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Plant-Fox AS, Tabori U. Future perspective of targeted treatments in pediatric low-grade glioma (pLGG): the evolution of standard-of-care and challenges of a new era. Childs Nerv Syst 2024; 40:3291-3299. [PMID: 39085626 DOI: 10.1007/s00381-024-06504-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 06/16/2024] [Indexed: 08/02/2024]
Abstract
While surgery, when possible, remains the mainstay of pediatric low-grade glioma (pLGG) management, adjuvant therapy has significantly evolved over time. Radiation therapy was commonly used in the late 1990s for tumors that could not be resected or recurred. This resulted in significant late morbidity in this population and mortality related to secondary malignancies and chronic health conditions. Chemotherapy became the mainstay of adjuvant therapy but children still experienced late morbidity secondary to exposure to multiple lines of treatment over time. Targeted therapies emerged after the identification of frequent genetic alterations in the mitogen activated protein kinase (MAPK) pathway including KIAA1549-BRAF fusions and BRAF-V600 mutations and the near universal upregulation of the MAPK pathway in these tumors. Both BRAF and MEK inhibitors have shown efficacy in the treatment of pLGG and have led to prolonged stability in some cases. Multiple phase III clinical trials are now comparing targeted therapy to standard-of-care chemotherapy regimens setting the stage for targeted therapy to replace chemotherapy as the first-line treatment in some cases. Targeted therapy, however, is not without its challenges. There are clear examples of resistance and mechanisms of resistance have not been fully elucidated. There is also no clear duration for these therapies and rebound growth is a well-known phenomenon especially in BRAF-V600 mutant tumors. Targeted therapies are also fairly recent developments and long-term toxicities and functional outcomes are still being monitored. Very young and adolescent/young adult LGGs also carry molecular features that may not be addressed by inhibition of the MAPK pathway. Adjuvant therapy for pLGG has evolved from radiation for all unresectable or residual tumors to molecularly driven targeted therapies with improved quality of life, late effects, and less off-target toxicities. While there is still much to learn in regard to newer targeted therapies for pLGG, the era of targeted therapies for pediatric LGG is upon us.
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Affiliation(s)
- Ashley S Plant-Fox
- Ann & Robert H. Lurie Children's Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
| | - Uri Tabori
- The Hospital for Sick Children, University of Toronto, Toronto, Canada
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Siegel BI, Duke ES, Kilburn LB, Packer RJ. Molecular-targeted therapy for childhood low-grade glial and glioneuronal tumors. Childs Nerv Syst 2024; 40:3251-3262. [PMID: 38877124 DOI: 10.1007/s00381-024-06486-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 06/01/2024] [Indexed: 06/16/2024]
Abstract
Since the discovery of the association between BRAF mutations and fusions in the development of childhood low-grade gliomas and the subsequent recognition that most childhood low-grade glial and glioneuronal tumors have aberrant signaling through the RAS/RAF/MAP kinase pathway, there has been a dramatic change in how these tumors are conceptualized. Many of the fusions and mutations present in these tumors are associated with molecular targets, which have agents in development or already in clinical use. Various agents, including MEK inhibitors, BRAF inhibitors, MTOR inhibitors and, in small subsets of patients NTRK inhibitors, have been used successfully to treat children with recurrent disease, after failure of conventional approaches such as surgery or chemotherapy. The relative benefits of chemotherapy as compared to molecular-targeted therapy for children with newly diagnosed gliomas and neuroglial tumors are under study. Already the combination of an MEK inhibitor and a BRAF inhibitor has been shown superior to conventional chemotherapy (carboplatin and vincristine) in newly diagnosed children with BRAF-V600E mutated low-grade gliomas and neuroglial tumors. However, the long-term effects of such molecular-targeted treatment are unknown. The potential use of molecular-targeted therapy in early treatment has made it mandatory that the molecular make-up of the majority of low-grade glial and glioneuronal tumors is known before initiation of therapy. The primary exception to this rule is in children with neurofibromatosis type 1 who, by definition, have NF1 loss; however, even in this population, gliomas arising in late childhood and adolescence or those not responding to conventional treatment may be candidates for biopsy, especially before entry on molecular-targeted therapy trials.
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Affiliation(s)
- Benjamin I Siegel
- Brain Tumor Institute, Children's National Hospital, 111 Michigan Ave NW, Washington, DC, 20010, USA.
- Gilbert Family Neurofibromatosis Institute, Children's National Hospital, Washington, DC, USA.
- Division of Neurology, Children's National Hospital, Washington, DC, USA.
- Division of Oncology, Children's National Hospital, Washington, DC, USA.
| | - Elizabeth S Duke
- Brain Tumor Institute, Children's National Hospital, 111 Michigan Ave NW, Washington, DC, 20010, USA
- Division of Neurology, Children's National Hospital, Washington, DC, USA
| | - Lindsay B Kilburn
- Brain Tumor Institute, Children's National Hospital, 111 Michigan Ave NW, Washington, DC, 20010, USA
- Division of Oncology, Children's National Hospital, Washington, DC, USA
| | - Roger J Packer
- Brain Tumor Institute, Children's National Hospital, 111 Michigan Ave NW, Washington, DC, 20010, USA
- Gilbert Family Neurofibromatosis Institute, Children's National Hospital, Washington, DC, USA
- Division of Neurology, Children's National Hospital, Washington, DC, USA
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3
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Chen Y, Yu J, Ge S, Jia R, Song X, Wang Y, Fan X. An Overview of Optic Pathway Glioma With Neurofibromatosis Type 1: Pathogenesis, Risk Factors, and Therapeutic Strategies. Invest Ophthalmol Vis Sci 2024; 65:8. [PMID: 38837168 PMCID: PMC11160950 DOI: 10.1167/iovs.65.6.8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Accepted: 05/14/2024] [Indexed: 06/06/2024] Open
Abstract
Optic pathway gliomas (OPGs) are most predominant pilocytic astrocytomas, which are typically diagnosed within the first decade of life. The majority of affected children with OPGs also present with neurofibromatosis type 1 (NF1), the most common tumor predisposition syndrome. OPGs in individuals with NF1 primarily affect the optic pathway and lead to visual disturbance. However, it is challenging to assess risk in asymptomatic patients without valid biomarkers. On the other hand, for symptomatic patients, there is still no effective treatment to prevent or recover vision loss. Therefore, this review summarizes current knowledge regarding the pathogenesis of NF1-associated OPGs (NF1-OPGs) from preclinical studies to seek potential prognostic markers and therapeutic targets. First, the loss of the NF1 gene activates 3 distinct Ras effector pathways, including the PI3K/AKT/mTOR pathway, the MEK/ERK pathway, and the cAMP pathway, which mediate glioma tumorigenesis. Meanwhile, non-neoplastic cells from the tumor microenvironment (microglia, T cells, neurons, etc.) also contribute to gliomagenesis via various soluble factors. Subsequently, we investigated potential genetic risk factors, molecularly targeted therapies, and neuroprotective strategies for tumor prevention and vision recovery. Last, potential directions and promising preclinical models of NF1-OPGs are presented for further research. On the whole, NF1-OPGs develop as a result of the interaction between glioma cells and the tumor microenvironment. Developing effective treatments require a better understanding of tumor molecular characteristics, as well as multistage interventions targeting both neoplastic cells and non-neoplastic cells.
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Affiliation(s)
- Ying Chen
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P.R. China
| | - Jie Yu
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P.R. China
| | - Shengfang Ge
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P.R. China
| | - Renbing Jia
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P.R. China
| | - Xin Song
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P.R. China
| | - Yefei Wang
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P.R. China
| | - Xianqun Fan
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P.R. China
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Yamada S, Tanikawa M, Matsushita Y, Fujinami R, Yamada H, Sakomi K, Sakata T, Inagaki H, Yokoo H, Ichimura K, Mase M. SEGA-like circumscribed astrocytoma in a non-NF1 patient, harboring molecular profile of GBM. A case report. Neuropathology 2024; 44:190-199. [PMID: 37919875 DOI: 10.1111/neup.12948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 10/03/2023] [Accepted: 10/04/2023] [Indexed: 11/04/2023]
Abstract
Subependymal giant cell astrocytoma (SEGA) is a low-grade periventricular tumor that is closely associated with tuberous sclerosis complex (TSC). SEGA typically arises during the first two decades of life and rarely arises after the age of 20-25 years. Nevertheless, it has also been reported that glioma histologically resembling SEGA, so-called SEGA-like astrocytoma, can arise in neurofibromatosis type 1 (NF1) patients, even in the elderly. Herein, we report a case of SEGA-like circumscribed astrocytoma arising in the lateral ventricle of a 75-year-old woman. Whole-exome sequencing revealed a somatic variant of NF1. Methylation array analysis led to a diagnosis of "methylation class glioblastoma, IDH-wildtype, mesenchymal-type (GBM, MES)" with a high calibrated score (0.99). EGFR amplification, CDKN2A/B homozygous deletion, chromosomal +7/-10 alterations, and TERT promoter mutation, typical molecular abnormalities usually found in GBM, were also observed. While most reported cases of SEGA-like astrocytoma have arisen in NF1 patients, the patient was neither TSC nor NF1. Near total removal was accomplished with endoscopic cylinder surgery. At the 36-month follow-up, there was no tumor recurrence without adjuvant therapies. This clinical behavior did not match GBM. SEGA-like astrocytoma of the elderly is rare, and this is the oldest case reported so far. In addition, high-grade molecular features found in circumscribed tumor remain unclear. Further investigations among larger series are needed for clarifying the underlying molecular mechanisms.
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Affiliation(s)
- Seiji Yamada
- Department of Neurosurgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
- Department of Diagnostic Pathology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Motoki Tanikawa
- Department of Neurosurgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yuko Matsushita
- Department of Brain Disease Translational Research, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Ryota Fujinami
- Department of Neurosurgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hiroshi Yamada
- Department of Neurosurgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Kaishi Sakomi
- Department of Pathology, Kyorin University Faculty of Medicine, Tokyo, Japan
| | - Tomohiro Sakata
- Department of Neurosurgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hidehito Inagaki
- Division of Molecular Genetics, Center for Medical Science, Fujita Health University, Toyoake, Japan
| | - Hideaki Yokoo
- Department of Human Pathology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Koichi Ichimura
- Department of Brain Disease Translational Research, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Mitsuhito Mase
- Department of Neurosurgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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Miyagishima KJ, Qiao F, Stasheff SF, Nadal-Nicolás FM. Visual Deficits and Diagnostic and Therapeutic Strategies for Neurofibromatosis Type 1: Bridging Science and Patient-Centered Care. Vision (Basel) 2024; 8:31. [PMID: 38804352 PMCID: PMC11130890 DOI: 10.3390/vision8020031] [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: 03/02/2024] [Revised: 05/03/2024] [Accepted: 05/04/2024] [Indexed: 05/29/2024] Open
Abstract
Neurofibromatosis type 1 (NF1) is an inherited autosomal dominant disorder primarily affecting children and adolescents characterized by multisystemic clinical manifestations. Mutations in neurofibromin, the protein encoded by the Nf1 tumor suppressor gene, result in dysregulation of the RAS/MAPK pathway leading to uncontrolled cell growth and migration. Neurofibromin is highly expressed in several cell lineages including melanocytes, glial cells, neurons, and Schwann cells. Individuals with NF1 possess a genetic predisposition to central nervous system neoplasms, particularly gliomas affecting the visual pathway, known as optic pathway gliomas (OPGs). While OPGs are typically asymptomatic and benign, they can induce visual impairment in some patients. This review provides insight into the spectrum and visual outcomes of NF1, current diagnostic techniques and therapeutic interventions, and explores the influence of NF1-OPGS on visual abnormalities. We focus on recent advancements in preclinical animal models to elucidate the underlying mechanisms of NF1 pathology and therapies targeting NF1-OPGs. Overall, our review highlights the involvement of retinal ganglion cell dysfunction and degeneration in NF1 disease, and the need for further research to transform scientific laboratory discoveries to improved patient outcomes.
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Affiliation(s)
- Kiyoharu J. Miyagishima
- Retinal Neurophysiology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA; (K.J.M.); (F.Q.); (S.F.S.)
| | - Fengyu Qiao
- Retinal Neurophysiology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA; (K.J.M.); (F.Q.); (S.F.S.)
| | - Steven F. Stasheff
- Retinal Neurophysiology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA; (K.J.M.); (F.Q.); (S.F.S.)
- Center for Neuroscience and Behavioral Medicine, Gilbert Neurofibromatosis Institute, Children’s National Health System, Washington, DC 20010, USA
- Neurology Department, George Washington University School of Medicine, Washington, DC 20037, USA
| | - Francisco M. Nadal-Nicolás
- Retinal Neurophysiology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA; (K.J.M.); (F.Q.); (S.F.S.)
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Yvone GM, Breunig JJ. Pediatric low-grade glioma models: advances and ongoing challenges. Front Oncol 2024; 13:1346949. [PMID: 38318325 PMCID: PMC10839015 DOI: 10.3389/fonc.2023.1346949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 12/29/2023] [Indexed: 02/07/2024] Open
Abstract
Pediatric low-grade gliomas represent the most common childhood brain tumor class. While often curable, some tumors fail to respond and even successful treatments can have life-long side effects. Many clinical trials are underway for pediatric low-grade gliomas. However, these trials are expensive and challenging to organize due to the heterogeneity of patients and subtypes. Advances in sequencing technologies are helping to mitigate this by revealing the molecular landscapes of mutations in pediatric low-grade glioma. Functionalizing these mutations in the form of preclinical models is the next step in both understanding the disease mechanisms as well as for testing therapeutics. However, such models are often more difficult to generate due to their less proliferative nature, and the heterogeneity of tumor microenvironments, cell(s)-of-origin, and genetic alterations. In this review, we discuss the molecular and genetic alterations and the various preclinical models generated for the different types of pediatric low-grade gliomas. We examined the different preclinical models for pediatric low-grade gliomas, summarizing the scientific advances made to the field and therapeutic implications. We also discuss the advantages and limitations of the various models. This review highlights the importance of preclinical models for pediatric low-grade gliomas while noting the challenges and future directions of these models to improve therapeutic outcomes of pediatric low-grade gliomas.
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Affiliation(s)
- Griselda Metta Yvone
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Joshua J. Breunig
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Center for Neural Sciences in Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
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7
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Brodaczewska K, Majewska A, Filipiak-Duliban A, Kieda C. Pten knockout affects drug resistance differently in melanoma and kidney cancer. Pharmacol Rep 2023; 75:1187-1199. [PMID: 37673853 PMCID: PMC10539195 DOI: 10.1007/s43440-023-00523-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 08/12/2023] [Accepted: 08/22/2023] [Indexed: 09/08/2023]
Abstract
BACKGROUND PTEN is a tumor suppressor that is often mutated and nonfunctional in many types of cancer. The high heterogeneity of PTEN function between tumor types makes new Pten knockout models necessary to assess its impact on cancer progression and/or treatment outcomes. METHODS We aimed to show the effect of CRISPR/Cas9-mediated Pten knockout on murine melanoma (B16 F10) and kidney cancer (Renca) cells. We evaluated the effect of PTEN deregulation on tumor progression in vivo and in vitro, as well as on the effectiveness of drug treatment in vitro. In addition, we studied the molecular changes induced by Pten knockout. RESULTS In both models, Pten mutation did not cause significant changes in cell proliferation in vitro or in vivo. Cells with Pten knockout differed in sensitivity to cisplatin treatment: in B16 F10 cells, the lack of PTEN induced sensitivity and, in Renca cells, resistance to drug treatment. Accumulation of pAKT was observed in both cell lines, but only Renca cells showed upregulation of the p53 level after Pten knockout. PTEN deregulation also varied in the way that it altered PAI-1 secretion in the tested models, showing a decrease in PAI-1 in B16 F10 Pten/KO and an increase in Renca Pten/KO cells. In kidney cancer cells, Pten knockout caused changes in epithelial to mesenchymal transition marker expression, with downregulation of E-cadherin and upregulation of Snail, Mmp9, and Acta2 (α-SMA). CONCLUSIONS The results confirmed heterogenous cell responses to PTEN loss, which may lead to a better understanding of the role of PTEN in particular types of tumors and points to PTEN as a therapeutic target for personalized medicine.
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Affiliation(s)
- Klaudia Brodaczewska
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine - National Research Institute, Szaserów 128, 01-141, Warsaw, Poland.
| | - Aleksandra Majewska
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine - National Research Institute, Szaserów 128, 01-141, Warsaw, Poland
- Postgraduate School of Molecular Medicine (Medical University of Warsaw), Żwirki I Wigury 61, 02-091, Warsaw, Poland
| | - Aleksandra Filipiak-Duliban
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine - National Research Institute, Szaserów 128, 01-141, Warsaw, Poland
- Postgraduate School of Molecular Medicine (Medical University of Warsaw), Żwirki I Wigury 61, 02-091, Warsaw, Poland
| | - Claudine Kieda
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine - National Research Institute, Szaserów 128, 01-141, Warsaw, Poland
- Center for Molecular Biophysics UPR 4301, CNRS, 45071, Orleans, France
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8
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Voss AJ, Lanjewar SN, Sampson MM, King A, Hill EJ, Sing A, Sojka C, Bhatia TN, Spangle JM, Sloan SA. Identification of ligand-receptor pairs that drive human astrocyte development. Nat Neurosci 2023; 26:1339-1351. [PMID: 37460808 PMCID: PMC11046429 DOI: 10.1038/s41593-023-01375-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 06/08/2023] [Indexed: 08/05/2023]
Abstract
Extrinsic signaling between diverse cell types is crucial for nervous system development. Ligand binding is a key driver of developmental processes. Nevertheless, it remains a significant challenge to disentangle which and how extrinsic signals act cooperatively to affect changes in recipient cells. In the developing human brain, cortical progenitors transition from neurogenesis to gliogenesis in a stereotyped sequence that is in part influenced by extrinsic ligands. Here we used published transcriptomic data to identify and functionally test five ligand-receptor pairs that synergistically drive human astrogenesis. We validate the synergistic contributions of TGFβ2, NLGN1, TSLP, DKK1 and BMP4 ligands on astrocyte development in both hCOs and primary fetal tissue. We confirm that the cooperative capabilities of these five ligands are greater than their individual capacities. Additionally, we discovered that their combinatorial effects converge in part on the mTORC1 signaling pathway, resulting in transcriptomic and morphological features of astrocyte development. Our data-driven framework can leverage single-cell and bulk genomic data to generate and test functional hypotheses surrounding cell-cell communication regulating neurodevelopmental processes.
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Affiliation(s)
- Anna J Voss
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Samantha N Lanjewar
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Maureen M Sampson
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Alexia King
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Emily J Hill
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Anson Sing
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Caitlin Sojka
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Tarun N Bhatia
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Jennifer M Spangle
- Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA, USA
| | - Steven A Sloan
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
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Park JW. Metabolic Rewiring in Adult-Type Diffuse Gliomas. Int J Mol Sci 2023; 24:ijms24087348. [PMID: 37108511 PMCID: PMC10138713 DOI: 10.3390/ijms24087348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 04/10/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
Multiple metabolic pathways are utilized to maintain cellular homeostasis. Given the evidence that altered cell metabolism significantly contributes to glioma biology, the current research efforts aim to improve our understanding of metabolic rewiring between glioma's complex genotype and tissue context. In addition, extensive molecular profiling has revealed activated oncogenes and inactivated tumor suppressors that directly or indirectly impact the cellular metabolism that is associated with the pathogenesis of gliomas. The mutation status of isocitrate dehydrogenases (IDHs) is one of the most important prognostic factors in adult-type diffuse gliomas. This review presents an overview of the metabolic alterations in IDH-mutant gliomas and IDH-wildtype glioblastoma (GBM). A particular focus is placed on targeting metabolic vulnerabilities to identify new therapeutic strategies for glioma.
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Affiliation(s)
- Jong-Whi Park
- Department of Life Sciences, College of BioNano Technology, Gachon University, Seongnam 13120, Republic of Korea
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Republic of Korea
- Neuroscience Research Institute, Gachon University, Incheon 21565, Republic of Korea
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10
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Anastasaki C, Orozco P, Gutmann DH. RAS and beyond: the many faces of the neurofibromatosis type 1 protein. Dis Model Mech 2022; 15:274437. [PMID: 35188187 PMCID: PMC8891636 DOI: 10.1242/dmm.049362] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Neurofibromatosis type 1 is a rare neurogenetic syndrome, characterized by pigmentary abnormalities, learning and social deficits, and a predisposition for benign and malignant tumor formation caused by germline mutations in the NF1 gene. With the cloning of the NF1 gene and the recognition that the encoded protein, neurofibromin, largely functions as a negative regulator of RAS activity, attention has mainly focused on RAS and canonical RAS effector pathway signaling relevant to disease pathogenesis and treatment. However, as neurofibromin is a large cytoplasmic protein the RAS regulatory domain of which occupies only 10% of its entire coding sequence, both canonical and non-canonical RAS pathway modulation, as well as the existence of potential non-RAS functions, are becoming apparent. In this Special article, we discuss our current understanding of neurofibromin function.
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Affiliation(s)
- Corina Anastasaki
- Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA
| | - Paola Orozco
- Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA
| | - David H Gutmann
- Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA
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11
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Boksha IS, Prokhorova TA, Tereshkina EB, Savushkina OK, Burbaeva GS. Protein Phosphorylation Signaling Cascades in Autism: The Role of mTOR Pathway. BIOCHEMISTRY (MOSCOW) 2021; 86:577-596. [PMID: 33993859 DOI: 10.1134/s0006297921050072] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The mammalian target of rapamycin (mTOR) signaling pathway is a central regulator of cell metabolism, growth, and survival in response to hormones, growth factors, nutrients, and stress-induced signals. In this review, we analyzed the studies on the molecular abnormalities of the mTOR-associated signaling cascades in autism spectrum disorders (ASDs) and outlined the prospects for the pathogenicity-targeting pharmacotherapeutic approaches to ASDs, in particular syndromic ASDs. Based on available experimental and clinical data, we suggest that very early detection of molecular abnormalities in the ASD risk groups can be facilitated by using peripheral blood platelets. Also, identification of the time window of critical dysregulations in the described pathways in the ASD risk groups might suggest further research directions leading to more efficacious pharmacotherapeutic interventions in ASDs.
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Affiliation(s)
- Irina S Boksha
- Mental Health Research Center, Moscow, 115522, Russia. .,Gamaleya Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, Moscow, 123098, Russia
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12
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Casingal CR, Kikkawa T, Inada H, Sasaki Y, Osumi N. Identification of FMRP target mRNAs in the developmental brain: FMRP might coordinate Ras/MAPK, Wnt/β-catenin, and mTOR signaling during corticogenesis. Mol Brain 2020; 13:167. [PMID: 33323119 PMCID: PMC7739466 DOI: 10.1186/s13041-020-00706-1] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 11/23/2020] [Indexed: 01/18/2023] Open
Abstract
Corticogenesis is one of the most critical and complicated processes during embryonic brain development. Any slight impairment in corticogenesis could cause neurodevelopmental disorders such as Fragile X syndrome (FXS), of which symptoms contain intellectual disability (ID) and autism spectrum disorder (ASD). Fragile X mental retardation protein (FMRP), an RNA-binding protein responsible for FXS, shows strong expression in neural stem/precursor cells (NPCs) during corticogenesis, although its function during brain development remains largely unknown. In this study, we attempted to identify the FMRP target mRNAs in the cortical primordium using RNA immunoprecipitation sequencing analysis in the mouse embryonic brain. We identified 865 candidate genes as targets of FMRP involving 126 and 118 genes overlapped with ID and ASD-associated genes, respectively. These overlapped genes were enriched with those related to chromatin/chromosome organization and histone modifications, suggesting the involvement of FMRP in epigenetic regulation. We further identified a common set of 17 FMRP “core” target genes involved in neurogenesis/FXS/ID/ASD, containing factors associated with Ras/mitogen-activated protein kinase, Wnt/β-catenin, and mammalian target of rapamycin (mTOR) pathways. We indeed showed overactivation of mTOR signaling via an increase in mTOR phosphorylation in the Fmr1 knockout (Fmr1 KO) neocortex. Our results provide further insight into the critical roles of FMRP in the developing brain, where dysfunction of FMRP may influence the regulation of its mRNA targets affecting signaling pathways and epigenetic modifications.
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Affiliation(s)
- Cristine R Casingal
- Department of Developmental Neuroscience, United Center for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Takako Kikkawa
- Department of Developmental Neuroscience, United Center for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Hitoshi Inada
- Department of Developmental Neuroscience, United Center for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.,Laboratory of Health and Sports Sciences, Division of Biomedical Engineering for Health and Welfare, Tohoku University Graduate School of Biomedical Engineering, 6-6-12, Aramaki Aza Aoba Aoba-ku, Sendai, Miyagi, 980-8579, Japan
| | - Yukio Sasaki
- Functional Structure Biology Laboratory, Department of Medical Life Science, Yokohama City University Graduate School of Medical Life Science, 1-7-29 Suehiro-cho, Tsumuri-ku, Yokohama, 230-0045, Japan
| | - Noriko Osumi
- Department of Developmental Neuroscience, United Center for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
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Oz O, Koyuncu I, Gonel A. A Pilot Study for Investigation of Plasma Amino Acid Profile in Neurofibromatosis Type 1 Patients. Comb Chem High Throughput Screen 2020; 25:114-122. [PMID: 33280590 DOI: 10.2174/1386207323666201204143206] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 11/01/2020] [Accepted: 11/09/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Neurofibromatosis, also known as Von Recklinghausen disease, is a systemic and progressive genetic disease that primarily affects the skin, eyes, nervous system and bones. The disease can occur in a variety of ways and can vary from individuals. Metabolomic-based research using blood samples has enabled new diagnostic methods to be used in the diagnosis of various diseases, especially cancer. Among metabolites, profiling of plasma free amino acids (PFAA) is a promising approach because PFAAs bind all organ systems and play an important role in metabolism. OBJECTIVE This study aimed to determine the characteristics of PFAA profiles in neurofibromatosis patients and the possibility of using them for early detection and treatment of the disease. METHOD Patients with a diagnosis of Neurofibromatosis Type I confirmed by genetic analysis and healthy individuals of the same age group without any disease were included in the study. We analysed the nineteen plasma free amino acids (phenylalanine, proline, threonine, arginine, asparagine, cystine, valine, glutamate, tyrosine, serine, glutamine, glycine, tryptophane, leucine, lysine, methionine, isoleucine, aspartate and alanine) from neurofibromatosis Type I patients and control group by liquid chromatography tandem mass spectrometry (LC-MS/MS) in Metabolism Laboratory of Harran University Research and Application Hospital. The results of the plasma free amino acid levels were divided into 3 groups as essential, semi-essential and non-essential. The differences of amino acid levels between groups were determined. RESULTS Eight amino acid levels (methionine, arginine, cystine, glutamine, proline, asparagine, serine, aspartate) were significantly altered in patients with neurofibromatosis type 1. In essential amino acids, methionine levels were significantly higher in the patient group than the control group. While the levels of arginine and glutamine in semi-essential amino acids were statistically significantly higher in the patient group, a significant decrease was observed in cystine and proline levels compared to the control group's amino acid levels. In non-essential amino acids group, asparagine, serine and aspartate amino acid levels were significantly higher in the patient group compared to the control group. CONCLUSION The current research predicates that eight amino acids, nsmely methionine, arginine, cystine, glutamine, proline, asparagine, serine, aspartate can be considered to be valuable biomarkers for neurofibromatosis type I. This present study is the first to build models for neurofibromatosis Type I screening using plasma free amino acids and the amino acid profile will guide the predicting of the complications that may occur during the course of the disease.
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Affiliation(s)
- Ozlem Oz
- Department of Medical Genetics, Harran University. Turkey
| | - Ismail Koyuncu
- Department of Medicinal Biochemistry, Harran University. Turkey
| | - Ataman Gonel
- Department of Medicinal Biochemistry, Harran University. Turkey
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14
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Ehrhart F, Coort SL, Eijssen L, Cirillo E, Smeets EE, Bahram Sangani N, Evelo CT, Curfs LMG. Integrated analysis of human transcriptome data for Rett syndrome finds a network of involved genes. World J Biol Psychiatry 2020; 21:712-725. [PMID: 30907210 DOI: 10.1080/15622975.2019.1593501] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
OBJECTIVES Rett syndrome (RTT) is a rare disorder causing severe intellectual and physical disability. The cause is a mutation in the gene coding for the methyl-CpG binding protein 2 (MECP2), a multifunctional regulator protein. Purpose of the study was integration and investigation of multiple gene expression profiles in human cells with impaired MECP2 gene to obtain a robust, data-driven insight in molecular disease mechanisms. METHODS Information about changed gene expression was extracted from five previously published studies, integrated and the resulting differentially expressed genes were analysed using overrepresentation analysis of biological pathways and gene ontology, and network analysis. RESULTS We identified a set of genes, which are significantly changed not in all but several transcriptomics datasets and were not mentioned in the context of RTT before. We found that these genes are involved in several processes and molecular pathways known to be affected in RTT. Integrating transcription factors we identified a possible link how MECP2 regulates cytoskeleton organisation via MEF2C and CAPG. CONCLUSIONS Integrative analysis of omics data and prior knowledge databases is a powerful approach to identify links between mutation and phenotype especially in rare disease research where little data is available.
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Affiliation(s)
- Friederike Ehrhart
- GCK - Rett Expertise Centre, Maastricht University Medical Centre, Maastricht, The Netherlands.,Department of Bioinformatics - BiGCaT, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Susan L Coort
- Department of Bioinformatics - BiGCaT, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Lars Eijssen
- Department of Bioinformatics - BiGCaT, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Elisa Cirillo
- Department of Bioinformatics - BiGCaT, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Eric E Smeets
- GCK - Rett Expertise Centre, Maastricht University Medical Centre, Maastricht, The Netherlands.,Department of Pediatrics, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Nasim Bahram Sangani
- GCK - Rett Expertise Centre, Maastricht University Medical Centre, Maastricht, The Netherlands.,Department of Bioinformatics - BiGCaT, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Chris T Evelo
- GCK - Rett Expertise Centre, Maastricht University Medical Centre, Maastricht, The Netherlands.,Department of Bioinformatics - BiGCaT, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Leopold M G Curfs
- GCK - Rett Expertise Centre, Maastricht University Medical Centre, Maastricht, The Netherlands
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15
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Mariano V, Achsel T, Bagni C, Kanellopoulos AK. Modelling Learning and Memory in Drosophila to Understand Intellectual Disabilities. Neuroscience 2020; 445:12-30. [PMID: 32730949 DOI: 10.1016/j.neuroscience.2020.07.034] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 07/19/2020] [Accepted: 07/20/2020] [Indexed: 12/24/2022]
Abstract
Neurodevelopmental disorders (NDDs) include a large number of conditions such as Fragile X syndrome, autism spectrum disorders and Down syndrome, among others. They are characterized by limitations in adaptive and social behaviors, as well as intellectual disability (ID). Whole-exome and whole-genome sequencing studies have highlighted a large number of NDD/ID risk genes. To dissect the genetic causes and underlying biological pathways, in vivo experimental validation of the effects of these mutations is needed. The fruit fly, Drosophila melanogaster, is an ideal model to study NDDs, with highly tractable genetics, combined with simple behavioral and circuit assays, permitting rapid medium-throughput screening of NDD/ID risk genes. Here, we review studies where the use of well-established assays to study mechanisms of learning and memory in Drosophila has permitted insights into molecular mechanisms underlying IDs. We discuss how technologies in the fly model, combined with a high degree of molecular and physiological conservation between flies and mammals, highlight the Drosophila system as an ideal model to study neurodevelopmental disorders, from genetics to behavior.
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Affiliation(s)
- Vittoria Mariano
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne 1005, Switzerland; Department of Human Genetics, KU Leuven, Leuven 3000, Belgium
| | - Tilmann Achsel
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne 1005, Switzerland
| | - Claudia Bagni
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne 1005, Switzerland; Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome 00133, Italy.
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16
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Hanz SZ, Adeuyan O, Lieberman G, Hennika T. Clinical trials using molecular stratification of pediatric brain tumors. Transl Pediatr 2020; 9:144-156. [PMID: 32477915 PMCID: PMC7237976 DOI: 10.21037/tp.2020.03.04] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Brain cancer is now the leading cause of cancer death in children and adolescents, surpassing leukemia. The heterogeneity and invasiveness of pediatric brain tumors have historically made them difficult to treat. Although surgical intervention and standard of care therapies such as radiation and chemotherapy have improved the outlook for those affected, results are often transient and lend themselves to tumor recurrence or resistance. There also still exists a subset of brain tumors which remain unresponsive to treatment altogether. Therefore, there is great need for new therapeutic approaches. With the recent advent of molecularly-driven technologies, many of these complex tumors can now be classified by integrating molecular profiling data with clinical information such as demographics and outcomes. This new knowledge has allowed for the molecular stratification of pediatric brain tumors into distinct subgroups and the identification of molecular targets, which is changing how these children are treated, namely in the setting of clinical trials. Notable examples include reduced doses of radiation and chemotherapy in the wingless-activated subgroup of medulloblastoma, which has a favorable prognosis, and novel experimental drugs targeting BRAF alterations in low-grade gliomas and dopamine receptors in high-grade gliomas. In this review, we highlight several key previous and ongoing clinical trials that utilize molecular stratifications and targets for the treatment of pediatric brain tumors.
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Affiliation(s)
- Samuel Z Hanz
- Department of Neurological Surgery, Division of Child Neurology, Weill Cornell Medicine, New York, NY, USA
| | - Oluwaseyi Adeuyan
- Department of Neurological Surgery, Division of Child Neurology, Weill Cornell Medicine, New York, NY, USA
| | - Grace Lieberman
- Department of Pediatrics, Division of Child Neurology, Weill Cornell Medicine, New York, NY, USA
| | - Tammy Hennika
- Department of Pediatrics, Division of Child Neurology, Weill Cornell Medicine, New York, NY, USA
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17
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Joshi V, Upadhyay A, Prajapati VK, Mishra A. How autophagy can restore proteostasis defects in multiple diseases? Med Res Rev 2020; 40:1385-1439. [PMID: 32043639 DOI: 10.1002/med.21662] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 01/03/2020] [Accepted: 01/28/2020] [Indexed: 12/12/2022]
Abstract
Cellular evolution develops several conserved mechanisms by which cells can tolerate various difficult conditions and overall maintain homeostasis. Autophagy is a well-developed and evolutionarily conserved mechanism of catabolism, which endorses the degradation of foreign and endogenous materials via autolysosome. To decrease the burden of the ubiquitin-proteasome system (UPS), autophagy also promotes the selective degradation of proteins in a tightly regulated way to improve the physiological balance of cellular proteostasis that may get perturbed due to the accumulation of misfolded proteins. However, the diverse as well as selective clearance of unwanted materials and regulations of several cellular mechanisms via autophagy is still a critical mystery. Also, the failure of autophagy causes an increase in the accumulation of harmful protein aggregates that may lead to neurodegeneration. Therefore, it is necessary to address this multifactorial threat for in-depth research and develop more effective therapeutic strategies against lethal autophagy alterations. In this paper, we discuss the most relevant and recent reports on autophagy modulations and their impact on neurodegeneration and other complex disorders. We have summarized various pharmacological findings linked with the induction and suppression of autophagy mechanism and their promising preclinical and clinical applications to provide therapeutic solutions against neurodegeneration. The conclusion, key questions, and future prospectives sections summarize fundamental challenges and their possible feasible solutions linked with autophagy mechanism to potentially design an impactful therapeutic niche to treat neurodegenerative diseases and imperfect aging.
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Affiliation(s)
- Vibhuti Joshi
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Karwar, India
| | - Arun Upadhyay
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Karwar, India
| | - Vijay K Prajapati
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer, India
| | - Amit Mishra
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Karwar, India
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18
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Lobbous M, Bernstock JD, Coffee E, Friedman GK, Metrock LK, Chagoya G, Elsayed G, Nakano I, Hackney JR, Korf BR, Nabors LB. An Update on Neurofibromatosis Type 1-Associated Gliomas. Cancers (Basel) 2020; 12:E114. [PMID: 31906320 PMCID: PMC7017116 DOI: 10.3390/cancers12010114] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 12/26/2019] [Accepted: 12/29/2019] [Indexed: 12/22/2022] Open
Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor predisposition syndrome that affects children and adults. Individuals with NF1 are at high risk for central nervous system neoplasms including gliomas. The purpose of this review is to discuss the spectrum of intracranial gliomas arising in individuals with NF1 with a focus on recent preclinical and clinical data. In this review, possible mechanisms of gliomagenesis are discussed, including the contribution of different signaling pathways and tumor microenvironment. Furthermore, we discuss the recent notable advances in the developing therapeutic landscape for NF1-associated gliomas including clinical trials and collaborative efforts.
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Affiliation(s)
- Mina Lobbous
- Division of Neuro Oncology, Department of Neurology, University of Alabama at Birmingham, 510 20th Street South, Faculty Office Tower Suite 1020 Birmingham, Birmingham, AL 35294, USA; (E.C.)
| | - Joshua D. Bernstock
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA;
| | - Elizabeth Coffee
- Division of Neuro Oncology, Department of Neurology, University of Alabama at Birmingham, 510 20th Street South, Faculty Office Tower Suite 1020 Birmingham, Birmingham, AL 35294, USA; (E.C.)
| | - Gregory K. Friedman
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (G.K.F.); (L.K.M.)
| | - Laura K. Metrock
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (G.K.F.); (L.K.M.)
| | - Gustavo Chagoya
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (G.C.); (G.E.); (I.N.)
| | - Galal Elsayed
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (G.C.); (G.E.); (I.N.)
| | - Ichiro Nakano
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (G.C.); (G.E.); (I.N.)
| | - James R. Hackney
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Bruce R. Korf
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Louis B. Nabors
- Division of Neuro Oncology, Department of Neurology, University of Alabama at Birmingham, 510 20th Street South, Faculty Office Tower Suite 1020 Birmingham, Birmingham, AL 35294, USA; (E.C.)
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19
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Kim JW, Jeong JH. Molecular Characterization of Primary Human Astrocytes Using Digital Gene Expression Analysis. Korean J Neurotrauma 2019; 15:2-10. [PMID: 31098343 PMCID: PMC6495576 DOI: 10.13004/kjnt.2019.15.e2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 06/06/2018] [Accepted: 06/26/2018] [Indexed: 11/15/2022] Open
Abstract
Objective Astrocyte dysfunctions are related to several central nervous system (CNS) pathologies. Transcriptomic profiling of human mRNAs to investigate astrocyte functions may provide the basic molecular-biological data pertaining to the cellular activities of astrocytes. Methods Human Primary astrocytes (HPAs) and human neural stem cell line (HB1.F3) were used for differential digital gene analysis. In this study, a massively parallel sequencing platform, next-generation sequencing (NGS), was used to obtain the digital gene expression (DGE) data from HPAs. A comparative analysis of the DGE from HPA and HB1.F3 cells was performed. Sequencing was performed using NGS platform, and subsequently, bioinformatic analyses were implemented to reveal the identity of the pathways, relatively up- or down-regulated in HPA cells. Results The top, novel canonical pathways up-regulated in HPA cells than in the HB1.F3 cells were "Cyclins and cell cycle regulation," "Integrin signaling," "Regulation of eIF4 and p70S6K signaling," "Wnt/β-catenin signaling," "mTOR signaling," "Aryl hydrocarbon receptor signaling," "Hippo signaling," "RhoA signaling," "Signaling by Rho family GTPases," and "Glioma signaling" pathways. The down-regulated pathways were "Cell cycle: G1/S checkpoint regulation," "eIF2 signaling," "Cell cycle: G2/M DNA damage checkpoint regulation," "Telomerase signaling," "RhoGDI signaling," "NRF2-mediated oxidative stress response," "ERK/MAPK signaling," "ATM signaling," "Pancreatic adenocarcinoma signaling," "VEGF signaling," and "Role of CHK proteins in cell cycle checkpoint control" pathways. Conclusion This study would be a good reference to understand astrocyte functions at the molecular level, and to develop a diagnostic test, based on the DGE pattern of astrocytes, as a powerful, new clinical tool in many CNS diseases.
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Affiliation(s)
- Jin Wook Kim
- Department of Neurosurgery, Dongguk University Gyeongju Hospital, Dongguk University College of Medicine, Gyeongju, Korea
| | - Ju Ho Jeong
- Department of Neurosurgery, Dongguk University Gyeongju Hospital, Dongguk University College of Medicine, Gyeongju, Korea
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20
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Molecular genetics and therapeutic targets of pediatric low-grade gliomas. Brain Tumor Pathol 2019; 36:74-83. [PMID: 30929113 DOI: 10.1007/s10014-019-00340-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 03/19/2019] [Indexed: 12/27/2022]
Abstract
Pediatric low-grade gliomas (PLGGs) have relatively favorable prognosis and some resectable PLGGs, such as cerebellar pilocytic astrocytoma, can be cured by surgery alone. However, many PLGG cases are unresectable and some of them undergo tumor progression. Therefore, a multidisciplinary approach is necessary to treat PLGG patients. Recent genomic analysis revealed a broad genomic landscape underlying PLGG. Notably, the majority of PLGGs present MAPK pathway-associated genomic alterations and MAPK signaling-dependent tumor progression. Following preclinical evidence, many clinical trials based on molecular target therapy have been conducted on PLGG patients, some of whom exhibited durable response to target therapy. Here, we provide an overview of PLGG genetics and the evidence supporting the application of molecular target therapy in these patients.
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21
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Abstract
PURPOSE OF REVIEW Pediatric low-grade gliomas (pLGGs) have been treated with similar therapies for the last 30 years. Recent biological insights have allowed a new generation of targeted therapies to be developed for these diverse tumors. At the same time, technological advances may redefine the late toxicities associated with radiation therapy. Understanding recent developments in pLGG therapy is essential to the management of these common pediatric tumors. RECENT FINDINGS It is now well understood that aberrations of the mitogen-activated protein kinase pathway are key to oncogenesis in low-grade gliomas. This understanding, along with the development of available targeted agents, have heralded a new era of understanding and treatment for these patients. Promising, sustained responses are now being seen in early phase trials among patients with multiply recurrent/progressive disease. Also, newer and highly conformal radiation approaches such as proton beam radiotherapy maintain efficacy of radiation but limit radiation-associated toxicities. SUMMARY Novel therapies offer the potential for tumor control with greatly reduced toxicities. However, late effects of these therapies are just now being explored. Improved radiation approaches and targeted agents have the potential to redefine traditional therapy for pLGG.
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22
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Hassanudin SA, Ponnampalam SN, Amini MN. Determination of genetic aberrations and novel transcripts involved in the pathogenesis of oligodendroglioma using array comparative genomic hybridization and next generation sequencing. Oncol Lett 2018; 17:1675-1687. [PMID: 30675227 PMCID: PMC6341554 DOI: 10.3892/ol.2018.9811] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Accepted: 09/17/2018] [Indexed: 01/11/2023] Open
Abstract
The aim of the present study was to determine the genetic aberrations and novel transcripts, particularly the fusion transcripts, involved in the pathogenesis of low-grade and anaplastic oligodendroglioma. In the present study, tissue samples were obtained from patients with oligodendroglioma and additionally from archived tissue samples from the Brain Tumor Tissue Bank of the Brain Tumor Foundation of Canada. Six samples were obtained, three of which were low-grade oligodendroglioma and the other three anaplastic oligodendroglioma. DNA and RNA were extracted from each tissue sample. The resulting genomic DNA was then hybridized using the Agilent CytoSure 4×180K oligonucleotide array. Human reference DNA and samples were labeled using Cy3 cytidine 5′-triphosphate (CTP) and Cy5 CTP, respectively, while human Cot-1 DNA was used to reduce non-specific binding. Microarray-based comparative genomic hybridization data was then analyzed for genetic aberrations using the Agilent Cytosure Interpret software v3.4.2. The total RNA isolated from each sample was mixed with oligo dT magnetic beads to enrich for poly(A) mRNA. cDNAs were then synthesized and subjected to end-repair, poly(A) addition and connected using sequencing adapters using the Illumina TruSeq RNA Sample Preparation kit. The fragments were then purified and selected as templates for polymerase chain reaction amplification. The final library was constructed with fragments between 350–450 base pairs and sequenced using deep transcriptome sequencing on an Illumina HiSeq 2500 sequencer. The array comparative genomic hybridization revealed numerous amplifications and deletions on several chromosomes in all samples. However, the most interesting result was from the next generation sequencing, where one anaplastic oligodendroglioma sample was demonstrated to have five novel fusion genes that may potentially serve a critical role in tumor pathogenesis and progression.
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Affiliation(s)
- Siti A Hassanudin
- Cancer Research Center, Institute for Medical Research, Jalan Pahang, 50588 Kuala Lumpur, Malaysia
| | - Stephen N Ponnampalam
- Cancer Research Center, Institute for Medical Research, Jalan Pahang, 50588 Kuala Lumpur, Malaysia
| | - Muhammad N Amini
- Cancer Research Center, Institute for Medical Research, Jalan Pahang, 50588 Kuala Lumpur, Malaysia
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23
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Palsgrove DN, Brosnan-Cashman JA, Giannini C, Raghunathan A, Jentoft M, Bettegowda C, Gokden M, Lin D, Yuan M, Lin MT, Heaphy CM, Rodriguez FJ. Subependymal giant cell astrocytoma-like astrocytoma: a neoplasm with a distinct phenotype and frequent neurofibromatosis type-1-association. Mod Pathol 2018; 31:1787-1800. [PMID: 29973652 PMCID: PMC6269209 DOI: 10.1038/s41379-018-0103-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 05/30/2018] [Accepted: 06/01/2018] [Indexed: 11/09/2022]
Abstract
Neurofibromatosis type-1 is a familial genetic syndrome associated with a predisposition to develop peripheral and central nervous system neoplasms. We have previously reported on a subset of gliomas developing in these patients with morphologic features resembling subependymal giant cell astrocytoma, but the molecular features of these tumors remain undefined. A total of 14 tumors were studied and all available slides were reviewed. Immunohistochemical stains and telomere-specific FISH were performed on all cases. In addition, next-generation sequencing was performed on 11 cases using a platform targeting 644 cancer-related genes. The average age at diagnosis was 28 years (range: 4-60, 9F/5M). All tumors involved the supratentorial compartment. Tumors were predominantly low grade (n = 12), with two high-grade tumors, and displayed consistent expression of glial markers. Next-generation sequencing demonstrated inactivating NF1 mutations in 10 (of 11) cases. Concurrent TSC2 and RPTOR mutations were present in two cases (1 sporadic and 1 neurofibromatosis type-1-associated). Interestingly, alternative lengthening of telomeres was present in 4 (of 14) (29%) cases. However, an ATRX mutation associated with aberrant nuclear ATRX expression was identified in only one (of four) cases with alternative lenghtening of telomeres. Gene variants in the DNA helicase RECQL4 (n = 2) and components of the Fanconi anemia complementation group (FANCD2, FANCF, FANCG) (n = 1) were identified in two alternative lenghtening of telomere-positive/ATRX-intact cases. Other variants involved genes related to NOTCH signaling, DNA maintenance/repair pathways, and epigenetic modulators. There were no mutations identified in DAXX, PTEN, PIK3C genes, TP53, H3F3A, HIST1H3B, or in canonical hotspots of IDH1, IDH2, or BRAF. A subset of subependymal giant cell astrocytoma-like astrocytomas are alternative lenghtening of telomere-positive and occur in the absence of ATRX alterations, thereby suggesting mutations in other DNA repair/maintenance genes may also facilitate alternative lenghtening of telomeres. These findings suggest that subependymal giant cell astrocytoma-like astrocytoma represents a biologically distinct group that merits further investigation.
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Affiliation(s)
- Doreen N Palsgrove
- Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
- Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Caterina Giannini
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Aditya Raghunathan
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | | | - Chetan Bettegowda
- Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neurosurgery, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
| | - Murat Gokden
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Doris Lin
- Department of Radiology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
| | - Ming Yuan
- Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
| | - Ming-Tseh Lin
- Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
- Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Christopher M Heaphy
- Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
- Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Fausto J Rodriguez
- Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
- Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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24
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25
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Woodford MR, Sager RA, Marris E, Dunn DM, Blanden AR, Murphy RL, Rensing N, Shapiro O, Panaretou B, Prodromou C, Loh SN, Gutmann DH, Bourboulia D, Bratslavsky G, Wong M, Mollapour M. Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding of kinase and non-kinase clients. EMBO J 2017; 36:3650-3665. [PMID: 29127155 PMCID: PMC5730846 DOI: 10.15252/embj.201796700] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 09/15/2017] [Accepted: 10/02/2017] [Indexed: 12/29/2022] Open
Abstract
The tumor suppressors Tsc1 and Tsc2 form the tuberous sclerosis complex (TSC), a regulator of mTOR activity. Tsc1 stabilizes Tsc2; however, the precise mechanism involved remains elusive. The molecular chaperone heat‐shock protein 90 (Hsp90) is an essential component of the cellular homeostatic machinery in eukaryotes. Here, we show that Tsc1 is a new co‐chaperone for Hsp90 that inhibits its ATPase activity. The C‐terminal domain of Tsc1 (998–1,164 aa) forms a homodimer and binds to both protomers of the Hsp90 middle domain. This ensures inhibition of both subunits of the Hsp90 dimer and prevents the activating co‐chaperone Aha1 from binding the middle domain of Hsp90. Conversely, phosphorylation of Aha1‐Y223 increases its affinity for Hsp90 and displaces Tsc1, thereby providing a mechanism for equilibrium between binding of these two co‐chaperones to Hsp90. Our findings establish an active role for Tsc1 as a facilitator of Hsp90‐mediated folding of kinase and non‐kinase clients—including Tsc2—thereby preventing their ubiquitination and proteasomal degradation.
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Affiliation(s)
- Mark R Woodford
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA.,Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Rebecca A Sager
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA.,Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA.,Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Elijah Marris
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA.,Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA.,Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Diana M Dunn
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA.,Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA.,Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Adam R Blanden
- Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA.,Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Ryan L Murphy
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA.,Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Nicholas Rensing
- Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.,Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
| | - Oleg Shapiro
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA.,Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Barry Panaretou
- Institute of Pharmaceutical Science, King's College London, London, UK
| | | | - Stewart N Loh
- Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA.,Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - David H Gutmann
- Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
| | - Dimitra Bourboulia
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA.,Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA.,Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Gennady Bratslavsky
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA.,Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Michael Wong
- Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.,Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
| | - Mehdi Mollapour
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA .,Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA.,Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA
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26
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Kim TH, Sung SE, Cheal Yoo J, Park JY, Yi GS, Heo JY, Lee JR, Kim NS, Lee DY. Copine1 regulates neural stem cell functions during brain development. Biochem Biophys Res Commun 2017; 495:168-173. [PMID: 29101038 DOI: 10.1016/j.bbrc.2017.10.167] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Accepted: 10/30/2017] [Indexed: 12/14/2022]
Abstract
Copine 1 (CPNE1) is a well-known phospholipid binding protein in plasma membrane of various cell types. In brain cells, CPNE1 is closely associated with AKT signaling pathway, which is important for neural stem cell (NSC) functions during brain development. Here, we investigated the role of CPNE1 in the regulation of brain NSC functions during brain development and determined its underlying mechanism. In this study, abundant expression of CPNE1 was observed in neural lineage cells including NSCs and immature neurons in human. With mouse brain tissues in various developmental stages, we found that CPNE1 expression was higher at early embryonic stages compared to postnatal and adult stages. To model developing brain in vitro, we used primary NSCs derived from mouse embryonic hippocampus. Our in vitro study shows decreased proliferation and multi-lineage differentiation potential in CPNE1 deficient NSCs. Finally, we found that the deficiency of CPNE1 downregulated mTOR signaling in embryonic NSCs. These data demonstrate that CPNE1 plays a key role in the regulation of NSC functions through the activation of AKT-mTOR signaling pathway during brain development.
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Affiliation(s)
- Tae Hwan Kim
- Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, South Korea; Department of Biochemistry, Chungnam National University School of Medicine, 266 Munhwa-ro, Jung-gu, Daejeon 35015, South Korea; Department of Medical Science, Chungnam National University School of Medicine, 266 Munhwa-ro, Jung-gu, Daejeon 35015, South Korea
| | - Soo-Eun Sung
- Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, South Korea
| | - Jae Cheal Yoo
- Department of Bio and Brain Engineering, KAIST, 291 Daehak-ro, Yuseong-gu, Daejeon 34141, South Korea
| | - Jae-Yong Park
- School of Biosystem and Biomedical Science, College of Health Science, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, South Korea
| | - Gwan-Su Yi
- Department of Bio and Brain Engineering, KAIST, 291 Daehak-ro, Yuseong-gu, Daejeon 34141, South Korea
| | - Jun Young Heo
- Department of Biochemistry, Chungnam National University School of Medicine, 266 Munhwa-ro, Jung-gu, Daejeon 35015, South Korea; Department of Medical Science, Chungnam National University School of Medicine, 266 Munhwa-ro, Jung-gu, Daejeon 35015, South Korea
| | - Jae-Ran Lee
- Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, South Korea
| | - Nam-Soon Kim
- Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, South Korea
| | - Da Yong Lee
- Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, South Korea.
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27
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Meyerholz DK, Ofori-Amanfo GK, Leidinger MR, Goeken JA, Khanna R, Sieren JC, Darbro BW, Quelle DE, Weimer JM. Immunohistochemical Markers for Prospective Studies in Neurofibromatosis-1 Porcine Models. J Histochem Cytochem 2017; 65:607-618. [PMID: 28846462 DOI: 10.1369/0022155417729357] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Neurofibromatosis type 1 (NF1) is a common, cancer-predisposing disease caused by mutations in the NF1 tumor gene. Patients with NF1 have an increased risk for benign and malignant tumors of the nervous system (e.g., neurofibromas, malignant peripheral nerve sheath tumors, gliomas) and other tissues (e.g., leukemias, rhabdomyosarcoma, etc.) as well as increased susceptibility to learning disabilities, chronic pain/migraines, hypertension, pigmentary changes, and developmental lesions (e.g., tibial pseudoarthrosis). Pigs are an attractive and upcoming animal model for future NF1 studies, but a potential limitation to porcine model research has been the lack of validated reagents for direct translational study to humans. To address that issue, we used formalin-fixed tissues (human and pigs) to evaluate select immunohistochemical markers (activated caspase-3, allograft inflammatory factor-1, beta-tubulin III, calbindin D, CD13, CD20, desmin, epithelial membrane antigen, glial fibrillary acidic protein, glucose transporter-1, laminin, myelin basic protein, myoglobin, proliferating cell nuclear antigen, S100, vimentin, and von Willebrand factor). The markers were validated by comparing known expression and localization in human and pig tissues. Validation of these markers on fixed tissues will facilitate prospective immunohistochemical studies of NF1 pigs, as well as other pig models, in a more efficient, reproducible, and translationally relevant manner.
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Affiliation(s)
| | | | | | | | - Rajesh Khanna
- University of Iowa, Iowa City, Iowa, Departments of Pharmacology and Anesthesiology, College of Medicine, University of Arizona, Tucson, Arizona.,Departments of Pharmacology and Anesthesiology, College of Medicine, University of Arizona, Tucson, Arizona
| | | | | | - Dawn E Quelle
- Department of Pathology.,Department of Pediatrics.,Department of Pharmacology
| | - Jill M Weimer
- Pediatrics and Rare Disease Group, Sanford Research, Sioux Falls, South Dakota.,Department of Pediatrics, University of South Dakota, Vermillion, South Dakota
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28
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Smithson LJ, Gutmann DH. Proteomic analysis reveals GIT1 as a novel mTOR complex component critical for mediating astrocyte survival. Genes Dev 2017; 30:1383-8. [PMID: 27340174 PMCID: PMC4926861 DOI: 10.1101/gad.279661.116] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 05/16/2016] [Indexed: 11/24/2022]
Abstract
Smithson and Gutmann reveal that mTOR complex molecular composition varies in different somatic tissues. In astrocytes and neural stem cells, they identified G-protein-coupled receptor kinase interactor protein 1 (GIT1) as a novel mTOR-binding protein, creating a unique mTOR complex lacking Raptor and Rictor. GIT1 binding to mTOR was essential for mTOR-mediated astrocyte survival. As a critical regulator of cell growth, the mechanistic target of rapamycin (mTOR) protein operates as part of two molecularly and functionally distinct complexes. Herein, we demonstrate that mTOR complex molecular composition varies in different somatic tissues. In astrocytes and neural stem cells, we identified G-protein-coupled receptor kinase-interacting protein 1 (GIT1) as a novel mTOR-binding protein, creating a unique mTOR complex lacking Raptor and Rictor. Moreover, GIT1 binding to mTOR is regulated by AKT activation and is essential for mTOR-mediated astrocyte survival. Together, these data reveal that mTOR complex function is partly dictated by its molecuflar composition in different cell types.
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Affiliation(s)
- Laura J Smithson
- Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA
| | - David H Gutmann
- Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA
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29
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Magdalon J, Sánchez-Sánchez SM, Griesi-Oliveira K, Sertié AL. Dysfunctional mTORC1 Signaling: A Convergent Mechanism between Syndromic and Nonsyndromic Forms of Autism Spectrum Disorder? Int J Mol Sci 2017; 18:ijms18030659. [PMID: 28335463 PMCID: PMC5372671 DOI: 10.3390/ijms18030659] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Revised: 03/13/2017] [Accepted: 03/14/2017] [Indexed: 12/28/2022] Open
Abstract
Whereas autism spectrum disorder (ASD) exhibits striking heterogeneity in genetics and clinical presentation, dysfunction of mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway has been identified as a molecular feature common to several well-characterized syndromes with high prevalence of ASD. Additionally, recent findings have also implicated mTORC1 signaling abnormalities in a subset of nonsyndromic ASD, suggesting that defective mTORC1 pathway may be a potential converging mechanism in ASD pathology across different etiologies. However, the mechanistic evidence for a causal link between aberrant mTORC1 pathway activity and ASD neurobehavioral features varies depending on the ASD form involved. In this review, we first discuss six monogenic ASD-related syndromes, including both classical and potentially novel mTORopathies, highlighting their contribution to our understanding of the neurobiological mechanisms underlying ASD, and then we discuss existing evidence suggesting that aberrant mTORC1 signaling may also play a role in nonsyndromic ASD.
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Affiliation(s)
- Juliana Magdalon
- Hospital Israelita Albert Einstein, Centro de Pesquisa Experimental, São Paulo 05652-900, Brazil.
| | - Sandra M Sánchez-Sánchez
- Hospital Israelita Albert Einstein, Centro de Pesquisa Experimental, São Paulo 05652-900, Brazil.
- Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo 05508-090, Brazil.
| | - Karina Griesi-Oliveira
- Hospital Israelita Albert Einstein, Centro de Pesquisa Experimental, São Paulo 05652-900, Brazil.
| | - Andréa L Sertié
- Hospital Israelita Albert Einstein, Centro de Pesquisa Experimental, São Paulo 05652-900, Brazil.
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30
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Abstract
Neurofibromatosis type 1 is a complex autosomal dominant disorder caused by germline mutations in the NF1 tumour suppressor gene. Nearly all individuals with neurofibromatosis type 1 develop pigmentary lesions (café-au-lait macules, skinfold freckling and Lisch nodules) and dermal neurofibromas. Some individuals develop skeletal abnormalities (scoliosis, tibial pseudarthrosis and orbital dysplasia), brain tumours (optic pathway gliomas and glioblastoma), peripheral nerve tumours (spinal neurofibromas, plexiform neurofibromas and malignant peripheral nerve sheath tumours), learning disabilities, attention deficits, and social and behavioural problems, which can negatively affect quality of life. With the identification of NF1 and the generation of accurate preclinical mouse strains that model some of these clinical features, therapies that target the underlying molecular and cellular pathophysiology for neurofibromatosis type 1 are becoming available. Although no single treatment exists, current clinical management strategies include early detection of disease phenotypes (risk assessment) and biologically targeted therapies. Similarly, new medical and behavioural interventions are emerging to improve the quality of life of patients. Although considerable progress has been made in understanding this condition, numerous challenges remain; a collaborative and interdisciplinary approach is required to manage individuals with neurofibromatosis type1 and to develop effective treatments.
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Affiliation(s)
- David H Gutmann
- Department of Neurology, Washington University School of Medicine, Box 8111, 660 S. Euclid Avenue, St. Louis, Missouri 63110, USA
| | - Rosalie E Ferner
- Department of Neurology, Guy's and St. Thomas' NHS Foundation Trust, London, UK
- Department of Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Robert H Listernick
- Department of Academic General Pediatrics and Primary Care, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
- Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Bruce R Korf
- Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Pamela L Wolters
- Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA
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31
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Switon K, Kotulska K, Janusz-Kaminska A, Zmorzynska J, Jaworski J. Molecular neurobiology of mTOR. Neuroscience 2017; 341:112-153. [PMID: 27889578 DOI: 10.1016/j.neuroscience.2016.11.017] [Citation(s) in RCA: 298] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 11/09/2016] [Accepted: 11/13/2016] [Indexed: 01/17/2023]
Abstract
Mammalian/mechanistic target of rapamycin (mTOR) is a serine-threonine kinase that controls several important aspects of mammalian cell function. mTOR activity is modulated by various intra- and extracellular factors; in turn, mTOR changes rates of translation, transcription, protein degradation, cell signaling, metabolism, and cytoskeleton dynamics. mTOR has been repeatedly shown to participate in neuronal development and the proper functioning of mature neurons. Changes in mTOR activity are often observed in nervous system diseases, including genetic diseases (e.g., tuberous sclerosis complex, Pten-related syndromes, neurofibromatosis, and Fragile X syndrome), epilepsy, brain tumors, and neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, and Huntington's disease). Neuroscientists only recently began deciphering the molecular processes that are downstream of mTOR that participate in proper function of the nervous system. As a result, we are gaining knowledge about the ways in which aberrant changes in mTOR activity lead to various nervous system diseases. In this review, we provide a comprehensive view of mTOR in the nervous system, with a special focus on the neuronal functions of mTOR (e.g., control of translation, transcription, and autophagy) that likely underlie the contribution of mTOR to nervous system diseases.
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Affiliation(s)
- Katarzyna Switon
- International Institute of Molecular and Cell Biology, 4 Ks. Trojdena Street, Warsaw 02-109, Poland
| | - Katarzyna Kotulska
- Department of Neurology and Epileptology, Children's Memorial Health Institute, Aleja Dzieci Polskich 20, Warsaw 04-730, Poland
| | | | - Justyna Zmorzynska
- International Institute of Molecular and Cell Biology, 4 Ks. Trojdena Street, Warsaw 02-109, Poland
| | - Jacek Jaworski
- International Institute of Molecular and Cell Biology, 4 Ks. Trojdena Street, Warsaw 02-109, Poland.
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32
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Orbital peripheral nerve sheath tumors. Surv Ophthalmol 2017; 62:43-57. [DOI: 10.1016/j.survophthal.2016.08.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Revised: 08/14/2016] [Accepted: 08/19/2016] [Indexed: 02/07/2023]
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33
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Xie K, Colgan LA, Dao MT, Muntean BS, Sutton LP, Orlandi C, Boye SL, Boye SE, Shih CC, Li Y, Xu B, Smith RG, Yasuda R, Martemyanov KA. NF1 Is a Direct G Protein Effector Essential for Opioid Signaling to Ras in the Striatum. Curr Biol 2016; 26:2992-3003. [PMID: 27773571 DOI: 10.1016/j.cub.2016.09.010] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Revised: 08/24/2016] [Accepted: 09/07/2016] [Indexed: 01/19/2023]
Abstract
It is well recognized that G-protein-coupled receptors (GPCRs) can activate Ras-regulated kinase pathways to produce lasting changes in neuronal function. Mechanisms by which GPCRs transduce these signals and their relevance to brain disorders are not well understood. Here, we identify a major Ras regulator, neurofibromin 1 (NF1), as a direct effector of GPCR signaling via Gβγ subunits in the striatum. We find that binding of Gβγ to NF1 inhibits its ability to inactivate Ras. Deletion of NF1 in striatal neurons prevents the opioid-receptor-induced activation of Ras and eliminates its coupling to Akt-mTOR-signaling pathway. By acting in the striatal medium spiny neurons of the direct pathway, NF1 regulates opioid-induced changes in Ras activity, thereby sensitizing mice to psychomotor and rewarding effects of morphine. These results delineate a novel mechanism of GPCR signaling to Ras pathways and establish a critical role of NF1 in opioid addiction.
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Affiliation(s)
- Keqiang Xie
- Department of Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA
| | - Lesley A Colgan
- Max Planck Florida Institute for Neuroscience, 1 Max Planck Way, Jupiter, FL 33458, USA
| | - Maria T Dao
- Department of Metabolism and Aging, The Scripps Research Institute, 120 Scripps Way, Jupiter, FL 33458, USA
| | - Brian S Muntean
- Department of Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA
| | - Laurie P Sutton
- Department of Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA
| | - Cesare Orlandi
- Department of Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA
| | - Sanford L Boye
- Department of Ophthalmology, University of Florida, 1395 Center Drive, Gainesville, FL 32610, USA
| | - Shannon E Boye
- Department of Ophthalmology, University of Florida, 1395 Center Drive, Gainesville, FL 32610, USA
| | - Chien-Cheng Shih
- Department of Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA
| | - Yuqing Li
- Department of Neurology, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610, USA
| | - Baoji Xu
- Department of Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA
| | - Roy G Smith
- Department of Metabolism and Aging, The Scripps Research Institute, 120 Scripps Way, Jupiter, FL 33458, USA
| | - Ryohei Yasuda
- Max Planck Florida Institute for Neuroscience, 1 Max Planck Way, Jupiter, FL 33458, USA
| | - Kirill A Martemyanov
- Department of Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
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34
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Physical interaction between neurofibromin and serotonin 5-HT6 receptor promotes receptor constitutive activity. Proc Natl Acad Sci U S A 2016; 113:12310-12315. [PMID: 27791021 DOI: 10.1073/pnas.1600914113] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Active G protein-coupled receptor (GPCR) conformations not only are promoted by agonists but also occur in their absence, leading to constitutive activity. Association of GPCRs with intracellular protein partners might be one of the mechanisms underlying GPCR constitutive activity. Here, we show that serotonin 5 hydroxytryptamine 6 (5-HT6) receptor constitutively activates the Gs/adenylyl cyclase pathway in various cell types, including neurons. Constitutive activity is strongly reduced by silencing expression of the Ras-GTPase activating protein (Ras-GAP) neurofibromin, a 5-HT6 receptor partner. Neurofibromin is a multidomain protein encoded by the NF1 gene, the mutation of which causes Neurofibromatosis type 1 (NF1), a genetic disorder characterized by multiple benign and malignant nervous system tumors and cognitive deficits. Disrupting association of 5-HT6 receptor with neurofibromin Pleckstrin Homology (PH) domain also inhibits receptor constitutive activity, and PH domain expression rescues 5-HT6 receptor-operated cAMP signaling in neurofibromin-deficient cells. Furthermore, PH domains carrying mutations identified in NF1 patients that prevent interaction with the 5-HT6 receptor fail to rescue receptor constitutive activity in neurofibromin-depleted cells. Further supporting a role of neurofibromin in agonist-independent Gs signaling elicited by native receptors, the phosphorylation of cAMP-responsive element-binding protein (CREB) is strongly decreased in prefrontal cortex of Nf1+/- mice compared with WT mice. Moreover, systemic administration of a 5-HT6 receptor inverse agonist reduces CREB phosphorylation in prefrontal cortex of WT mice but not Nf1+/- mice. Collectively, these findings suggest that disrupting 5-HT6 receptor-neurofibromin interaction prevents agonist-independent 5-HT6 receptor-operated cAMP signaling in prefrontal cortex, an effect that might underlie neuronal abnormalities in NF1 patients.
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35
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Abstract
The formation and maintenance of an organism are highly dependent on the orderly control of cell growth, differentiation, death, and migration. These processes are tightly regulated by signaling cascades in which a limited number of molecules dictate these cellular events. While these signaling pathways are highly conserved across species and cell types, the functional outcomes that result from their engagement are specified by the context in which they are activated. Using the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome as an illustrative platform, we discuss how NF1/RAS signaling can create functional diversity at multiple levels (molecular, cellular, tissue, and genetic/genomic). As such, the ability of related molecules (e.g., K-RAS, H-RAS) to activate distinct effectors, as well as cell type- and tissue-specific differences in molecular composition and effector engagement, generate numerous unique functional effects. These variations, coupled with a multitude of extracellular cues and genomic/genetic changes that each modify the innate signaling properties of the cell, enable precise control of cellular physiology in both health and disease. Understanding these contextual influences is important when trying to dissect the underlying pathogenic mechanisms of cancer relevant to molecularly-targeted therapeutics.
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36
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Helfferich J, Nijmeijer R, Brouwer OF, Boon M, Fock A, Hoving EW, Meijer L, den Dunnen WFA, de Bont ESJM. Neurofibromatosis type 1 associated low grade gliomas: A comparison with sporadic low grade gliomas. Crit Rev Oncol Hematol 2016; 104:30-41. [PMID: 27263935 DOI: 10.1016/j.critrevonc.2016.05.008] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Revised: 03/24/2016] [Accepted: 05/12/2016] [Indexed: 11/29/2022] Open
Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder, associated with a variable clinical phenotype including café-au-lait spots, intertriginous freckling, Lisch nodules, neurofibromas, optic pathway gliomas and distinctive bony lesions. NF1 is caused by a mutation in the NF1 gene, which codes for neurofibromin, a large protein involved in the MAPK- and the mTOR-pathway through RAS-RAF signalling. NF1 is a known tumour predisposition syndrome, associated with different tumours of the nervous system including low grade gliomas (LGGs) in the paediatric population. The focus of this review is on grade I pilocytic astrocytomas (PAs), the most commonly observed histologic subtype of low grade gliomas in NF1. Clinically, these PAs have a better prognosis and show different localisation patterns than their sporadic counterparts, which are most commonly associated with a KIAA1549:BRAF fusion. In this review, possible mechanisms of tumourigenesis in LGGs with and without NF1 will be discussed, including the contribution of different signalling pathways and tumour microenvironment. Furthermore we will discuss how increased understanding of tumourigenesis may lead to new potential targets for treatment.
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Affiliation(s)
- Jelte Helfferich
- Department of Paediatrics, Beatrix Children's Hospital, Paediatric Oncology/Hematology Division, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Neurology, Paediatric Neurology Division, University Medical Center Groningen, University of Groningen, The Netherlands
| | - Ronald Nijmeijer
- Department of Pathology and Medical Biology, Pathology Division, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Oebele F Brouwer
- Department of Neurology, Paediatric Neurology Division, University Medical Center Groningen, University of Groningen, The Netherlands
| | - Maartje Boon
- Department of Neurology, Paediatric Neurology Division, University Medical Center Groningen, University of Groningen, The Netherlands
| | - Annemarie Fock
- Department of Neurology, Paediatric Neurology Division, University Medical Center Groningen, University of Groningen, The Netherlands
| | - Eelco W Hoving
- Department of Neurosurgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Lisethe Meijer
- Department of Paediatrics, Beatrix Children's Hospital, Paediatric Oncology/Hematology Division, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Wilfred F A den Dunnen
- Department of Pathology and Medical Biology, Pathology Division, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Eveline S J M de Bont
- Department of Paediatrics, Beatrix Children's Hospital, Paediatric Oncology/Hematology Division, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
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Le TP, Vuong LT, Kim AR, Hsu YC, Choi KW. 14-3-3 proteins regulate Tctp-Rheb interaction for organ growth in Drosophila. Nat Commun 2016; 7:11501. [PMID: 27151460 PMCID: PMC4859069 DOI: 10.1038/ncomms11501] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 04/04/2016] [Indexed: 12/17/2022] Open
Abstract
14-3-3 family proteins regulate multiple signalling pathways. Understanding biological functions of 14-3-3 proteins has been limited by the functional redundancy of conserved isotypes. Here we provide evidence that 14-3-3 proteins regulate two interacting components of Tor signalling in Drosophila, translationally controlled tumour protein (Tctp) and Rheb GTPase. Single knockdown of 14-3-3ɛ or 14-3-3ζ isoform does not show obvious defects in organ development but causes synergistic genetic interaction with Tctp and Rheb to impair tissue growth. 14-3-3 proteins physically interact with Tctp and Rheb. Knockdown of both 14-3-3 isoforms abolishes the binding between Tctp and Rheb, disrupting organ development. Depletion of 14-3-3s also reduces the level of phosphorylated S6 kinase, phosphorylated Thor/4E-BP and cyclin E (CycE). Growth defects from knockdown of 14-3-3 and Tctp are suppressed by CycE overexpression. This study suggests a novel mechanism of Tor regulation mediated by 14-3-3 interaction with Tctp and Rheb. 14-3-3 proteins regulate several signalling pathways but often act redundantly; however, the molecular mechanisms behind such redundancy are unclear. Here, the authors show that 14-3-3 proteins regulate two interacting components of Tor signalling in Drosophila, Tctp and Rheb, disrupting organ development.
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Affiliation(s)
- Thao Phuong Le
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon 305-701, Korea
| | - Linh Thuong Vuong
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon 305-701, Korea
| | - Ah-Ram Kim
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon 305-701, Korea
| | - Ya-Chieh Hsu
- Department of Stem Cell and Regenerative Biology, Harvard University, Sherman Fairchild 358A, 7 Divinity Avenue Cambridge, Massachusetts 02138, USA
| | - Kwang-Wook Choi
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon 305-701, Korea
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Jindal GA, Goyal Y, Burdine RD, Rauen KA, Shvartsman SY. RASopathies: unraveling mechanisms with animal models. Dis Model Mech 2016. [PMID: 26203125 PMCID: PMC4527292 DOI: 10.1242/dmm.020339] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
RASopathies are developmental disorders caused by germline mutations in the Ras-MAPK pathway, and are characterized by a broad spectrum of functional and morphological abnormalities. The high incidence of these disorders (∼1/1000 births) motivates the development of systematic approaches for their efficient diagnosis and potential treatment. Recent advances in genome sequencing have greatly facilitated the genotyping and discovery of mutations in affected individuals, but establishing the causal relationships between molecules and disease phenotypes is non-trivial and presents both technical and conceptual challenges. Here, we discuss how these challenges could be addressed using genetically modified model organisms that have been instrumental in delineating the Ras-MAPK pathway and its roles during development. Focusing on studies in mice, zebrafish and Drosophila, we provide an up-to-date review of animal models of RASopathies at the molecular and functional level. We also discuss how increasingly sophisticated techniques of genetic engineering can be used to rigorously connect changes in specific components of the Ras-MAPK pathway with observed functional and morphological phenotypes. Establishing these connections is essential for advancing our understanding of RASopathies and for devising rational strategies for their management and treatment. Summary: Developmental disorders caused by germline mutations in the Ras-MAPK pathway are called RASopathies. Studies with animal models, including mice, zebrafish and Drosophila, continue to enhance our understanding of these diseases.
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Affiliation(s)
- Granton A Jindal
- Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
| | - Yogesh Goyal
- Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
| | - Rebecca D Burdine
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Katherine A Rauen
- Department of Pediatrics, MIND Institute, Division of Genomic Medicine, University of California, Davis, Sacramento, CA 95817, USA
| | - Stanislav Y Shvartsman
- Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
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Deletion of mTOR in Reactive Astrocytes Suppresses Chronic Seizures in a Mouse Model of Temporal Lobe Epilepsy. Mol Neurobiol 2016; 54:175-187. [PMID: 26732600 DOI: 10.1007/s12035-015-9590-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 11/29/2015] [Indexed: 01/28/2023]
Abstract
Germline and somatic mutations in key genes of the mammalian target of rapamycin (mTOR) pathway have been identified in seizure-associated disorders. mTOR mutations lead to aberrant activation of mTOR signaling, and, although affected neurons are critical for epileptogenesis, the role of mTOR activation in glial cells remains poorly understood. We previously reported a consistent activation of the mTOR pathway in astrocytes in the epileptic foci of temporal lobe epilepsy. In this study, it was demonstrated that mTOR deletion from reactive astrocytes prevents increases in seizure frequency over the disease course. By using a tamoxifen-inducible mTOR conditional knockout system and kainic acid, a model was developed that allowed astrocyte-specific mTOR gene deletion in mice with chronic epilepsy. Animals in which mTOR was deleted from 44 % of the astrocyte population exhibited a lower seizure frequency compared with controls. Down-regulation of mTOR significantly ameliorated astrogliosis in the sclerotic hippocampus but did not rescue mossy fiber sprouting. In cultured astrocytes, the mTOR pathway modulated the stability of the astroglial glutamate transporter 1 (Glt1) and influenced the ability of astrocytes to remove extracellular glutamate. Taken together, these data indicate that astrocytes with activated mTOR signaling may provide conditions that are favorable for spontaneous recurrent seizures.
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Biever A, Valjent E, Puighermanal E. Ribosomal Protein S6 Phosphorylation in the Nervous System: From Regulation to Function. Front Mol Neurosci 2015; 8:75. [PMID: 26733799 PMCID: PMC4679984 DOI: 10.3389/fnmol.2015.00075] [Citation(s) in RCA: 166] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 11/23/2015] [Indexed: 01/31/2023] Open
Abstract
Since the discovery of the phosphorylation of the 40S ribosomal protein S6 (rpS6) about four decades ago, much effort has been made to uncover the molecular mechanisms underlying the regulation of this post-translational modification. In the field of neuroscience, rpS6 phosphorylation is commonly used as a readout of the mammalian target of rapamycin complex 1 signaling activation or as a marker for neuronal activity. Nevertheless, its biological role in neurons still remains puzzling. Here we review the pharmacological and physiological stimuli regulating this modification in the nervous system as well as the pathways that transduce these signals into rpS6 phosphorylation. Altered rpS6 phosphorylation observed in various genetic and pathophysiological mouse models is also discussed. Finally, we examine the current state of knowledge on the physiological role of this post-translational modification and highlight the questions that remain to be addressed.
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Affiliation(s)
- Anne Biever
- Centre National de la Recherche Scientifique, UMR5203, Institut de Génomique FonctionnelleMontpellier, France; Institut National de la Santé et de la Recherche Médicale, U1191Montpellier, France; Université de Montpellier, UMR-5203Montpellier, France
| | - Emmanuel Valjent
- Centre National de la Recherche Scientifique, UMR5203, Institut de Génomique FonctionnelleMontpellier, France; Institut National de la Santé et de la Recherche Médicale, U1191Montpellier, France; Université de Montpellier, UMR-5203Montpellier, France
| | - Emma Puighermanal
- Centre National de la Recherche Scientifique, UMR5203, Institut de Génomique FonctionnelleMontpellier, France; Institut National de la Santé et de la Recherche Médicale, U1191Montpellier, France; Université de Montpellier, UMR-5203Montpellier, France
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Tafe LJ, Gorlov IP, de Abreu FB, Lefferts JA, Liu X, Pettus JR, Marotti JD, Bloch KJ, Memoli VA, Suriawinata AA, Dragnev KH, Fadul CE, Schwartz GN, Morgan CR, Holderness BM, Peterson JD, Tsongalis GJ, Miller TW, Chamberlin MD. Implementation of a Molecular Tumor Board: The Impact on Treatment Decisions for 35 Patients Evaluated at Dartmouth-Hitchcock Medical Center. Oncologist 2015. [PMID: 26205736 DOI: 10.1634/theoncologist.2015-0097] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Although genetic profiling of tumors is a potentially powerful tool to predict drug sensitivity and resistance, its routine use has been limited because clinicians are often unfamiliar with interpretation and incorporation of the information into practice. We established a Molecular Tumor Board (MTB) to interpret individual patients' tumor genetic profiles and provide treatment recommendations. PATIENTS AND METHODS DNA from tumor specimens was sequenced in a Clinical Laboratory Improvement Amendments-certified laboratory to identify coding mutations in a 50-gene panel (n = 34) or a 255-gene panel (n = 1). Cases were evaluated by a multidisciplinary MTB that included pathologists, oncologists, hematologists, basic scientists, and genetic counselors. RESULTS During the first year, 35 cases were evaluated by the MTB, with 32 presented for recommendations on targeted therapies, and 3 referred for potential germline mutations. In 56.3% of cases, MTB recommended treatment with a targeted agent based on evaluation of tumor genetic profile and treatment history. Four patients (12.5%) were subsequently treated with a MTB-recommended targeted therapy; 3 of the 4 patients remain on therapy, 2 of whom experienced clinical benefit lasting >10 months. CONCLUSION For the majority of cases evaluated, the MTB was able to provide treatment recommendations based on targetable genetic alterations. The most common reasons that MTB-recommended therapy was not administered stemmed from patient preferences and genetic profiling at either very early or very late stages of disease; lack of drug access was rarely encountered. Increasing awareness of molecular profiling and targeted therapies by both clinicians and patients will improve acceptance and adherence to treatments that could significantly improve outcomes. IMPLICATIONS FOR PRACTICE Case evaluation by a multidisciplinary Molecular Tumor Board (MTB) is critical to benefit from individualized genetic data and maximize clinical impact. MTB recommendations shaped treatment options for the majority of cases evaluated. In the few patients treated with MTB-recommended therapy, disease outcomes were positive and support genetically informed treatment.
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Affiliation(s)
- Laura J Tafe
- Departments of Pathology, Community and Family Medicine, Medicine, and Pharmacology & Toxicology, Comprehensive Breast Program, and Familial Cancer Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Ivan P Gorlov
- Departments of Pathology, Community and Family Medicine, Medicine, and Pharmacology & Toxicology, Comprehensive Breast Program, and Familial Cancer Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Francine B de Abreu
- Departments of Pathology, Community and Family Medicine, Medicine, and Pharmacology & Toxicology, Comprehensive Breast Program, and Familial Cancer Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Joel A Lefferts
- Departments of Pathology, Community and Family Medicine, Medicine, and Pharmacology & Toxicology, Comprehensive Breast Program, and Familial Cancer Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Xiaoying Liu
- Departments of Pathology, Community and Family Medicine, Medicine, and Pharmacology & Toxicology, Comprehensive Breast Program, and Familial Cancer Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Jason R Pettus
- Departments of Pathology, Community and Family Medicine, Medicine, and Pharmacology & Toxicology, Comprehensive Breast Program, and Familial Cancer Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Jonathan D Marotti
- Departments of Pathology, Community and Family Medicine, Medicine, and Pharmacology & Toxicology, Comprehensive Breast Program, and Familial Cancer Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Kasia J Bloch
- Departments of Pathology, Community and Family Medicine, Medicine, and Pharmacology & Toxicology, Comprehensive Breast Program, and Familial Cancer Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Vincent A Memoli
- Departments of Pathology, Community and Family Medicine, Medicine, and Pharmacology & Toxicology, Comprehensive Breast Program, and Familial Cancer Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Arief A Suriawinata
- Departments of Pathology, Community and Family Medicine, Medicine, and Pharmacology & Toxicology, Comprehensive Breast Program, and Familial Cancer Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Konstantin H Dragnev
- Departments of Pathology, Community and Family Medicine, Medicine, and Pharmacology & Toxicology, Comprehensive Breast Program, and Familial Cancer Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Camilo E Fadul
- Departments of Pathology, Community and Family Medicine, Medicine, and Pharmacology & Toxicology, Comprehensive Breast Program, and Familial Cancer Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Gary N Schwartz
- Departments of Pathology, Community and Family Medicine, Medicine, and Pharmacology & Toxicology, Comprehensive Breast Program, and Familial Cancer Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Clinton R Morgan
- Departments of Pathology, Community and Family Medicine, Medicine, and Pharmacology & Toxicology, Comprehensive Breast Program, and Familial Cancer Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Britt M Holderness
- Departments of Pathology, Community and Family Medicine, Medicine, and Pharmacology & Toxicology, Comprehensive Breast Program, and Familial Cancer Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Jason D Peterson
- Departments of Pathology, Community and Family Medicine, Medicine, and Pharmacology & Toxicology, Comprehensive Breast Program, and Familial Cancer Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Gregory J Tsongalis
- Departments of Pathology, Community and Family Medicine, Medicine, and Pharmacology & Toxicology, Comprehensive Breast Program, and Familial Cancer Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Todd W Miller
- Departments of Pathology, Community and Family Medicine, Medicine, and Pharmacology & Toxicology, Comprehensive Breast Program, and Familial Cancer Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Mary D Chamberlin
- Departments of Pathology, Community and Family Medicine, Medicine, and Pharmacology & Toxicology, Comprehensive Breast Program, and Familial Cancer Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
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Agnihotri S, Zadeh G. Metabolic reprogramming in glioblastoma: the influence of cancer metabolism on epigenetics and unanswered questions. Neuro Oncol 2015; 18:160-72. [PMID: 26180081 DOI: 10.1093/neuonc/nov125] [Citation(s) in RCA: 206] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2014] [Accepted: 06/15/2015] [Indexed: 12/21/2022] Open
Abstract
A defining hallmark of glioblastoma is altered tumor metabolism. The metabolic shift towards aerobic glycolysis with reprogramming of mitochondrial oxidative phosphorylation, regardless of oxygen availability, is a phenomenon known as the Warburg effect. In addition to the Warburg effect, glioblastoma tumor cells also utilize the tricarboxylic acid cycle/oxidative phosphorylation in a different capacity than normal tissue. Altered metabolic enzymes and their metabolites are oncogenic and not simply a product of tumor proliferation. Here we highlight the advantages of why tumor cells, including glioblastoma cells, require metabolic reprogramming and how tumor metabolism can converge on tumor epigenetics and unanswered questions in the field.
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Affiliation(s)
- Sameer Agnihotri
- MacFeeters-Hamilton Brain Tumor Centre, Toronto, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada (S.A., G.Z.); Department of Neurosurgery, Toronto Western Hospital, University Health Network, Toronto, Canada (G.Z)
| | - Gelareh Zadeh
- MacFeeters-Hamilton Brain Tumor Centre, Toronto, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada (S.A., G.Z.); Department of Neurosurgery, Toronto Western Hospital, University Health Network, Toronto, Canada (G.Z)
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Sadowski K, Kotulska-Jóźwiak K, Jóźwiak S. Role of mTOR inhibitors in epilepsy treatment. Pharmacol Rep 2015; 67:636-646. [PMID: 25933981 DOI: 10.1016/j.pharep.2014.12.017] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2014] [Revised: 12/24/2014] [Accepted: 12/30/2014] [Indexed: 01/16/2023]
Abstract
In spite of the fact, that subsequent new antiepileptic drugs (AEDs) are being introduced into clinical practice, the percentage of drug-resistant epilepsy cases remains stable. Although a substantial progress has been made in safety profile of antiepileptic drugs, currently available substances have not been unambiguously proven to display disease-modifying effect in epilepsy and their mechanisms of action influence mainly on the end-stage phase of epileptogenesis, namely seizures. Prevention of epileptogenesis requires new generation of drugs modulating molecular pathways engaged in epileptogenesis processes. The mammalian target of rapamycin (mTOR) pathway is involved in highly epileptogenic conditions, such as tuberous sclerosis complex (TSC) and represents a reasonable target for antiepileptogenic interventions. In animal models of TSC mTOR inhibitors turned out to prevent the development of epilepsy and reduce underlying brain abnormalities. Accumulating evidence from animal studies suggest the role of mTOR pathway in acquired forms of epilepsy. Preliminary clinical studies with patients affected by TSC demonstrated seizure reduction and potential disease-modifying effect of mTOR inhibitors. Further studies will determine the place for mTOR inhibitors in the treatment of patients with TSC as well as its potential antiepileptogenic effect in other types of genetic and acquired epilepsies. This review presents current knowledge of mTOR pathway physiology and pathology in the brain, as well as potential clinical use of its inhibitors.
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Affiliation(s)
| | | | - Sergiusz Jóźwiak
- Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warszawa, Poland
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44
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Rodriguez FJ, Raabe EH. mTOR: a new therapeutic target for pediatric low-grade glioma? CNS Oncol 2015; 3:89-91. [PMID: 25055011 DOI: 10.2217/cns.14.4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
- Fausto J Rodriguez
- Division of Neuropathology, Johns Hopkins University, Baltimore, MD, USA
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45
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Brossier NM, Gutmann DH. Improving outcomes for neurofibromatosis 1-associated brain tumors. Expert Rev Anticancer Ther 2015; 15:415-23. [PMID: 25652347 DOI: 10.1586/14737140.2015.1009043] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Children and adults with neurofibromatosis type 1 (NF1) are predisposed to developing CNS tumors, including optic pathway gliomas (OPGs), brainstem gliomas (BSGs) and high-grade gliomas. Although current first-line treatments for low-grade gliomas (OPGs and BSGs) may prevent further tumor growth, they rarely result in restoration of the associated visual or neurological deficits. The availability of accurate small-animal models of NF1-associated brain tumors has established tractable experimental platforms for the discovery and evaluation of promising therapeutic agents. On the basis of these preclinical studies, biologically targeted agents are now being evaluated in children with NF1-associated low-grade brain tumors. Collectively, these models have also begun to reveal potential neuroprotective and risk assessment strategies for this brain tumor-prone population.
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Affiliation(s)
- Nicole M Brossier
- Department of Pediatrics, St. Louis Children's Hospital, St. Louis, MO, USA
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Kaul A, Toonen JA, Cimino PJ, Gianino SM, Gutmann DH. Akt- or MEK-mediated mTOR inhibition suppresses Nf1 optic glioma growth. Neuro Oncol 2014; 17:843-53. [PMID: 25534823 DOI: 10.1093/neuonc/nou329] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2014] [Accepted: 11/08/2014] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Children with neurofibromatosis type 1 (NF1) develop optic pathway gliomas, which result from impaired NF1 protein regulation of Ras activity. One obstacle to the implementation of biologically targeted therapies is an incomplete understanding of the individual contributions of the downstream Ras effectors (mitogen-activated protein kinase kinase [MEK], Akt) to optic glioma maintenance. This study was designed to address the importance of MEK and Akt signaling to Nf1 optic glioma growth. METHODS Primary neonatal mouse astrocyte cultures were employed to determine the consequence of phosphatidylinositol-3 kinase (PI3K)/Akt and MEK inhibition on Nf1-deficient astrocyte growth. Nf1 optic glioma-bearing mice were used to assess the effect of Akt and MEK inhibition on tumor volume, proliferation, and retinal ganglion cell dysfunction. RESULTS Both MEK and Akt were hyperactivated in Nf1-deficient astrocytes in vitro and in Nf1 murine optic gliomas in vivo. Pharmacologic PI3K or Akt inhibition reduced Nf1-deficient astrocyte proliferation to wild-type levels, while PI3K inhibition decreased Nf1 optic glioma volume and proliferation. Akt inhibition of Nf1-deficient astrocyte and optic glioma growth reflected Akt-dependent activation of mammalian target of rapamycin (mTOR). Sustained MEK pharmacologic blockade also attenuated Nf1-deficient astrocytes as well as Nf1 optic glioma volume and proliferation. Importantly, these MEK inhibitory effects resulted from p90RSK-mediated, Akt-independent mTOR activation. Finally, both PI3K and MEK inhibition reduced optic glioma-associated retinal ganglion cell loss and nerve fiber layer thinning. CONCLUSION These findings establish that the convergence of 2 distinct Ras effector pathways on mTOR signaling maintains Nf1 mouse optic glioma growth, supporting the evaluation of pharmacologic inhibitors that target mTOR function in future human NF1-optic pathway glioma clinical trials.
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Affiliation(s)
- Aparna Kaul
- Department of Neurology, Washington University School of Medicine, St. Louis, Missouri (A.K., J.A.T., S.M.G., D.H.G.); Department of Pathology, Washington University School of Medicine, St. Louis, Missouri (P.J.C.)
| | - Joseph A Toonen
- Department of Neurology, Washington University School of Medicine, St. Louis, Missouri (A.K., J.A.T., S.M.G., D.H.G.); Department of Pathology, Washington University School of Medicine, St. Louis, Missouri (P.J.C.)
| | - Patrick J Cimino
- Department of Neurology, Washington University School of Medicine, St. Louis, Missouri (A.K., J.A.T., S.M.G., D.H.G.); Department of Pathology, Washington University School of Medicine, St. Louis, Missouri (P.J.C.)
| | - Scott M Gianino
- Department of Neurology, Washington University School of Medicine, St. Louis, Missouri (A.K., J.A.T., S.M.G., D.H.G.); Department of Pathology, Washington University School of Medicine, St. Louis, Missouri (P.J.C.)
| | - David H Gutmann
- Department of Neurology, Washington University School of Medicine, St. Louis, Missouri (A.K., J.A.T., S.M.G., D.H.G.); Department of Pathology, Washington University School of Medicine, St. Louis, Missouri (P.J.C.)
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Ma DJ, Galanis E, Anderson SK, Schiff D, Kaufmann TJ, Peller PJ, Giannini C, Brown PD, Uhm JH, McGraw S, Jaeckle KA, Flynn PJ, Ligon KL, Buckner JC, Sarkaria JN. A phase II trial of everolimus, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma: NCCTG N057K. Neuro Oncol 2014; 17:1261-9. [PMID: 25526733 DOI: 10.1093/neuonc/nou328] [Citation(s) in RCA: 116] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2007] [Accepted: 10/31/2014] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The mammalian target of rapamycin (mTOR) functions within the phosphatidylinositol-3 kinase (PI3K)/Akt pathway as a critical modulator of cell survival. This clinical trial evaluated the combination of the mTOR inhibitor everolimus with conventional temozolomide (TMZ)-based chemoradiotherapy. METHODS Newly diagnosed patients with glioblastoma multiforme were eligible for this single arm, phase II study. Everolimus (70 mg/wk) was started 1 week prior to radiation and TMZ, followed by adjuvant TMZ, and continued until disease progression. The primary endpoint was overall survival at 12 months, and secondary endpoints were toxicity and time to progression. Eleven patients were imaged with 3'-deoxy-3'-(18)F-fluorothymidine ((18)FLT)-PET/CT before and after the initial 2 doses of everolimus before initiating radiation/TMZ. Imaged patients with sufficient tumor samples also underwent immunohistochemical and focused exon sequencing analysis. RESULTS This study accrued 100 evaluable patients. Fourteen percent of patients had grade 4 hematologic toxicities. Twelve percent had at least one grade 4 nonhematologic toxicity, and there was one treatment-related death. Overall survival at 12 months was 64% and median time to progression was 6.4 months. Of the patients who had (18)FLT-PET data, 4/9 had a partial response after 2 doses of everolimus. Focused exon sequencing demonstrated that (18)FLT-PET responders were less likely to have alterations within the PI3K/Akt/mTOR or tuberous sclerosis complex/neurofibromatosis type 1 pathway compared with nonresponders. CONCLUSION Combining everolimus with conventional chemoradiation had moderate toxicity. (18)FLT-PET studies suggested an initial antiproliferative effect in a genetically distinct subset of tumors, but this did not translate into an appreciable survival benefit compared with historical controls treated with conventional therapy.
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Affiliation(s)
- Daniel J Ma
- Mayo Clinic, Rochester, Minnesota (D.J.M., E.G., T.J.K., P.J.P., C.G., P.D.B., J.H.U., J.C.B., J.N.S.); Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota (S.K.A.); University of Virginia, Charlottesville, Virginia (D.S.); MD Anderson Cancer Center, Houston, Texas (P.D.B.); Sioux Community Cancer Consortium, Sioux Falls, South Dakota (S.M.); Mayo Clinic, Jacksonville, Florida (K.A.J.); Metro-Minnesota Community Clinical Oncology Program, St. Louis Park, Minnesota (P.J.F.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts (K.L.L.)
| | - Evanthia Galanis
- Mayo Clinic, Rochester, Minnesota (D.J.M., E.G., T.J.K., P.J.P., C.G., P.D.B., J.H.U., J.C.B., J.N.S.); Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota (S.K.A.); University of Virginia, Charlottesville, Virginia (D.S.); MD Anderson Cancer Center, Houston, Texas (P.D.B.); Sioux Community Cancer Consortium, Sioux Falls, South Dakota (S.M.); Mayo Clinic, Jacksonville, Florida (K.A.J.); Metro-Minnesota Community Clinical Oncology Program, St. Louis Park, Minnesota (P.J.F.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts (K.L.L.)
| | - S Keith Anderson
- Mayo Clinic, Rochester, Minnesota (D.J.M., E.G., T.J.K., P.J.P., C.G., P.D.B., J.H.U., J.C.B., J.N.S.); Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota (S.K.A.); University of Virginia, Charlottesville, Virginia (D.S.); MD Anderson Cancer Center, Houston, Texas (P.D.B.); Sioux Community Cancer Consortium, Sioux Falls, South Dakota (S.M.); Mayo Clinic, Jacksonville, Florida (K.A.J.); Metro-Minnesota Community Clinical Oncology Program, St. Louis Park, Minnesota (P.J.F.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts (K.L.L.)
| | - David Schiff
- Mayo Clinic, Rochester, Minnesota (D.J.M., E.G., T.J.K., P.J.P., C.G., P.D.B., J.H.U., J.C.B., J.N.S.); Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota (S.K.A.); University of Virginia, Charlottesville, Virginia (D.S.); MD Anderson Cancer Center, Houston, Texas (P.D.B.); Sioux Community Cancer Consortium, Sioux Falls, South Dakota (S.M.); Mayo Clinic, Jacksonville, Florida (K.A.J.); Metro-Minnesota Community Clinical Oncology Program, St. Louis Park, Minnesota (P.J.F.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts (K.L.L.)
| | - Timothy J Kaufmann
- Mayo Clinic, Rochester, Minnesota (D.J.M., E.G., T.J.K., P.J.P., C.G., P.D.B., J.H.U., J.C.B., J.N.S.); Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota (S.K.A.); University of Virginia, Charlottesville, Virginia (D.S.); MD Anderson Cancer Center, Houston, Texas (P.D.B.); Sioux Community Cancer Consortium, Sioux Falls, South Dakota (S.M.); Mayo Clinic, Jacksonville, Florida (K.A.J.); Metro-Minnesota Community Clinical Oncology Program, St. Louis Park, Minnesota (P.J.F.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts (K.L.L.)
| | - Patrick J Peller
- Mayo Clinic, Rochester, Minnesota (D.J.M., E.G., T.J.K., P.J.P., C.G., P.D.B., J.H.U., J.C.B., J.N.S.); Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota (S.K.A.); University of Virginia, Charlottesville, Virginia (D.S.); MD Anderson Cancer Center, Houston, Texas (P.D.B.); Sioux Community Cancer Consortium, Sioux Falls, South Dakota (S.M.); Mayo Clinic, Jacksonville, Florida (K.A.J.); Metro-Minnesota Community Clinical Oncology Program, St. Louis Park, Minnesota (P.J.F.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts (K.L.L.)
| | - Caterina Giannini
- Mayo Clinic, Rochester, Minnesota (D.J.M., E.G., T.J.K., P.J.P., C.G., P.D.B., J.H.U., J.C.B., J.N.S.); Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota (S.K.A.); University of Virginia, Charlottesville, Virginia (D.S.); MD Anderson Cancer Center, Houston, Texas (P.D.B.); Sioux Community Cancer Consortium, Sioux Falls, South Dakota (S.M.); Mayo Clinic, Jacksonville, Florida (K.A.J.); Metro-Minnesota Community Clinical Oncology Program, St. Louis Park, Minnesota (P.J.F.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts (K.L.L.)
| | - Paul D Brown
- Mayo Clinic, Rochester, Minnesota (D.J.M., E.G., T.J.K., P.J.P., C.G., P.D.B., J.H.U., J.C.B., J.N.S.); Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota (S.K.A.); University of Virginia, Charlottesville, Virginia (D.S.); MD Anderson Cancer Center, Houston, Texas (P.D.B.); Sioux Community Cancer Consortium, Sioux Falls, South Dakota (S.M.); Mayo Clinic, Jacksonville, Florida (K.A.J.); Metro-Minnesota Community Clinical Oncology Program, St. Louis Park, Minnesota (P.J.F.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts (K.L.L.)
| | - Joon H Uhm
- Mayo Clinic, Rochester, Minnesota (D.J.M., E.G., T.J.K., P.J.P., C.G., P.D.B., J.H.U., J.C.B., J.N.S.); Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota (S.K.A.); University of Virginia, Charlottesville, Virginia (D.S.); MD Anderson Cancer Center, Houston, Texas (P.D.B.); Sioux Community Cancer Consortium, Sioux Falls, South Dakota (S.M.); Mayo Clinic, Jacksonville, Florida (K.A.J.); Metro-Minnesota Community Clinical Oncology Program, St. Louis Park, Minnesota (P.J.F.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts (K.L.L.)
| | - Steven McGraw
- Mayo Clinic, Rochester, Minnesota (D.J.M., E.G., T.J.K., P.J.P., C.G., P.D.B., J.H.U., J.C.B., J.N.S.); Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota (S.K.A.); University of Virginia, Charlottesville, Virginia (D.S.); MD Anderson Cancer Center, Houston, Texas (P.D.B.); Sioux Community Cancer Consortium, Sioux Falls, South Dakota (S.M.); Mayo Clinic, Jacksonville, Florida (K.A.J.); Metro-Minnesota Community Clinical Oncology Program, St. Louis Park, Minnesota (P.J.F.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts (K.L.L.)
| | - Kurt A Jaeckle
- Mayo Clinic, Rochester, Minnesota (D.J.M., E.G., T.J.K., P.J.P., C.G., P.D.B., J.H.U., J.C.B., J.N.S.); Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota (S.K.A.); University of Virginia, Charlottesville, Virginia (D.S.); MD Anderson Cancer Center, Houston, Texas (P.D.B.); Sioux Community Cancer Consortium, Sioux Falls, South Dakota (S.M.); Mayo Clinic, Jacksonville, Florida (K.A.J.); Metro-Minnesota Community Clinical Oncology Program, St. Louis Park, Minnesota (P.J.F.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts (K.L.L.)
| | - Patrick J Flynn
- Mayo Clinic, Rochester, Minnesota (D.J.M., E.G., T.J.K., P.J.P., C.G., P.D.B., J.H.U., J.C.B., J.N.S.); Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota (S.K.A.); University of Virginia, Charlottesville, Virginia (D.S.); MD Anderson Cancer Center, Houston, Texas (P.D.B.); Sioux Community Cancer Consortium, Sioux Falls, South Dakota (S.M.); Mayo Clinic, Jacksonville, Florida (K.A.J.); Metro-Minnesota Community Clinical Oncology Program, St. Louis Park, Minnesota (P.J.F.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts (K.L.L.)
| | - Keith L Ligon
- Mayo Clinic, Rochester, Minnesota (D.J.M., E.G., T.J.K., P.J.P., C.G., P.D.B., J.H.U., J.C.B., J.N.S.); Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota (S.K.A.); University of Virginia, Charlottesville, Virginia (D.S.); MD Anderson Cancer Center, Houston, Texas (P.D.B.); Sioux Community Cancer Consortium, Sioux Falls, South Dakota (S.M.); Mayo Clinic, Jacksonville, Florida (K.A.J.); Metro-Minnesota Community Clinical Oncology Program, St. Louis Park, Minnesota (P.J.F.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts (K.L.L.)
| | - Jan C Buckner
- Mayo Clinic, Rochester, Minnesota (D.J.M., E.G., T.J.K., P.J.P., C.G., P.D.B., J.H.U., J.C.B., J.N.S.); Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota (S.K.A.); University of Virginia, Charlottesville, Virginia (D.S.); MD Anderson Cancer Center, Houston, Texas (P.D.B.); Sioux Community Cancer Consortium, Sioux Falls, South Dakota (S.M.); Mayo Clinic, Jacksonville, Florida (K.A.J.); Metro-Minnesota Community Clinical Oncology Program, St. Louis Park, Minnesota (P.J.F.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts (K.L.L.)
| | - Jann N Sarkaria
- Mayo Clinic, Rochester, Minnesota (D.J.M., E.G., T.J.K., P.J.P., C.G., P.D.B., J.H.U., J.C.B., J.N.S.); Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota (S.K.A.); University of Virginia, Charlottesville, Virginia (D.S.); MD Anderson Cancer Center, Houston, Texas (P.D.B.); Sioux Community Cancer Consortium, Sioux Falls, South Dakota (S.M.); Mayo Clinic, Jacksonville, Florida (K.A.J.); Metro-Minnesota Community Clinical Oncology Program, St. Louis Park, Minnesota (P.J.F.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts (K.L.L.)
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48
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Solin SL, Wang Y, Mauldin J, Schultz LE, Lincow DE, Brodskiy PA, Jones CA, Syrkin-Nikolau J, Linn JM, Essner JJ, Hostetter JM, Whitley EM, Cameron JD, Chou HH, Severin AJ, Sakaguchi DS, McGrail M. Molecular and cellular characterization of a zebrafish optic pathway tumor line implicates glia-derived progenitors in tumorigenesis. PLoS One 2014; 9:e114888. [PMID: 25485542 PMCID: PMC4259487 DOI: 10.1371/journal.pone.0114888] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 11/14/2014] [Indexed: 12/29/2022] Open
Abstract
In this study we describe the molecular and cellular characterization of a zebrafish mutant that develops tumors in the optic pathway. Heterozygous Tg(flk1:RFP)is18 transgenic adults develop tumors of the retina, optic nerve and optic tract. Molecular and genetic mapping demonstrate the tumor phenotype is linked to a high copy number transgene array integrated in the lincRNA gene lincRNAis18/Zv9_00007276 on chromosome 3. TALENs were used to isolate a 147kb deletion allele that removes exons 2–5 of the lincRNAis18 gene. Deletion allele homozygotes are viable and do not develop tumors, indicating loss of function of the lincRNAis18 locus is not the trigger for tumor onset. Optic pathway tumors in the Tg(flk1:RFP)is18 mutant occur with a penetrance of 80–100% by 1 year of age. The retinal tumors are highly vascularized and composed of rosettes of various sizes embedded in a fibrous matrix. Immunohistochemical analysis showed increased expression of the glial markers GFAP and BLBP throughout retinal tumors and in dysplastic optic nerve. We performed transcriptome analysis of pre-tumorous retina and retinal tumor tissue and found changes in gene expression signatures of radial glia and astrocytes (slc1a3), activated glia (atf3, blbp, apoeb), proliferating neural progenitors (foxd3, nestin, cdh2, her9/hes1), and glioma markers (S100β, vim). The transcriptome also revealed activation of cAMP, Stat3 and Wnt signal transduction pathways. qRT-PCR confirmed >10-fold overexpression of the Wnt pathway components hbegfa, ascl1a, and insm1a. Together the data indicate Müller glia and/or astrocyte-derived progenitors could contribute to the zebrafish Tg(flk1:RFP)is18 optic pathway tumors.
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Affiliation(s)
- Staci L. Solin
- Department of Genetics, Development and Cell Biology, Iowa State University, Ames, Iowa, United States of America
| | - Ying Wang
- Department of Genetics, Development and Cell Biology, Iowa State University, Ames, Iowa, United States of America
| | - Joshua Mauldin
- Department of Genetics, Development and Cell Biology, Iowa State University, Ames, Iowa, United States of America
| | - Laura E. Schultz
- Department of Genetics, Development and Cell Biology, Iowa State University, Ames, Iowa, United States of America
| | - Deborah E. Lincow
- Department of Genetics, Development and Cell Biology, Iowa State University, Ames, Iowa, United States of America
| | - Pavel A. Brodskiy
- Department of Genetics, Development and Cell Biology, Iowa State University, Ames, Iowa, United States of America
| | - Crystal A. Jones
- Department of Genetics, Development and Cell Biology, Iowa State University, Ames, Iowa, United States of America
| | - Judith Syrkin-Nikolau
- Department of Genetics, Development and Cell Biology, Iowa State University, Ames, Iowa, United States of America
| | - Jasmine M. Linn
- Department of Genetics, Development and Cell Biology, Iowa State University, Ames, Iowa, United States of America
| | - Jeffrey J. Essner
- Department of Genetics, Development and Cell Biology, Iowa State University, Ames, Iowa, United States of America
| | - Jesse M. Hostetter
- Department of Veterinary Pathology, Iowa State University, Ames, Iowa, United States of America
| | - Elizabeth M. Whitley
- Department of Veterinary Pathology, Iowa State University, Ames, Iowa, United States of America
| | - J. Douglas Cameron
- Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Hui-Hsien Chou
- Department of Genetics, Development and Cell Biology, Iowa State University, Ames, Iowa, United States of America
| | - Andrew J. Severin
- Genome Informatics Facility, Office of Biotechnology, Iowa State University, Ames, Iowa, United States of America
| | - Donald S. Sakaguchi
- Department of Genetics, Development and Cell Biology, Iowa State University, Ames, Iowa, United States of America
| | - Maura McGrail
- Department of Genetics, Development and Cell Biology, Iowa State University, Ames, Iowa, United States of America
- * E-mail:
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49
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Abstract
The mechanistic target of rapamycin (mTOR) signaling pathway is a crucial cellular signaling hub that, like the nervous system itself, integrates internal and external cues to elicit critical outputs including growth control, protein synthesis, gene expression, and metabolic balance. The importance of mTOR signaling to brain function is underscored by the myriad disorders in which mTOR pathway dysfunction is implicated, such as autism, epilepsy, and neurodegenerative disorders. Pharmacological manipulation of mTOR signaling holds therapeutic promise and has entered clinical trials for several disorders. Here, we review the functions of mTOR signaling in the normal and pathological brain, highlighting ongoing efforts to translate our understanding of cellular physiology into direct medical benefit for neurological disorders.
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50
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Bastien JIL, McNeill KA, Fine HA. Molecular characterizations of glioblastoma, targeted therapy, and clinical results to date. Cancer 2014; 121:502-16. [PMID: 25250735 DOI: 10.1002/cncr.28968] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Revised: 06/18/2014] [Accepted: 06/26/2014] [Indexed: 12/22/2022]
Abstract
During the last decade, extensive multiplatform genome-wide analysis has yielded a wealth of knowledge regarding the genetic and molecular makeup of glioblastoma multiforme (GBM). These profiling studies support the emerging view that GBM comprises a group of highly heterogeneous tumor types, each with its own distinct molecular and genetic signatures. This heterogeneity complicates the process of defining reliable intertumor/intratumor biological states, which will ultimately be needed for classifying tumors and for designing effective customized therapies that target resultant disease pathways. The increased understanding of the molecular pathogenesis of GBM has brought the hope and expectation that such knowledge will lead to better and more rational therapies directed toward specific molecular targets. To date, however, these expectations have largely been unrealized. This review discusses some of the principal genetic and epigenetic aberrations found in GBM that appear promising for targeted therapies now and in the near future, and it offers suggestions for future directions concerning the rather disappointing results of clinical trials to date.
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Affiliation(s)
- Jayson I L Bastien
- Laura & Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, New York
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