakia D, McNall-Knapp R, Farouk Sait S, Khakoo Y, Karajannis MA, Woodling K, Palmer JD, Osorio DS, Leonard J, Abdelbaki MS, Madan-Swain A, Atkinson TP, Whitley RJ, Fiveash JB, Markert JM, Gillespie GY. Oncolytic HSV-1 G207 Immunovirotherapy for Pediatric High-Grade Gliomas. N Engl J Med 2021; 384:1613-1622. [PMID: 33838625 PMCID: PMC8284840 DOI: 10.1056/nejmoa2024947] [Citation(s) in RCA: 229] [Impact Index Per Article: 57.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Outcomes in children and adolescents with recurrent or progressive high-grade glioma are poor, with a historical median overall survival of 5.6 months. Pediatric high-grade gliomas are largely immunologically silent or "cold," with few tumor-infiltrating lymphocytes. Preclinically, pediatric brain tumors are highly sensitive to oncolytic virotherapy with genetically engineered herpes simplex virus type 1 (HSV-1) G207, which lacks genes essential for replication in normal brain tissue. METHODS We conducted a phase 1 trial of G207, which used a 3+3 design with four dose cohorts of children and adolescents with biopsy-confirmed recurrent or progressive supratentorial brain tumors. Patients underwent stereotactic placement of up to four intratumoral catheters. The following day, they received G207 (107 or 108 plaque-forming units) by controlled-rate infusion over a period of 6 hours. Cohorts 3 and 4 received radiation (5 Gy) to the gross tumor volume within 24 hours after G207 administration. Viral shedding from saliva, conjunctiva, and blood was assessed by culture and polymerase-chain-reaction assay. Matched pre- and post-treatment tissue samples were examined for tumor-infiltrating lymphocytes by immunohistologic analysis. RESULTS Twelve patients 7 to 18 years of age with high-grade glioma received G207. No dose-limiting toxic effects or serious adverse events were attributed to G207 by the investigators. Twenty grade 1 adverse events were possibly related to G207. No virus shedding was detected. Radiographic, neuropathological, or clinical responses were seen in 11 patients. The median overall survival was 12.2 months (95% confidence interval, 8.0 to 16.4); as of June 5, 2020, a total of 4 of 11 patients were still alive 18 months after G207 treatment. G207 markedly increased the number of tumor-infiltrating lymphocytes. CONCLUSIONS Intratumoral G207 alone and with radiation had an acceptable adverse-event profile with evidence of responses in patients with recurrent or progressive pediatric high-grade glioma. G207 converted immunologically "cold" tumors to "hot." (Supported by the Food and Drug Administration and others; ClinicalTrials.gov number, NCT02457845.).
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Affiliation(s)
- Gregory K Friedman
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - James M Johnston
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Asim K Bag
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Joshua D Bernstock
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Rong Li
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Inmaculada Aban
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Kara Kachurak
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Li Nan
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Kyung-Don Kang
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Stacie Totsch
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Charles Schlappi
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Allison M Martin
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Devang Pastakia
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Rene McNall-Knapp
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Sameer Farouk Sait
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Yasmin Khakoo
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Matthias A Karajannis
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Karina Woodling
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Joshua D Palmer
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Diana S Osorio
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Jeffrey Leonard
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Mohamed S Abdelbaki
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Avi Madan-Swain
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - T Prescott Atkinson
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Richard J Whitley
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - John B Fiveash
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - James M Markert
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - G Yancey Gillespie
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
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Li Z, Langhans SA. In Vivo and Ex Vivo Pediatric Brain Tumor Models: An Overview. Front Oncol 2021; 11:620831. [PMID: 33869004 PMCID: PMC8047472 DOI: 10.3389/fonc.2021.620831] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 03/15/2021] [Indexed: 12/18/2022] Open
Abstract
After leukemia, tumors of the brain and spine are the second most common form of cancer in children. Despite advances in treatment, brain tumors remain a leading cause of death in pediatric cancer patients and survivors often suffer from life-long consequences of side effects of therapy. The 5-year survival rates, however, vary widely by tumor type, ranging from over 90% in more benign tumors to as low as 20% in the most aggressive forms such as glioblastoma. Even within historically defined tumor types such as medulloblastoma, molecular analysis identified biologically heterogeneous subgroups each with different genetic alterations, age of onset and prognosis. Besides molecularly driven patient stratification to tailor disease risk to therapy intensity, such a diversity demonstrates the need for more precise and disease-relevant pediatric brain cancer models for research and drug development. Here we give an overview of currently available in vitro and in vivo pediatric brain tumor models and discuss the opportunities that new technologies such as 3D cultures and organoids that can bridge limitations posed by the simplicity of monolayer cultures and the complexity of in vivo models, bring to accommodate better precision in drug development for pediatric brain tumors.
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Affiliation(s)
| | - Sigrid A. Langhans
- Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, DE, United States
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23
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Garcia-Moure M, Gonzalez-Huarriz M, Labiano S, Guruceaga E, Bandres E, Zalacain M, Marrodan L, de Andrea C, Villalba M, Martinez-Velez N, Laspidea V, Puigdelloses M, Gallego Perez-Larraya J, Iñigo-Marco I, Stripecke R, Chan JA, Raabe EH, Kool M, Gomez-Manzano C, Fueyo J, Patiño-García A, Alonso MM. Delta-24-RGD, an Oncolytic Adenovirus, Increases Survival and Promotes Proinflammatory Immune Landscape Remodeling in Models of AT/RT and CNS-PNET. Clin Cancer Res 2021; 27:1807-1820. [PMID: 33376098 PMCID: PMC7617079 DOI: 10.1158/1078-0432.ccr-20-3313] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 10/14/2020] [Accepted: 12/22/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE Atypical teratoid/rhabdoid tumors (AT/RT) and central nervous system primitive neuroectodermal tumors (CNS-PNET) are pediatric brain tumors with poor survival and life-long negative side effects. Here, the aim was to characterize the efficacy and safety of the oncolytic adenovirus, Delta-24-RGD, which selectively replicates in and kills tumor cells. EXPERIMENTAL DESIGN Delta-24-RGD determinants for infection and replication were evaluated in patient expression datasets. Viral replication and cytotoxicity were assessed in vitro in a battery of CNS-PNET and AT/RT cell lines. In vivo, efficacy was determined in different orthotopic mouse models, including early and established tumor models, a disseminated AT/RT lesion model, and immunocompetent humanized mouse models (hCD34+-NSG-SGM3). RESULTS Delta-24-RGD infected and replicated efficiently in all the cell lines tested. In addition, the virus induced dose-dependent cytotoxicity [IC50 value below 1 plaque-forming unit (PFU)/cell] and the release of immunogenic markers. In vivo, a single intratumoral Delta-24-RGD injection (107 or 108 PFU) significantly increased survival and led to long-term survival in AT/RT and PNET models. Delta-24-RGD hindered the dissemination of AT/RTs and increased survival, leading to 70% of long-term survivors. Of relevance, viral administration to established tumor masses (30 days after engraftment) showed therapeutic benefit. In humanized immunocompetent models, Delta-24-RGD significantly extended the survival of mice bearing AT/RTs or PNETs (ranging from 11 to 27 days) and did not display any toxicity associated with inflammation. Immunophenotyping of Delta-24-RGD-treated tumors revealed increased CD8+ T-cell infiltration. CONCLUSIONS Delta-24-RGD is a feasible therapeutic option for AT/RTs and CNS-PNETs. This work constitutes the basis for potential translation to the clinical setting.
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Affiliation(s)
- Marc Garcia-Moure
- Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain.
- Program in Solid Tumors, Foundation for the Applied Medical Research, Pamplona, Navarra, Spain
- Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Navarra, Spain
| | - Marisol Gonzalez-Huarriz
- Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain
- Program in Solid Tumors, Foundation for the Applied Medical Research, Pamplona, Navarra, Spain
- Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Navarra, Spain
| | - Sara Labiano
- Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain
- Program in Solid Tumors, Foundation for the Applied Medical Research, Pamplona, Navarra, Spain
- Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Navarra, Spain
| | - Elizabeth Guruceaga
- Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain
- Bioinformatics Platform, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain
| | - Eva Bandres
- Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain
- Immunology Unit, Department of Hematology, Complejo Hospitalario de Navarra, Pamplona, Navarra, Spain
| | - Marta Zalacain
- Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain
- Program in Solid Tumors, Foundation for the Applied Medical Research, Pamplona, Navarra, Spain
- Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Navarra, Spain
| | - Lucia Marrodan
- Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain
- Program in Solid Tumors, Foundation for the Applied Medical Research, Pamplona, Navarra, Spain
- Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Navarra, Spain
| | - Carlos de Andrea
- Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain
- Department of Pathology, Clínica Universidad de Navarra, Pamplona, Navarra, Spain
| | - Maria Villalba
- Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain
- Department of Pathology, Clínica Universidad de Navarra, Pamplona, Navarra, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Naiara Martinez-Velez
- Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain
- Program in Solid Tumors, Foundation for the Applied Medical Research, Pamplona, Navarra, Spain
- Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Navarra, Spain
| | - Virginia Laspidea
- Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain
- Program in Solid Tumors, Foundation for the Applied Medical Research, Pamplona, Navarra, Spain
- Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Navarra, Spain
| | - Montse Puigdelloses
- Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain
- Program in Solid Tumors, Foundation for the Applied Medical Research, Pamplona, Navarra, Spain
- Department of Neurology, Clínica Universidad de Navarra, Pamplona, Navarra, Spain
| | - Jaime Gallego Perez-Larraya
- Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain
- Program in Solid Tumors, Foundation for the Applied Medical Research, Pamplona, Navarra, Spain
- Department of Neurology, Clínica Universidad de Navarra, Pamplona, Navarra, Spain
| | - Ignacio Iñigo-Marco
- Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain
- Program in Solid Tumors, Foundation for the Applied Medical Research, Pamplona, Navarra, Spain
- Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Navarra, Spain
| | - Renata Stripecke
- Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Laboratory of Regenerative Immune Therapies Applied of the Research Network REBIRTH, German Centre for Infection Research (DZIF), partner site Hannover, Hannover, Germany
| | - Jennifer A Chan
- Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Eric H Raabe
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
- Division of Pediatric Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Marcel Kool
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Hopp Children's Cancer Center (KITZ), Heidelberg, Germany
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | - Candelaria Gomez-Manzano
- Department of NeuroOncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Juan Fueyo
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ana Patiño-García
- Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain
- Program in Solid Tumors, Foundation for the Applied Medical Research, Pamplona, Navarra, Spain
- Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Navarra, Spain
| | - Marta M Alonso
- Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain.
- Program in Solid Tumors, Foundation for the Applied Medical Research, Pamplona, Navarra, Spain
- Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Navarra, Spain
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Targeted Delivery of IL-12 Adjuvants Immunotherapy by Oncolytic Viruses. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1290:67-80. [PMID: 33559855 DOI: 10.1007/978-3-030-55617-4_4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
The great hopes raised by the discovery of the immunoregulatory cytokine interleukin 12 (IL-12) as an anticancer agent were marred during early clinical experimentation because of severe adverse effects, which prompted a search for alternative formulations and routes of administration. Onco-immunotherapeutic viruses (OIVs) are wild-type or genetically engineered viruses that exert antitumor activity by causing death of the tumor cells they infect and by overcoming a variety of immunosuppressive mechanisms put in place by the tumors. OIVs have renewed the interest in IL-12, as they offer the opportunity to encode the cytokine transgenically from the viral genome and to produce it at high concentrations in the tumor bed. A large body of evidence indicates that IL-12 serves as a potent adjuvant for the immunotherapeutic response elicited by OIVs in murine tumor models. The list of OIVs includes onco-immunotherapeutic herpes simplex, adeno, measles, Newcastle disease, and Maraba viruses, among others. The large increase in IL-12-mediated adjuvanticity was invariably observed for all the OIVs analyzed. Indirect evidence suggests that locally delivered IL-12 may also increase tumor antigenicity. Importantly, the OIV/IL-12 treatment was not accompanied by adverse effects and elicited a long-lasting immune response capable of halting the growth of distant tumors. Thus, OIVs provide an avenue for reducing the clinical toxicity associated with systemic IL-12 therapy, by concentrating the cytokine at the site of disease. The changes to the tumor microenvironment induced by the IL-12-armed OIVs primed the tumors to an improved response to the checkpoint blockade therapy, suggesting that the triple combination is worth pursuing in the future. The highly encouraging results in preclinical models have prompted translation to the clinic. How well the IL-12-OIV-checkpoint inhibitors' combination will perform in humans remains to be fully investigated.
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Olatz C, Patricia GG, Jon L, Iker B, Carmen DLH, Fernando U, Gaskon I, Ramon PJ. Is There Such a Thing as a Genuine Cancer Stem Cell Marker? Perspectives from the Gut, the Brain and the Dental Pulp. BIOLOGY 2020; 9:biology9120426. [PMID: 33260962 PMCID: PMC7760753 DOI: 10.3390/biology9120426] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 11/24/2020] [Accepted: 11/26/2020] [Indexed: 12/24/2022]
Abstract
The conversion of healthy stem cells into cancer stem cells (CSCs) is believed to underlie tumor relapse after surgical removal and fuel tumor growth and invasiveness. CSCs often arise from the malignant transformation of resident multipotent stem cells, which are present in most human tissues. Some organs, such as the gut and the brain, can give rise to very aggressive types of cancers, contrary to the dental pulp, which is a tissue with a very remarkable resistance to oncogenesis. In this review, we focus on the similarities and differences between gut, brain and dental pulp stem cells and their related CSCs, placing a particular emphasis on both their shared and distinctive cell markers, including the expression of pluripotency core factors. We discuss some of their similarities and differences with regard to oncogenic signaling, telomerase activity and their intrinsic propensity to degenerate to CSCs. We also explore the characteristics of the events and mutations leading to malignant transformation in each case. Importantly, healthy dental pulp stem cells (DPSCs) share a great deal of features with many of the so far reported CSC phenotypes found in malignant neoplasms. However, there exist literally no reports about the contribution of DPSCs to malignant tumors. This raises the question about the particularities of the dental pulp and what specific barriers to malignancy might be present in the case of this tissue. These notable differences warrant further research to decipher the singular properties of DPSCs that make them resistant to transformation, and to unravel new therapeutic targets to treat deadly tumors.
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Affiliation(s)
- Crende Olatz
- Department of Cell Biology and Histology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain; (C.O.); (G.-G.P.); (L.J.); (B.I.); (d.l.H.C.); (U.F.)
| | - García-Gallastegui Patricia
- Department of Cell Biology and Histology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain; (C.O.); (G.-G.P.); (L.J.); (B.I.); (d.l.H.C.); (U.F.)
| | - Luzuriaga Jon
- Department of Cell Biology and Histology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain; (C.O.); (G.-G.P.); (L.J.); (B.I.); (d.l.H.C.); (U.F.)
| | - Badiola Iker
- Department of Cell Biology and Histology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain; (C.O.); (G.-G.P.); (L.J.); (B.I.); (d.l.H.C.); (U.F.)
| | - de la Hoz Carmen
- Department of Cell Biology and Histology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain; (C.O.); (G.-G.P.); (L.J.); (B.I.); (d.l.H.C.); (U.F.)
| | - Unda Fernando
- Department of Cell Biology and Histology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain; (C.O.); (G.-G.P.); (L.J.); (B.I.); (d.l.H.C.); (U.F.)
| | - Ibarretxe Gaskon
- Department of Cell Biology and Histology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain; (C.O.); (G.-G.P.); (L.J.); (B.I.); (d.l.H.C.); (U.F.)
- Correspondence: (I.G.); (P.J.R.); Tel.: +34-946-013-218 (I.G.); +34-946-012-426 (P.J.R.)
| | - Pineda Jose Ramon
- Department of Cell Biology and Histology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain; (C.O.); (G.-G.P.); (L.J.); (B.I.); (d.l.H.C.); (U.F.)
- Achucarro Basque Center for Neuroscience Fundazioa, 48940 Leioa, Spain
- Correspondence: (I.G.); (P.J.R.); Tel.: +34-946-013-218 (I.G.); +34-946-012-426 (P.J.R.)
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26
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Menotti L, Avitabile E. Herpes Simplex Virus Oncolytic Immunovirotherapy: The Blossoming Branch of Multimodal Therapy. Int J Mol Sci 2020; 21:ijms21218310. [PMID: 33167582 PMCID: PMC7664223 DOI: 10.3390/ijms21218310] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 10/30/2020] [Accepted: 11/02/2020] [Indexed: 02/06/2023] Open
Abstract
Oncolytic viruses are smart therapeutics against cancer due to their potential to replicate and produce the needed therapeutic dose in the tumor, and to their ability to self-exhaust upon tumor clearance. Oncolytic virotherapy strategies based on the herpes simplex virus are reaching their thirties, and a wide variety of approaches has been envisioned and tested in many different models, and on a range of tumor targets. This huge effort has culminated in the primacy of an oncolytic HSV (oHSV) being the first oncolytic virus to be approved by the FDA and EMA for clinical use, for the treatment of advanced melanoma. The path has just been opened; many more cancer types with poor prognosis await effective and innovative therapies, and oHSVs could provide a promising solution, especially as combination therapies and immunovirotherapies. In this review, we analyze the most recent advances in this field, and try to envision the future ahead of oHSVs.
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Menyhárt O, Győrffy B. Molecular stratifications, biomarker candidates and new therapeutic options in current medulloblastoma treatment approaches. Cancer Metastasis Rev 2020; 39:211-233. [PMID: 31970590 PMCID: PMC7098941 DOI: 10.1007/s10555-020-09854-1] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Medulloblastoma (MB) is the most common malignant childhood tumor of the brain. Multimodal treatment consisting of surgery, radiation therapy, and chemotherapy reduced cumulative incidence of late mortality but increased the incidence of subsequent neoplasms and severe, incapacitating chronic health conditions. Present treatment strategies fail to recognize heterogeneity within patients despite wide divergence in individual responses. The persistent mortality rates and serious side effects of non-targeted cytotoxic therapies indicate a need for more refined therapeutic approaches. Advanced genomic research has led to the accumulation of an enormous amount of genetic information and resulted in a consensus distinguishing four molecular subgroups, WNT-activated, SHH-activated, and Group 3 and 4 medulloblastomas. These have distinct origin, demographics, molecular alterations, and clinical outcomes. Although subgroup affiliation does not predict response to therapy, new subgroup-specific markers of prognosis can enable a more layered risk stratification with additional subtypes within each primary subgroup. Here, we summarize subgroup-specific genetic alterations and their utility in current treatment strategies. The transition toward molecularly targeted interventions for newly diagnosed MBs remains slow, and prospective trials are needed to confirm stratifications based on molecular alterations. At the same time, numerous studies focus at fine-tuning the intensity of invasive radio- and chemotherapies to reduce intervention-related long-term morbidity. There are an increasing number of immunotherapy-based treatment strategies including immune checkpoint-inhibitors, oncolytic viruses, CAR-T therapy, and NK cells in recurrent and refractory MBs. Although most trials are in early phase, there is hope for therapeutic breakthroughs for advanced MBs within the next decade.
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Affiliation(s)
- Otília Menyhárt
- 2nd Department of Pediatrics and Department of Bioinformatics, Semmelweis University, Budapest, Hungary.,Research Centre for Natural Sciences, Cancer Biomarker Research Group, Institute of Enzymology, Magyar tudósok körútja 2, Budapest, H-1117, Hungary
| | - Balázs Győrffy
- 2nd Department of Pediatrics and Department of Bioinformatics, Semmelweis University, Budapest, Hungary. .,Research Centre for Natural Sciences, Cancer Biomarker Research Group, Institute of Enzymology, Magyar tudósok körútja 2, Budapest, H-1117, Hungary.
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Oncolytic Viruses as a Platform for the Treatment of Malignant Brain Tumors. Int J Mol Sci 2020; 21:ijms21207449. [PMID: 33050329 PMCID: PMC7589928 DOI: 10.3390/ijms21207449] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 10/07/2020] [Accepted: 10/07/2020] [Indexed: 12/11/2022] Open
Abstract
Malignant brain tumors remain incurable diseases. Although much effort has been devoted to improving patient outcome, multiple factors such as the high tumor heterogeneity, the strong tumor-induced immunosuppressive microenvironment, and the low mutational burden make the treatment of these tumors especially challenging. Thus, novel therapeutic strategies are urgent. Oncolytic viruses (OVs) are biotherapeutics that have been selected or engineered to infect and selectively kill cancer cells. Increasingly, preclinical and clinical studies demonstrate the ability of OVs to recruit T cells and induce durable immune responses against both virus and tumor, transforming a “cold” tumor microenvironment into a “hot” environment. Besides promising clinical results as a monotherapy, OVs can be powerfully combined with other cancer therapies, helping to overcome critical barriers through the creation of synergistic effects in the fight against brain cancer. Although many questions remain to be answered to fully exploit the therapeutic potential of OVs, oncolytic virotherapy will clearly be part of future treatments for patients with malignant brain tumors.
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29
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Lospinoso Severini L, Ghirga F, Bufalieri F, Quaglio D, Infante P, Di Marcotullio L. The SHH/GLI signaling pathway: a therapeutic target for medulloblastoma. Expert Opin Ther Targets 2020; 24:1159-1181. [PMID: 32990091 DOI: 10.1080/14728222.2020.1823967] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Medulloblastoma (MB) is a heterogeneous tumor of the cerebellum that is divided into four main subgroups with distinct molecular and clinical features. Sonic Hedgehog MB (SHH-MB) is the most genetically understood and occurs predominantly in childhood. Current therapies consist of aggressive and non-targeted multimodal approaches that are often ineffective and cause long-term complications. These problems intensify the need to develop molecularly targeted therapies to improve outcome and reduce treatment-related morbidities. In this scenario, Hedgehog (HH) signaling, a developmental pathway whose deregulation is involved in the pathogenesis of several malignancies, has emerged as an attractive druggable pathway for SHH-MB therapy. AREAS COVERED This review provides an overview of the advancements in the HH antagonist research field. We place an emphasis on Smoothened (SMO) and glioma-associated oncogene homolog (GLI) inhibitors and immunotherapy approaches that are validated in preclinical SHH-MB models and that have therapeutic potential for MB patients. Literature from Pubmed and data reported on ClinicalTrial.gov up to August 2020 were considered. EXPERT OPINION Extensive-omics analysis has enhanced our knowledge and has transformed the way that MB is studied and managed. The clinical use of SMO antagonists has yet to be determined, however, future GLI inhibitors and multitargeting approaches are promising.
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Affiliation(s)
| | - Francesca Ghirga
- Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia , 00161, Rome, Italy
| | - Francesca Bufalieri
- Department of Molecular Medicine, University of Rome La Sapienza , 00161, Rome, Italy
| | - Deborah Quaglio
- Department of Chemistry and Technology of Drugs, University of Rome La Sapienza, 00185 , Rome, Italy
| | - Paola Infante
- Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia , 00161, Rome, Italy
| | - Lucia Di Marcotullio
- Department of Molecular Medicine, University of Rome La Sapienza , 00161, Rome, Italy.,Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome La Sapienza , 00161, Rome, Italy
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30
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Blanas A, Zaal A, van der Haar Àvila I, Kempers M, Kruijssen L, de Kok M, Popovic MA, van der Horst JC, J. van Vliet S. FUT9-Driven Programming of Colon Cancer Cells towards a Stem Cell-Like State. Cancers (Basel) 2020; 12:cancers12092580. [PMID: 32927726 PMCID: PMC7565653 DOI: 10.3390/cancers12092580] [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: 06/09/2020] [Revised: 08/20/2020] [Accepted: 09/01/2020] [Indexed: 02/07/2023] Open
Abstract
Cancer stem cells (CSCs) are located in dedicated niches, where they remain inert to chemotherapeutic drugs and drive metastasis. Although plasticity in the CSC pool is well appreciated, the molecular mechanisms implicated in the regulation of cancer stemness are still elusive. Here, we define a fucosylation-dependent reprogramming of colon cancer cells towards a stem cell-like phenotype and function. De novo transcriptional activation of Fut9 in the murine colon adenocarcinoma cell line, MC38, followed by RNA seq-based regulon analysis, revealed major gene regulatory networks related to stemness. Lewisx, Sox2, ALDH and CD44 expression, tumorsphere formation, resistance to 5-FU treatment and in vivo tumor growth were increased in FUT9-expressing MC38 cells compared to the control cells. Likewise, human CRC cell lines highly expressing FUT9 displayed phenotypic features of CSCs, which were significantly impaired upon FUT9 knock-out. Finally, in primary CRC FUT9+ tumor cells pathways related to cancer stemness were enriched, providing a clinically meaningful annotation of the complicity of FUT9 in stemness regulation and may open new avenues for therapeutic intervention.
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Bernstock JD, Bag AK, Fiveash J, Kachurak K, Elsayed G, Chagoya G, Gessler F, Valdes PA, Madan-Swain A, Whitley R, Markert JM, Gillespie GY, Johnston JM, Friedman GK. Design and Rationale for First-in-Human Phase 1 Immunovirotherapy Clinical Trial of Oncolytic HSV G207 to Treat Malignant Pediatric Cerebellar Brain Tumors. Hum Gene Ther 2020; 31:1132-1139. [PMID: 32657154 DOI: 10.1089/hum.2020.101] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Brain tumors represent the most common pediatric solid neoplasms and leading cause of childhood cancer-related morbidity and mortality. Although most adult brain tumors are supratentorial and arise in the cerebrum, the majority of pediatric brain tumors are infratentorial and arise in the posterior fossa, specifically the cerebellum. Outcomes from malignant cerebellar tumors are unacceptable despite aggressive treatments (surgery, radiation, and/or chemotherapy) that are harmful to the developing brain. Novel treatments/approaches such as oncolytic virotherapy are urgently needed. Preclinical and prior clinical studies suggest that genetically engineered oncolytic herpes simplex virus (HSV-1) G207 can safely target cerebellar malignancies and has potential to induce an antitumor immune response at local and distant sites of disease, including spinal metastases and leptomeningeal disease. Herein, we outline the rationale, design, and significance of a first-in-human immunotherapy Phase 1 clinical trial targeting recurrent cerebellar malignancies with HSV G207 combined with a single low-dose of radiation (5 Gy), designed to enhance virus replication and innate and adaptive immune responses. We discuss the unique challenges of inoculating virus through intratumoral catheters into cerebellar tumors. The trial utilizes a single arm open-label traditional 3 + 3 design with four dose cohorts. The primary objective is to assess safety and tolerability of G207 with radiation in recurrent/progressive malignant pediatric cerebellar tumors. After biopsy to prove recurrence/progression, one to four intratumoral catheters will be placed followed by a controlled-rate infusion of G207 for 6 h followed by the removal of catheters at the bedside. Radiation will be given within 24 h of virus inoculation. Patients will be monitored closely for toxicity and virus shedding. Efficacy will be assessed by measuring radiographic response, performance score, progression-free and overall survival, and quality of life. The data obtained will be invaluable in our efforts to produce more effective and less toxic therapies for children with high-grade brain tumors.
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Affiliation(s)
- Joshua D Bernstock
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard University, Boston, Massachusetts, USA
| | - Asim K Bag
- Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - John Fiveash
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Kara Kachurak
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Galal Elsayed
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Gustavo Chagoya
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Florian Gessler
- Department for Neurosurgery, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Pablo A Valdes
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard University, Boston, Massachusetts, USA
| | - Avi Madan-Swain
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Richard Whitley
- Division of Pediatric Infectious Disease, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - James M Markert
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - G Yancey Gillespie
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - James M Johnston
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Gregory K Friedman
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama, USA.,Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA
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Luzzi S, Giotta Lucifero A, Brambilla I, Semeria Mantelli S, Mosconi M, Foiadelli T, Savasta S. Targeting the medulloblastoma: a molecular-based approach. ACTA BIO-MEDICA : ATENEI PARMENSIS 2020; 91:79-100. [PMID: 32608377 PMCID: PMC7975825 DOI: 10.23750/abm.v91i7-s.9958] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 06/01/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND The lack of success of standard therapies for medulloblastoma has highlighted the need to plan a new therapeutic approach. The purpose of this article is to provide an overview of the novel treatment strategies based on the molecular characterization and risk categories of the medulloblastoma, also focusing on up-to-date relevant clinical trials and the challenges in translating tailored approaches into clinical practice. METHODS An online search of the literature was carried out on the PubMed/MEDLINE and ClinicalTrials.gov websites about molecular classification of medulloblastomas, ongoing clinical trials and new treatment strategies. Only articles in the English language and published in the last five years were selected. The research was refined based on the best match and relevance. RESULTS A total 58 articles and 51 clinical trials were analyzed. Trials were of phase I, II, and I/II in 55%, 33% and 12% of the cases, respectively. Target and adoptive immunotherapies were the treatment strategies for newly diagnosed and recurrent medulloblastoma in 71% and 29% of the cases, respectively. CONCLUSION Efforts are focused on the fine-tuning of target therapies and immunotherapies, including agents directed to specific pathways, engineered T-cells and oncoviruses. The blood-brain barrier, chemoresistance, the tumor microenvironment and cancer stem cells are the main translational challenges to be overcome in order to optimize medulloblastoma treatment, reduce the long-term morbidity and increase the overall survival.
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Affiliation(s)
- Sabino Luzzi
- Neurosurgery Unit, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy; Neurosurgery Unit, Department of Surgical Sciences, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
| | - Alice Giotta Lucifero
- Neurosurgery Unit, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy.
| | - Ilaria Brambilla
- Pediatric Clinic, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, Uni-versity of Pavia, Pavia, Italy.
| | - Simona Semeria Mantelli
- Pediatric Clinic, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, Uni-versity of Pavia, Pavia, Italy.
| | - Mario Mosconi
- Orthopaedic and Traumatology Unit, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy.
| | - Thomas Foiadelli
- Pediatric Clinic, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, Uni-versity of Pavia, Pavia, Italy.
| | - Salvatore Savasta
- Pediatric Clinic, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, Uni-versity of Pavia, Pavia, Italy.
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Soldozy S, Skaff A, Soldozy K, Sokolowski JD, Norat P, Yagmurlu K, Sharifi KA, Tvrdik P, Park MS, Kalani MYS, Jane JA, Syed HR. From Bench to Bedside, the Current State of Oncolytic Virotherapy in Pediatric Glioma. Neurosurgery 2020; 87:1091-1097. [PMID: 32542365 DOI: 10.1093/neuros/nyaa247] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 04/10/2020] [Indexed: 12/26/2022] Open
Abstract
Glioma continues to be a challenging disease process, making up the most common tumor type within the pediatric population. While low-grade gliomas are typically amenable to surgical resection, higher grade gliomas often require additional radiotherapy in conjunction with adjuvant chemotherapy. Molecular profiling of these lesions has led to the development of various pharmacologic and immunologic agents, although these modalities are not without great systemic toxicity. In addition, the molecular biology of adult glioma and pediatric glioma has been shown to differ substantially, making the application of current chemotherapies dubious in children and adolescents. For this reason, therapies with high tumor specificity based on pediatric tumor cell biology that spare healthy tissue are needed. Oncolytic virotherapy serves to fill this niche, as evidenced by renewed interest in this domain of cancer therapy. Initially discovered by chance in the early 20th century, virotherapy has emerged as a viable treatment option. With promising results based on preclinical studies, the authors review several oncolytic viruses, with a focus on molecular mechanism and efficacy of these viruses in tumor cell lines and murine models. In addition, current phase I clinical trials evaluating oncolytic virotherapy in the treatment of pediatric glioma are summarized.
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Affiliation(s)
- Sauson Soldozy
- Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia.,Deparment of Neuroscience, University of Virginia Health System, Charlottesville, Virginia
| | - Anthony Skaff
- Deparment of Neuroscience, University of Virginia Health System, Charlottesville, Virginia
| | - Kamron Soldozy
- Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey
| | - Jennifer D Sokolowski
- Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia.,Deparment of Neuroscience, University of Virginia Health System, Charlottesville, Virginia
| | - Pedro Norat
- Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia.,Deparment of Neuroscience, University of Virginia Health System, Charlottesville, Virginia
| | - Kaan Yagmurlu
- Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia.,Deparment of Neuroscience, University of Virginia Health System, Charlottesville, Virginia
| | - Khadijeh A Sharifi
- Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia.,Deparment of Neuroscience, University of Virginia Health System, Charlottesville, Virginia
| | - Petr Tvrdik
- Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia.,Deparment of Neuroscience, University of Virginia Health System, Charlottesville, Virginia
| | - Min S Park
- Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia
| | - M Yashar S Kalani
- Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia.,Deparment of Neuroscience, University of Virginia Health System, Charlottesville, Virginia
| | - John A Jane
- Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia
| | - Hasan R Syed
- Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia
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Bahmad HF, Poppiti RJ. Medulloblastoma cancer stem cells: molecular signatures and therapeutic targets. J Clin Pathol 2020; 73:243-249. [PMID: 32034059 DOI: 10.1136/jclinpath-2019-206246] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 12/12/2019] [Accepted: 12/16/2019] [Indexed: 12/11/2022]
Abstract
Medulloblastoma (MB) is the most common malignant primary intracranial neoplasm diagnosed in childhood. Although numerous efforts have been made during the past few years to exploit novel targeted therapies for this aggressive neoplasm, there still exist substantial hitches hindering successful management of MB. Lately, progress in cancer biology has shown evidence that a subpopulation of cells within the tumour, namely cancer stem cells (CSCs), are thought to be responsible for the resistance to most chemotherapeutic agents and radiation therapy, accounting for cancer recurrence. Hence, it is crucial to identify the molecular signatures and genetic aberrations that characterise those CSCs and develop therapies that specifically target them. In this review, we aim to give an overview of the main genetic and molecular cues that depict MB-CSCs and provide a synopsis of the novel therapeutic approaches that specifically target this population of cells to attain enhanced antitumorous effects and therefore overcome resistance to therapy.
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Affiliation(s)
- Hisham F Bahmad
- Arkadi M Rywlin MD Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, Florida, USA.,Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Robert J Poppiti
- Arkadi M Rywlin MD Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, Florida, USA .,Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA
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35
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Bernstock JD, Vicario N, Rong L, Valdes PA, Choi BD, Chen JA, DiToro D, Osorio DS, Kachurak K, Gessler F, Johnston JM, Atkinson TP, Whitley RJ, Bag AK, Gillespie GY, Markert JM, Maric D, Friedman GK. A novel in situ multiplex immunofluorescence panel for the assessment of tumor immunopathology and response to virotherapy in pediatric glioblastoma reveals a role for checkpoint protein inhibition. Oncoimmunology 2019; 8:e1678921. [PMID: 31741780 PMCID: PMC6844311 DOI: 10.1080/2162402x.2019.1678921] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Revised: 09/09/2019] [Accepted: 09/29/2019] [Indexed: 01/31/2023] Open
Abstract
Immunotherapy with oncolytic herpes simplex virus-1 therapy offers an innovative, targeted, less-toxic approach for treating brain tumors. However, a major obstacle in maximizing oncolytic virotherapy is a lack of comprehensive understanding of the underlying mechanisms that unfold in CNS tumors/associated microenvironments after infusion of virus. We demonstrate that our multiplex biomarker screening platform comprehensively informs changes in both topographical location and functional states of resident/infiltrating immune cells that play a role in neuropathology after treatment with HSV G207 in a pediatric Phase 1 patient. Using this approach, we identified robust infiltration of CD8+ T cells suggesting activation of the immune response following virotherapy; however there was a corresponding upregulation of checkpoint proteins PD-1, PD-L1, CTLA-4, and IDO revealing a potential role for checkpoint inhibitors. Such work may ultimately lead to an understanding of the governing pathobiology of tumors, thereby fostering development of novel therapeutics tailored to produce optimal responses.
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Affiliation(s)
- Joshua D Bernstock
- Medical Scientist Training Program, University of Alabama at Birmingham, Birmingham, AL, USA.,Department of Neurosurgery, Brigham and Women's, Harvard Medical School, Boston, MA, USA
| | - Nunzio Vicario
- Department of Biomedical and Biotechnological Sciences, Physiology Section, University of Catania, Catania, Italy
| | - Li Rong
- Department of Pathology, Children's of Alabama, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Pablo A Valdes
- Department of Neurosurgery, Brigham and Women's, Harvard Medical School, Boston, MA, USA
| | - Bryan D Choi
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jason A Chen
- Medical Scientist Training Program, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Daniel DiToro
- Medical Scientist Training Program, University of Alabama at Birmingham, Birmingham, AL, USA.,Department of Pathology, Brigham and Women's, Harvard Medical School, Boston, MA, USA
| | - Diana S Osorio
- Division of Pediatric Hematology/Oncology, Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA
| | - Kara Kachurak
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Florian Gessler
- Department for Neurosurgery, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - James M Johnston
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - T Prescott Atkinson
- Division of Pediatric Allergy, Asthma & Immunology, Department of Pediatrics and Diagnostic Mycoplasma Laboratory, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Richard J Whitley
- Division of Infectious Diseases, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Asim K Bag
- Division of Neuroradiology, Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - G Yancey Gillespie
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - James M Markert
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Dragan Maric
- Flow and Imaging Cytometry Core Facility, National Institute of Neurological Disordersand Stroke, National Institutes of Health (NINDS/NIH), Bethesda, MD, USA
| | - Gregory K Friedman
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA.,Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
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Williams AP, Garner EF, Stafman LL, Aye JM, Quinn CH, Marayati R, Stewart JE, Atigadda VR, Mroczek-Musulman E, Moore BP, Beierle EA, Friedman GK. UAB30, A Novel Rexinoid Agonist, Decreases Stemness In Group 3 Medulloblastoma Human Cell Line Xenografts. Transl Oncol 2019; 12:1364-1374. [PMID: 31362265 PMCID: PMC6664160 DOI: 10.1016/j.tranon.2019.07.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 06/29/2019] [Accepted: 07/08/2019] [Indexed: 12/29/2022] Open
Abstract
PURPOSE: In spite of advances in therapy for some subtypes, group 3 medulloblastoma continues to portend a poor prognosis. A subpopulation of medulloblastoma cells expressing the cell surface marker CD133 have been posited as possible stem cell like cancer cells (SCLCC), a potential source of drug resistance and relapse. Retinoids have been shown to affect SCLCC in other brain tumors. Based on these findings, we hypothesized that the CD133-enriched cell population group 3 medulloblastoma cells would be sensitive to the novel rexinoid, UAB30. METHODS: Human medulloblastoma cell lines were studied. Cell sorting based on CD133 expression was performed. Both in vitro and in vivo extreme limiting dilution assays were completed to establish CD133 as a SCLCC marker in these cell lines. Cells were treated with either retinoic acid (RA) or UAB30 and sphere forming capacity and CD133 expression were assessed. Immunoblotting was used to assess changes in stem cell markers. Finally, mice injected with CD133-enriched or CD133-depleted cells were treated with UAB30. RESULTS: CD133-enriched cells more readily formed tumorspheres in vitro at lower cell concentrations and formed tumors in vivo at low cell numbers. Treatment with RA or UAB30 decreased CD133 expression, decreased tumorsphere formation, and decreased expression of cancer stem cell markers. In vivo studies demonstrated that tumors from both CD133-enriched and CD133-depleted cells were sensitive to treatment with UAB30. CONCLUSIONS: CD133 is a marker for medulloblastoma SCLCCs. Both CD133-enriched and CD133-depleted medulloblastoma cell populations demonstrated sensitivity to UAB30, indicating its potential as a therapeutic option for group 3 medulloblastoma.
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Affiliation(s)
- Adele P Williams
- Division of Pediatric Surgery, Department of Surgery, University of Alabama, Birmingham, Birmingham, AL
| | - Evan F Garner
- Division of Pediatric Surgery, Department of Surgery, University of Alabama, Birmingham, Birmingham, AL
| | - Laura L Stafman
- Division of Pediatric Surgery, Department of Surgery, University of Alabama, Birmingham, Birmingham, AL
| | - Jamie M Aye
- Division of Pediatric Hematology Oncology, Department of Pediatrics, University of Alabama, Birmingham, Birmingham, AL
| | - Colin H Quinn
- Division of Pediatric Surgery, Department of Surgery, University of Alabama, Birmingham, Birmingham, AL
| | - Raoud Marayati
- Division of Pediatric Surgery, Department of Surgery, University of Alabama, Birmingham, Birmingham, AL
| | - Jerry E Stewart
- Division of Pediatric Surgery, Department of Surgery, University of Alabama, Birmingham, Birmingham, AL
| | | | | | - Blake P Moore
- Division of Pediatric Hematology Oncology, Department of Pediatrics, University of Alabama, Birmingham, Birmingham, AL
| | - Elizabeth A Beierle
- Division of Pediatric Surgery, Department of Surgery, University of Alabama, Birmingham, Birmingham, AL.
| | - Gregory K Friedman
- Division of Pediatric Hematology Oncology, Department of Pediatrics, University of Alabama, Birmingham, Birmingham, AL
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The oncolytic virus Delta-24-RGD elicits an antitumor effect in pediatric glioma and DIPG mouse models. Nat Commun 2019; 10:2235. [PMID: 31138805 PMCID: PMC6538754 DOI: 10.1038/s41467-019-10043-0] [Citation(s) in RCA: 107] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Accepted: 04/16/2019] [Indexed: 12/17/2022] Open
Abstract
Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors in desperate need of a curative treatment. Oncolytic virotherapy is emerging as a solid therapeutic approach. Delta-24-RGD is a replication competent adenovirus engineered to replicate in tumor cells with an aberrant RB pathway. This virus has proven to be safe and effective in adult gliomas. Here we report that the administration of Delta-24-RGD is safe in mice and results in a significant increase in survival in immunodeficient and immunocompetent models of pHGG and DIPGs. Our results show that the Delta-24-RGD antiglioma effect is mediated by the oncolytic effect and the immune response elicited against the tumor. Altogether, our data highlight the potential of this virus as treatment for patients with these tumors. Of clinical significance, these data have led to the start of a phase I/II clinical trial at our institution for newly diagnosed DIPG (NCT03178032).
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Safety and efficacy of oncolytic HSV-1 G207 inoculated into the cerebellum of mice. Cancer Gene Ther 2019; 27:246-255. [PMID: 30918335 DOI: 10.1038/s41417-019-0091-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 03/12/2019] [Indexed: 12/25/2022]
Abstract
Primary malignant central nervous system (CNS) tumors are the leading cause of childhood cancer-related death and morbidity. While advances in surgery, radiation, and chemotherapy have improved the survival rates in children with malignant brain tumors, mortality persists in certain subpopulations and current therapies are associated with extreme morbidity. This is especially true for children with malignant infratentorial tumors. Accordingly, G207, a genetically engineered herpes simplex virus (HSV-1) capable of selectively targeting cancer cells has emerged as a promising therapeutic option for this patient population. Herein, we demonstrate that cerebellar inoculation of G207 was systemically non-toxic in an immunocompetent, HSV-1 sensitive mouse strain (CBA/J). Mice had neither abnormal brain/organ pathology nor evidence of G207 replication by immunohistochemistry at days 7 and 30 after cerebellar G207 inoculation. While a minute amount viral DNA was recovered in the cerebellum and brainstem of mice at day 7, no viral DNA persisted at day 30. Critically, G207 delivered to the cerebellum was able to target/treat the highly aggressive MYC-overexpressed group 3 murine medulloblastoma increasing survival vs controls. These results provide critical safety and efficacy data to support the translation of G207 for pediatric clinical trials in intractable cerebellar malignancies.
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Bernstock JD, Wright Z, Bag AK, Gessler F, Gillespie GY, Markert JM, Friedman GK, Johnston JM. Stereotactic Placement of Intratumoral Catheters for Continuous Infusion Delivery of Herpes Simplex Virus -1 G207 in Pediatric Malignant Supratentorial Brain Tumors. World Neurosurg 2018; 122:e1592-e1598. [PMID: 30481622 DOI: 10.1016/j.wneu.2018.11.122] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 11/13/2018] [Accepted: 11/15/2018] [Indexed: 01/20/2023]
Abstract
OBJECTIVE The engineered herpes simplex virus-1 G207, is a promising therapeutic option for central nervous system tumors. The first-ever pediatric phase 1 trial of continuous-infusion delivery of G207 via intratumoral catheters for recurrent or progressive malignant brain tumors is ongoing. In this article, we describe surgical techniques for the accurate placement of catheters in multiple supratentorial locations and perioperative complications associated with such procedures. METHODS A prospective study of G207 in children with recurrent malignant supratentorial tumors is ongoing. Preoperative stereotactic protocol magnetic resonance imaging was performed, and catheter trajectories planned using StealthStation planning software. Children underwent placement of 3-4 silastic catheters using a small incision burr hole and the Vertek system. Patients had a preinfusion computed tomography scan to confirm correct placement of catheters. RESULTS Six children underwent implantation of 3-4 catheters. Locations of catheter placement included frontal, temporal, parietal, and occipital lobes, and the insula and thalamus. There were no clinically significant perioperative complications. Postoperative computed tomography scans coupled with preoperative MRI scans demonstrated accurate placement of 21 of 22 catheters, with 1 misplaced catheter pulled back to an optimal location at the bedside. One patient had hemorrhage along the catheter tract that was clinically asymptomatic. Another patient had cerebrospinal fluid leak from a biopsy incision 9 days after surgery that was oversewn without complication. CONCLUSIONS The placement of multiple intratumoral catheters in pediatric patients with supratentorial tumors via frameless stereotactic techniques is feasible and safe. Intratumoral catheters provide a potentially effective route for the delivery of G207 and may be employed in other trials utilizing oncolytic virotherapy for brain tumors.
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Affiliation(s)
- Joshua D Bernstock
- Medical Scientist Training Program, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Zachary Wright
- Department of Neurosurgery, Division of Pediatric Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Asim K Bag
- Department of Radiology, Neuroradiology Section, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Florian Gessler
- Department of Neurosurgery, Goethe University Frankfurt, Frankfurt am Main, Germany
| | | | - James M Markert
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Gregory K Friedman
- Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Neurosurgery, Division of Pediatric Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama, USA.
| | - James M Johnston
- Department of Neurosurgery, Division of Pediatric Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
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Garner EF, Stafman LL, Williams AP, Aye JM, Goolsby C, Atigadda VR, Moore BP, Nan L, Stewart JE, Hjelmeland AB, Friedman GK, Beierle EA. UAB30, a novel RXR agonist, decreases tumorigenesis and leptomeningeal disease in group 3 medulloblastoma patient-derived xenografts. J Neurooncol 2018; 140:209-224. [PMID: 30132166 PMCID: PMC6239946 DOI: 10.1007/s11060-018-2950-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Accepted: 07/12/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Group 3 tumors account for approximately 25-30% of medulloblastomas and have the worst prognosis. UAB30 is a novel synthetic rexinoid shown to have limited toxicities in humans and significant efficacy in the pediatric neuroectodermal tumor, neuroblastoma. We hypothesized that treatment with UAB30 would decrease tumorigenicity in medulloblastoma patient-derived xenografts (PDXs). METHODS Three group 3 medulloblastoma PDXs (D341, D384 and D425) were utilized. Cell viability, proliferation, migration and invasion assays were performed after treatment with UAB30 or 13-cis-retinoic acid (RA). Cell cycle analysis was completed using flow cytometry. A flank model, a cerebellar model, and a model of leptomeningeal metastasis using human medulloblastoma PDX cells was used to assess the in vivo effects of UAB30 and RA. RESULTS UAB30 treatment led to cell differentiation and decreased medulloblastoma PDX cell viability, proliferation, migration and invasion and G1 cell cycle arrest in all three PDXs similar to RA. UAB30 and RA treatment of mice bearing medulloblastoma PDX tumors resulted in a significant decrease in tumor growth and metastasis compared to vehicle treated animals. CONCLUSIONS UAB30 decreased viability, proliferation, and motility in group 3 medulloblastoma PDX cells and significantly decreased tumor growth in vivo in a fashion similar to RA, suggesting that further investigations into the potential therapeutic application of UAB30 for medulloblastoma are warranted.
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Affiliation(s)
- Evan F Garner
- Division of Pediatric Surgery, Department of Surgery, University of Alabama, Birmingham, Birmingham, AL, USA
| | - Laura L Stafman
- Division of Pediatric Surgery, Department of Surgery, University of Alabama, Birmingham, Birmingham, AL, USA
| | - Adele P Williams
- Division of Pediatric Surgery, Department of Surgery, University of Alabama, Birmingham, Birmingham, AL, USA
| | - Jamie M Aye
- Division of Pediatric Hematology Oncology, Department of Pediatrics, University of Alabama, Birmingham, Birmingham, AL, USA
| | - Caroline Goolsby
- Division of Pediatric Surgery, Department of Surgery, University of Alabama, Birmingham, Birmingham, AL, USA
| | - Venkatram R Atigadda
- Department of Dermatology, University of Alabama, Birmingham, Birmingham, AL, USA
| | - Blake P Moore
- Division of Pediatric Hematology Oncology, Department of Pediatrics, University of Alabama, Birmingham, Birmingham, AL, USA
| | - Li Nan
- Division of Pediatric Hematology Oncology, Department of Pediatrics, University of Alabama, Birmingham, Birmingham, AL, USA
| | - Jerry E Stewart
- Division of Pediatric Surgery, Department of Surgery, University of Alabama, Birmingham, Birmingham, AL, USA
| | - Anita B Hjelmeland
- Department of Cell, Developmental and Integrative Biology, University of Alabama, Birmingham, Birmingham, AL, USA
| | - Gregory K Friedman
- Division of Pediatric Hematology Oncology, Department of Pediatrics, University of Alabama, Birmingham, Birmingham, AL, USA
| | - Elizabeth A Beierle
- Division of Pediatric Surgery, Department of Surgery, University of Alabama, Birmingham, Birmingham, AL, USA.
- , Birmingham, USA.
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Friedman GK, Bernstock JD, Chen D, Nan L, Moore BP, Kelly VM, Youngblood SL, Langford CP, Han X, Ring EK, Beierle EA, Gillespie GY, Markert JM. Enhanced Sensitivity of Patient-Derived Pediatric High-Grade Brain Tumor Xenografts to Oncolytic HSV-1 Virotherapy Correlates with Nectin-1 Expression. Sci Rep 2018; 8:13930. [PMID: 30224769 PMCID: PMC6141470 DOI: 10.1038/s41598-018-32353-x] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 09/04/2018] [Indexed: 12/30/2022] Open
Abstract
Pediatric high-grade brain tumors and adult glioblastoma are associated with significant morbidity and mortality. Oncolytic herpes simplex virus-1 (oHSV) is a promising approach to target brain tumors; oHSV G207 and M032 (encodes human interleukin-12) are currently in phase I clinical trials in children with malignant supratentorial brain tumors and adults with glioblastoma, respectively. We sought to compare the sensitivity of patient-derived pediatric malignant brain tumor and adult glioblastoma xenografts to these clinically-relevant oHSV. In so doing we found that pediatric brain tumors were more sensitive to the viruses and expressed significantly more nectin-1 (CD111) than adult glioblastoma. Pediatric embryonal and glial tumors were 74-fold and 14-fold more sensitive to M002 and 16-fold and 6-fold more sensitive to G207 than adult glioblastoma, respectively. Of note, pediatric embryonal tumors were more sensitive than glial tumors. Differences in sensitivity may be due in part to nectin-1 expression, which predicted responses to the viruses. Treatment with oHSV resulted in prolonged survival in both pediatric and adult intracranial patient-dervied tumor xenograft models. Our results suggest that pediatric brain tumors are ideal targets for oHSV and that brain tumor expression of nectin-1 may be a useful biomarker to predict patient response to oHSV.
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Affiliation(s)
- Gregory K Friedman
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
| | - Joshua D Bernstock
- School of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - Dongquan Chen
- Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - Li Nan
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - Blake P Moore
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - Virginia M Kelly
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - Samantha L Youngblood
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - Catherine P Langford
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - Xiaosi Han
- Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - Eric K Ring
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - Elizabeth A Beierle
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - G Yancey Gillespie
- Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - James M Markert
- Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
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Oncolytic Viruses as Therapeutic Tools for Pediatric Brain Tumors. Cancers (Basel) 2018; 10:cancers10070226. [PMID: 29987215 PMCID: PMC6071081 DOI: 10.3390/cancers10070226] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 07/04/2018] [Indexed: 12/18/2022] Open
Abstract
In recent years, we have seen an important progress in our comprehension of the molecular basis of pediatric brain tumors (PBTs). However, they still represent the main cause of death by disease in children. Due to the poor prognosis of some types of PBTs and the long-term adverse effects associated with the traditional treatments, oncolytic viruses (OVs) have emerged as an interesting therapeutic option since they displayed safety and high tolerability in pre-clinical and clinical levels. In this review, we summarize the OVs evaluated in different types of PBTs, mostly in pre-clinical studies, and we discuss the possible future direction of research in this field. In this sense, one important aspect of OVs antitumoral effect is the stimulation of an immune response against the tumor which is necessary for a complete response in preclinical immunocompetent models and in the clinic. The role of the immune system in the response of OVs needs to be evaluated in PBTs and represents an experimental challenge due to the limited immunocompetent models of these diseases available for pre-clinical research.
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FTY720 Decreases Tumorigenesis in Group 3 Medulloblastoma Patient-Derived Xenografts. Sci Rep 2018; 8:6913. [PMID: 29720672 PMCID: PMC5932040 DOI: 10.1038/s41598-018-25263-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2017] [Accepted: 03/14/2018] [Indexed: 12/20/2022] Open
Abstract
Group 3 tumors account for 28% of medulloblastomas and have the worst prognosis. FTY720, an immunosuppressant currently approved for treatment of multiple sclerosis, has shown antitumor effects in several human cancer cell lines. We hypothesized that treatment with FTY720 (fingolimod) would decrease tumorigenicity in medulloblastoma patient-derived xenografts (PDXs). Three Group 3 medulloblastoma PDXs (D341, D384 and D425) were utilized. Expression of PP2A and its endogenous inhibitors I2PP2A and CIP2A was detected by immunohistochemistry and immunoblotting. PP2A activation was measured via phosphatase activation kit. Cell viability, proliferation, migration and invasion assays were performed after treatment with FTY720. Cell cycle analysis was completed using flow cytometry. A flank model using D425 human medulloblastoma PDX cells was used to assess the in vivo effects of FTY720. FTY720 activated PP2A and led to decreased medulloblastoma PDX cell viability, proliferation, migration and invasion and G1 cell cycle arrest in all three PDXs. FTY720 treatment of mice bearing D425 medulloblastoma PDX tumors resulted in a significant decrease in tumor growth compared to vehicle treated animals. FTY720 decreased viability, proliferation, and motility in Group 3 medulloblastoma PDX cells and significantly decreased tumor growth in vivo. These results suggest that FTY720 should be investigated further as a potential therapeutic agent for medulloblastoma.
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Wang J, Garancher A, Ramaswamy V, Wechsler-Reya RJ. Medulloblastoma: From Molecular Subgroups to Molecular Targeted Therapies. Annu Rev Neurosci 2018; 41:207-232. [PMID: 29641939 DOI: 10.1146/annurev-neuro-070815-013838] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Brain tumors are the leading cause of cancer-related death in children, and medulloblastoma (MB) is the most common malignant pediatric brain tumor. Advances in surgery, radiation, and chemotherapy have improved the survival of MB patients. But despite these advances, 25-30% of patients still die from the disease, and survivors suffer severe long-term side effects from the aggressive therapies they receive. Although MB is often considered a single disease, molecular profiling has revealed a significant degree of heterogeneity, and there is a growing consensus that MB consists of multiple subgroups with distinct driver mutations, cells of origin, and prognosis. Here, we review recent progress in MB research, with a focus on the genes and pathways that drive tumorigenesis, the animal models that have been developed to study tumor biology, and the advances in conventional and targeted therapy.
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Affiliation(s)
- Jun Wang
- Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, USA;
| | - Alexandra Garancher
- Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, USA;
| | - Vijay Ramaswamy
- Division of Haematology/Oncology and Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
| | - Robert J Wechsler-Reya
- Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, USA;
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45
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Veillon L, Fakih C, Abou-El-Hassan H, Kobeissy F, Mechref Y. Glycosylation Changes in Brain Cancer. ACS Chem Neurosci 2018; 9:51-72. [PMID: 28982002 DOI: 10.1021/acschemneuro.7b00271] [Citation(s) in RCA: 97] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Protein glycosylation is a posttranslational modification that affects more than half of all known proteins. Glycans covalently bound to biomolecules modulate their functions by both direct interactions, such as the recognition of glycan structures by binding partners, and indirect mechanisms that contribute to the control of protein conformation, stability, and turnover. The focus of this Review is the discussion of aberrant glycosylation related to brain cancer. Altered sialylation and fucosylation of N- and O-glycans play a role in the development and progression of brain cancer. Additionally, aberrant O-glycan expression has been implicated in brain cancer. This Review also addresses the clinical potential and applications of aberrant glycosylation for the detection and treatment of brain cancer. The viable roles glycans may play in the development of brain cancer therapeutics are addressed as well as cancer-glycoproteomics and personalized medicine. Glycoprotein alterations are considered as a hallmark of cancer while high expression in body fluids represents an opportunity for cancer assessment.
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Affiliation(s)
- Lucas Veillon
- Department
of Chemistry and Biochemistry, Texas Tech University, Lubbock Texas 79409, United States
| | - Christina Fakih
- Department
of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Hadi Abou-El-Hassan
- Department
of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Firas Kobeissy
- Department
of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Yehia Mechref
- Department
of Chemistry and Biochemistry, Texas Tech University, Lubbock Texas 79409, United States
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46
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Lieberman NAP, Vitanza NA, Crane CA. Immunotherapy for brain tumors: understanding early successes and limitations. Expert Rev Neurother 2018; 18:251-259. [DOI: 10.1080/14737175.2018.1425617] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Nicole A. P. Lieberman
- Ben Towne Center for Childhood Cancer Research, Seattle Children’s Research Institute, Seattle, WA, USA
| | - Nicholas A. Vitanza
- Division of Hematology/Oncology, Department of Pediatrics, Seattle Children's Hospital, University of Washington School of Medicine, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Courtney A. Crane
- Ben Towne Center for Childhood Cancer Research, Seattle Children’s Research Institute, Seattle, WA, USA
- Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA, USA
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47
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Waters AM, Johnston JM, Reddy AT, Fiveash J, Madan-Swain A, Kachurak K, Bag AK, Gillespie GY, Markert JM, Friedman GK. Rationale and Design of a Phase 1 Clinical Trial to Evaluate HSV G207 Alone or with a Single Radiation Dose in Children with Progressive or Recurrent Malignant Supratentorial Brain Tumors. HUM GENE THER CL DEV 2017; 28:7-16. [PMID: 28319448 DOI: 10.1089/humc.2017.002] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Primary central nervous system tumors are the most common solid neoplasm of childhood and the leading cause of cancer-related death in pediatric patients. Survival rates for children with malignant supratentorial brain tumors are poor despite aggressive treatment with combinations of surgery, radiation, and chemotherapy, and survivors often suffer from damaging lifelong sequelae from current therapies. Novel innovative treatments are greatly needed. One promising new approach is the use of a genetically engineered, conditionally replicating herpes simplex virus (HSV) that has shown tumor-specific tropism and potential efficacy in the treatment of malignant brain tumors. G207 is a genetically engineered HSV-1 lacking genes essential for replication in normal brain cells. Safety has been established in preclinical investigations involving intracranial inoculation in the highly HSV-sensitive owl monkey (Aotus nancymai), and in three adult phase 1 trials in recurrent/progressive high-grade gliomas. No dose-limiting toxicities were seen in the adult studies and a maximum tolerated dose was not reached. Approximately half of the 35 treated adults had radiographic or neuropathologic evidence of response at a minimum of one time point. Preclinical studies in pediatric brain tumor models indicate that a variety of pediatric tumor types are highly sensitive to killing by G207. This clinical protocol outlines a first in human children study of intratumoral inoculation of an oncolytic virus via catheters placed directly into recurrent or progressive supratentorial malignant tumors.
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Affiliation(s)
- Alicia M Waters
- 1 Department of Surgery, Division of Pediatric Surgery, University of Alabama at Birmingham , Birmingham, Alabama
| | - James M Johnston
- 2 Department of Neurosurgery, University of Alabama at Birmingham , Birmingham, Alabama
| | - Alyssa T Reddy
- 3 Department of Pediatrics, Division of Hematology/Oncology, University of Alabama at Birmingham , Birmingham, Alabama
| | - John Fiveash
- 4 Department of Radiation Oncology, University of Alabama at Birmingham , Birmingham, Alabama
| | - Avi Madan-Swain
- 3 Department of Pediatrics, Division of Hematology/Oncology, University of Alabama at Birmingham , Birmingham, Alabama
| | - Kara Kachurak
- 5 Division of Hematology/Oncology, Children's of Alabama , Birmingham, Alabama
| | - Asim K Bag
- 6 Department of Radiology, University of Alabama at Birmingham , Birmingham, Alabama
| | - G Yancey Gillespie
- 2 Department of Neurosurgery, University of Alabama at Birmingham , Birmingham, Alabama
| | - James M Markert
- 2 Department of Neurosurgery, University of Alabama at Birmingham , Birmingham, Alabama.,3 Department of Pediatrics, Division of Hematology/Oncology, University of Alabama at Birmingham , Birmingham, Alabama
| | - Gregory K Friedman
- 3 Department of Pediatrics, Division of Hematology/Oncology, University of Alabama at Birmingham , Birmingham, Alabama
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48
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Yin J, Markert JM, Leavenworth JW. Modulation of the Intratumoral Immune Landscape by Oncolytic Herpes Simplex Virus Virotherapy. Front Oncol 2017; 7:136. [PMID: 28695111 PMCID: PMC5483455 DOI: 10.3389/fonc.2017.00136] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2017] [Accepted: 06/09/2017] [Indexed: 12/28/2022] Open
Abstract
Vaccines and immunotherapeutic approaches to cancers with the advent of immune checkpoint inhibitors and chimeric antigen receptor-modified T cells have recently demonstrated preclinical success and entered clinical trials. Despite advances in these approaches and combinatorial therapeutic regimens, depending on the nature of the cancer and the immune and metabolic landscape within the tumor microenvironment, current immunotherapeutic modalities remain inadequate. Recent clinical trials have demonstrated clear evidence of significant, and sometimes dramatic, antitumor activity, and long-term survival effects of a variety of oncolytic viruses (OVs), particularly oncolytic herpes simplex virus (oHSV). Acting as a multifaceted gene therapy vector and potential adjuvant-like regimens, oHSV can carry genes encoding immunostimulatory molecules in its genome. The oncolytic effect of oHSV and the inflammatory response that the virus stimulates provide a one-two punch at attacking tumors. However, mechanisms underlying oHSV-induced restoration of intratumoral immunosuppression demand extensive research in order to further improve its therapeutic efficacy. In this review, we discuss the current OV-based therapy, with a focus on the unique aspects of oHSV-initiated antiviral and antitumor immune responses, arising from virus-mediated immunological cell death to intratumoral innate and adaptive immunity.
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Affiliation(s)
- Jie Yin
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, United States.,Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - James M Markert
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, United States.,Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, United States.,Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Jianmei W Leavenworth
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, United States.,Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States
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49
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Studebaker AW, Hutzen BJ, Pierson CR, Haworth KB, Cripe TP, Jackson EM, Leonard JR. Oncolytic Herpes Virus rRp450 Shows Efficacy in Orthotopic Xenograft Group 3/4 Medulloblastomas and Atypical Teratoid/Rhabdoid Tumors. MOLECULAR THERAPY-ONCOLYTICS 2017. [PMID: 28649600 PMCID: PMC5472147 DOI: 10.1016/j.omto.2017.05.005] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
Pediatric brain tumors including medulloblastoma and atypical teratoid/rhabdoid tumor are associated with significant mortality and treatment-associated morbidity. While medulloblastoma tumors within molecular subgroups 3 and 4 have a propensity to metastasize, atypical teratoid/rhabdoid tumors frequently afflict a very young patient population. Adjuvant treatment options for children suffering with these tumors are not only sub-optimal but also associated with many neurocognitive obstacles. A potentially novel treatment approach is oncolytic virotherapy, a developing therapeutic platform currently in early-phase clinical trials for pediatric brain tumors and recently US Food and Drug Administration (FDA)-approved to treat melanoma in adults. We evaluated the therapeutic potential of the clinically available oncolytic herpes simplex vector rRp450 in cell lines derived from medulloblastoma and atypical teratoid/rhabdoid tumor. Cells of both tumor types were supportive of virus replication and virus-mediated cytotoxicity. Orthotopic xenograft models of medulloblastoma and atypical teratoid/rhabdoid tumors displayed significantly prolonged survival following a single, stereotactic intratumoral injection of rRp450. Furthermore, addition of the chemotherapeutic prodrug cyclophosphamide (CPA) enhanced rRp450's in vivo efficacy. In conclusion, oncolytic herpes viruses with the ability to bioactivate the prodrug CPA within the tumor microenvironment warrant further investigation as a potential therapy for pediatric brain tumors.
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Affiliation(s)
- Adam W Studebaker
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA
| | - Brian J Hutzen
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA
| | - Christopher R Pierson
- Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH 43205, USA.,Department of Pathology, The Ohio State University College of Medicine, Columbus, OH 43210, USA.,Division of Anatomy, The Ohio State University, Columbus, OH 43210, USA
| | - Kellie B Haworth
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.,Division of Hematology/Oncology/Blood and Marrow Transplant, Nationwide Children's Hospital, Columbus, OH 43205, USA
| | - Timothy P Cripe
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.,Division of Hematology/Oncology/Blood and Marrow Transplant, Nationwide Children's Hospital, Columbus, OH 43205, USA
| | - Eric M Jackson
- Department of Neurosurgery, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Jeffrey R Leonard
- Department of Neurosurgery, Nationwide Children's Hospital, Columbus, OH 43205, USA
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50
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Foreman PM, Friedman GK, Cassady KA, Markert JM. Oncolytic Virotherapy for the Treatment of Malignant Glioma. Neurotherapeutics 2017; 14:333-344. [PMID: 28265902 PMCID: PMC5398989 DOI: 10.1007/s13311-017-0516-0] [Citation(s) in RCA: 102] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Malignant glioma is the most common primary brain tumor and carries a grim prognosis, with a median survival of just over 14 months. Given the poor outcomes with standard-of-care treatments, novel treatment strategies are needed. The concept of virotherapy for the treatment of malignant tumors dates back more than a century and can be divided into replication-competent oncolytic viruses and replication-deficient viral vectors. Oncolytic viruses are designed to selectively target, infect, and replicate in tumor cells, while sparing surrounding normal brain. A host of oncolytic viruses has been evaluated in early phase human trials with promising safety results, but none has progressed to phase III trials. Despite the 25 years that has passed since the initial publication of genetically engineered oncolytic viruses for the treatment of glioma, much remains to be learned about the use of this therapy, including its mechanism of action, optimal treatment paradigm, appropriate targets, and integration with adjuvant agents. Oncolytic viral therapy for glioma remains promising and will undoubtedly impact the future of patient care.
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Affiliation(s)
- Paul M Foreman
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Gregory K Friedman
- Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA
| | | | - James M Markert
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA.
- Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA.
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