1
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Lucas CHG, Gross AM, Romo CG, Dehner CA, Lazar AJ, Miettinen M, Pekmezci M, Quezado M, Rodriguez FJ, Stemmer-Rachamimov A, Viskochil D, Perry A. Consensus recommendations for an integrated diagnostic approach to peripheral nerve sheath tumors arising in the setting of Neurofibromatosis Type 1. Neuro Oncol 2025; 27:616-624. [PMID: 39500722 PMCID: PMC11889724 DOI: 10.1093/neuonc/noae235] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/09/2025] Open
Abstract
Consensus recommendations published in 2017 histologically defining atypical neurofibromatous neoplasm of uncertain biologic potential (ANNUBP) and malignant peripheral nerve sheath tumor (MPNST) were codified in the 2021 WHO Classification of Tumors of the Central Nervous System and the 2022 WHO Classification of Tumors of Soft Tissue and Bone. However, given the shift in diagnostic pathology toward the use of integrated histopathologic and genomic approaches, the incorporation of additional molecular strata in the classification of Neurofibromatosis Type 1 (NF1)-associated peripheral nerve sheath tumors should be formalized to aid in accurate diagnosis and early identification of malignant transformation and enable appropriate intervention for affected patients. To this end, we assembled a multi-institutional expert pathology working group as part of a "Symposium on Atypical Neurofibroma: State of the Science." Herein, we provide a suggested framework for adequate interventional radiology and surgical sampling and recommend molecular profiling for clinically or radiologically worrisome noncutaneous lesions in patients with NF1 to identify diagnostically-relevant molecular features, including CDKN2A/B inactivation for ANNUBP, as well as SUZ12, EED, or TP53 inactivating mutations, or significant aneuploidy for MPNST. We also propose renaming "low-grade MPNST" to "ANNUBP with increased proliferation" to avoid the use of the "malignant" term in this group of tumors with persistent unknown biologic potential. This refined integrated diagnostic approach for NF1-associated peripheral nerve sheath tumors should continue to evolve in concert with our understanding of these neoplasms.
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Affiliation(s)
- Calixto-Hope G Lucas
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Andrea M Gross
- Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Carlos G Romo
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Carina A Dehner
- Department of Pathology, Indiana University, Indianapolis, Indiana, USA
| | - Alexander J Lazar
- Departments of Pathology and Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Markku Miettinen
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Melike Pekmezci
- Department of Ophthalmology, University of California San Francisco, San Francisco, California, USA
- Department of Pathology, University of California San Francisco, San Francisco, California, USA
| | - Martha Quezado
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Fausto J Rodriguez
- Department of Pathology, University of California Los Angeles, Los Angeles, California, USA
| | | | - David Viskochil
- Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA
| | - Arie Perry
- Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA
- Department of Pathology, University of California San Francisco, San Francisco, California, USA
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2
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Pasquali S, Moura DS, Danks MR, Manasterski PJ, Zaffaroni N, Stacchiotti S, Mondaza-Hernandez JL, Kerrison WGJ, Martin-Broto J, Huang PH, Brunton VG. Preclinical models of soft tissue sarcomas - generation and applications to enhance translational research. Crit Rev Oncol Hematol 2025; 207:104621. [PMID: 39824369 DOI: 10.1016/j.critrevonc.2025.104621] [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: 11/21/2024] [Revised: 01/13/2025] [Accepted: 01/14/2025] [Indexed: 01/20/2025] Open
Abstract
Soft tissue sarcomas (STS) represent a large group of rare and ultra-rare tumors distinguished by unique morphological, molecular and clinical features. Patients with such rare cancers are generally underrepresented in clinical trials which has limited the introduction of new treatment options and subsequent improvement of patient outcomes. Preclinical models of STS that recapitulate the human disease can aid progress in identifying new effective treatments. However, due to the rarity of these tumors there are limited STS models available. Here we review the existing preclinical models of STS, including patient-derived cell lines and organoids, patient-derived xenografts and genetically engineered mouse models. We discuss the advantages and disadvantages of the different models and describe to what extent they have aided clinical translation. Finally, we consider what can be done in the future to enhance their predictivity in the preclinical setting.
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Affiliation(s)
- Sandro Pasquali
- Molecular Pharmacology, Department of Experimental Oncology, Fondazione IRCCS Instituto Nazionale dei Tumori di Milano, via G. Amadeo 42, Milano 20133, Italy
| | - David S Moura
- Research Health Institute of Fundacion Jimenez Diaz (IIS/FJD; UAM), Madrid, Spain; Department of Medical Oncology, Fundacion Jimenez Diaz University Hospital, Madrid, Spain; University Hospital General of Villalba, Madrid, Spain
| | - Molly R Danks
- Edinburgh Cancer Research, CRUK Scotland Centre, University of Edinburgh, Crewe Road South, Edinburgh EH4 2RX, UK
| | - Piotr J Manasterski
- Edinburgh Cancer Research, CRUK Scotland Centre, University of Edinburgh, Crewe Road South, Edinburgh EH4 2RX, UK
| | - Nadia Zaffaroni
- Molecular Pharmacology, Department of Experimental Oncology, Fondazione IRCCS Instituto Nazionale dei Tumori di Milano, via G. Amadeo 42, Milano 20133, Italy
| | - Silvia Stacchiotti
- Molecular Pharmacology, Department of Experimental Oncology, Fondazione IRCCS Instituto Nazionale dei Tumori di Milano, via G. Amadeo 42, Milano 20133, Italy
| | - Jose L Mondaza-Hernandez
- Research Health Institute of Fundacion Jimenez Diaz (IIS/FJD; UAM), Madrid, Spain; Department of Medical Oncology, Fundacion Jimenez Diaz University Hospital, Madrid, Spain; University Hospital General of Villalba, Madrid, Spain
| | - William G J Kerrison
- Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road Sutton, London, SM2 5NG, UK
| | - Javier Martin-Broto
- Research Health Institute of Fundacion Jimenez Diaz (IIS/FJD; UAM), Madrid, Spain; Department of Medical Oncology, Fundacion Jimenez Diaz University Hospital, Madrid, Spain; University Hospital General of Villalba, Madrid, Spain
| | - Paul H Huang
- Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road Sutton, London, SM2 5NG, UK
| | - Valerie G Brunton
- Edinburgh Cancer Research, CRUK Scotland Centre, University of Edinburgh, Crewe Road South, Edinburgh EH4 2RX, UK.
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3
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Sait SF, Tang KH, Angus SP, Brown R, Sun D, Xie X, Iltis C, Lien M, D. Socci N, Bale TA, Davis C, Dixon SAH, Zhang C, Wade Clapp D, Neel BG, Parada LF. Hydroxychloroquine prevents resistance and potentiates the antitumor effect of SHP2 inhibition in NF1-associated malignant peripheral nerve sheath tumors. Proc Natl Acad Sci U S A 2025; 122:e2407745121. [PMID: 39793045 PMCID: PMC11725864 DOI: 10.1073/pnas.2407745121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 10/07/2024] [Indexed: 01/12/2025] Open
Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas and the primary cause of mortality in patients with neurofibromatosis type 1 (NF1). These malignancies develop within preexisting benign lesions called plexiform neurofibromas (PNs). PNs are solely driven by biallelic NF1 loss eliciting RAS pathway activation, and they respond favorably to MEK inhibitor therapy. MPNSTs harbor additional mutations and respond poorly to MEK inhibition. Our analysis of genetically engineered and orthotopic patient-derived xenograft MPNST models indicates that MEK inhibition has poor antitumor efficacy. By contrast, upstream inhibition of RAS through the protein-tyrosine phosphatase SHP2 reduced downstream signaling and suppressed NF1 MPNST growth, although resistance eventually emerged. To investigate possible mechanisms of acquired resistance, kinomic analyses of resistant tumors were performed, and data analysis identified enrichment of activated autophagy pathway protein kinases. Combining SHP2 inhibition with hydroxychloroquine (HQ) resulted in durable responses in NF1 MPNSTs in both genetic and orthotopic xenograft mouse models. Our studies could be rapidly translated into a clinical trial to evaluate SHP2 inhibition in conjunction with HQ as a unique treatment approach for NF1 MPNSTs.
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Affiliation(s)
- Sameer Farouk Sait
- Cancer Biology & Genetics Program, Sloan Kettering Institute, New York, NY10065
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY10065
| | - Kwan Ho Tang
- Laura and Isaac Perlmutter Cancer Center, Department of Medicine, New York University, New York, NY10016
- Translational Medicine, AstraZeneca, Waltham, MA02451
| | - Steven P. Angus
- Indiana University School of Medicine, Department of Pediatrics, Riley Hospital for Children at IU Health, Indianapolis, IN46202
| | - Rebecca Brown
- Medicine, Hematology and Medical Oncology, Neurosurgery, The Mount Sinai Hospital, New York, NY10029
| | - Daochun Sun
- Cancer Biology & Genetics Program, Sloan Kettering Institute, New York, NY10065
- Department of Cell Biology, Neurobiology and Anatomy, The Medical College of Wisconsin, Milwaukee, WI53226
- Cancer Center, The Medical College of Wisconsin, Milwaukee, WI53226
| | - Xuanhua Xie
- Cancer Biology & Genetics Program, Sloan Kettering Institute, New York, NY10065
| | - Charlene Iltis
- Cancer Biology & Genetics Program, Sloan Kettering Institute, New York, NY10065
| | - Michelle Lien
- Brain Tumor Center, Memorial Sloan Kettering Cancer Center, New York, NY10065
| | - Nicholas D. Socci
- Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, NY10065
| | - Tejus A. Bale
- Brain Tumor Center, Memorial Sloan Kettering Cancer Center, New York, NY10065
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY10065
| | - Christopher Davis
- Indiana University School of Medicine, Department of Pediatrics, Riley Hospital for Children at IU Health, Indianapolis, IN46202
| | - Shelley A. H. Dixon
- Indiana University School of Medicine, Department of Pediatrics, Riley Hospital for Children at IU Health, Indianapolis, IN46202
| | - Chi Zhang
- Indiana University School of Medicine, Department of Pediatrics, Riley Hospital for Children at IU Health, Indianapolis, IN46202
| | - D. Wade Clapp
- Indiana University School of Medicine, Department of Pediatrics, Riley Hospital for Children at IU Health, Indianapolis, IN46202
| | - Benjamin G. Neel
- Laura and Isaac Perlmutter Cancer Center, Department of Medicine, New York University, New York, NY10016
| | - Luis F. Parada
- Cancer Biology & Genetics Program, Sloan Kettering Institute, New York, NY10065
- Brain Tumor Center, Memorial Sloan Kettering Cancer Center, New York, NY10065
- Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY10065
- Department of Neurology, Memorial Sloan Kettering Cancer Center, NY10065
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4
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Cole JJ, Ferner RE, Gutmann DH. Neurofibromatosis type 1. ROSENBERG'S MOLECULAR AND GENETIC BASIS OF NEUROLOGICAL AND PSYCHIATRIC DISEASE 2025:231-249. [DOI: 10.1016/b978-0-443-19176-3.00017-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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5
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Cannizzaro IR, Treccani M, Taiani A, Ambrosini E, Busciglio S, Cesarini S, Luberto A, De Sensi E, Moschella B, Gismondi P, Azzoni C, Bottarelli L, Giordano G, Corradi D, Silini EM, Zanatta V, Cennamo F, Bertolini P, Caggiati P, Martorana D, Uliana V, Percesepe A, Barili V. Proof of Concept for Genome Profiling of the Neurofibroma/Sarcoma Sequence in Neurofibromatosis Type 1. Int J Mol Sci 2024; 25:10822. [PMID: 39409151 PMCID: PMC11476461 DOI: 10.3390/ijms251910822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 09/27/2024] [Accepted: 10/06/2024] [Indexed: 10/20/2024] Open
Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder characterized by the predisposition to develop tumors such as malignant peripheral nerve sheath tumors (MPNSTs) which represents the primary cause of death for NF1-affected patients. Regardless of the high incidence and mortality, the molecular mechanisms underneath MPNST growth and metastatic progression remain poorly understood. In this proof-of-concept study, we performed somatic whole-exome sequencing (WES) to profile the genomic alterations in four samples from a patient with NF1-associated MPNST, consisting of a benign plexiform neurofibroma, a primary MPNST, and metastases from lung and skin tissues. By comparing genomic patterns, we identified a high level of variability across samples with distinctive genetic changes which allow for the definition of profiles of the early phase with respect to the late metastatic stages. Pathogenic and likely pathogenic variants were abundant in the primary tumor, whereas the metastatic samples exhibited a high level of copy-number variations (CNVs), highlighting a possible genomic instability in the late phases. The most known MPNST-related genes, such as TP53 and SUZ12, were identified in CNVs observed within the primary tumor. Pathway analysis of altered early genes in MPNST pointed to a potential role in cell motility, division and metabolism. Moreover, we employed survival analysis with the TCGA sarcoma genomic dataset on 262 affected patients, in order to corroborate the predictive significance of the identified early and metastatic MPNST driver genes. Specifically, the expression changes related to the mutated genes, such as in RBMX, PNPLA6 and AGAP2, were associated with reduced patient survival, distinguishing them as potential prognostic biomarkers. This study underlines the relevance of integrating genomic results with clinical information for early diagnosis and prognostic understanding of tumor aggressiveness.
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Affiliation(s)
- Ilenia Rita Cannizzaro
- Medical Genetics, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Mirko Treccani
- Medical Genetics, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
- Human Nutrition Unit, Department of Food and Drug, University of Parma, 43125 Parma, Italy
| | - Antonietta Taiani
- Medical Genetics, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Enrico Ambrosini
- Medical Genetics, University Hospital of Parma, 43126 Parma, Italy
| | - Sabrina Busciglio
- Medical Genetics, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Sofia Cesarini
- Medical Genetics, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Anita Luberto
- Medical Genetics, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Erika De Sensi
- Medical Genetics, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Barbara Moschella
- Medical Genetics, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Pierpacifico Gismondi
- Pediatric Clinic, Pietro Barilla Children’s Hospital, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Cinzia Azzoni
- Pathology Unit, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Lorena Bottarelli
- Pathology Unit, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Giovanna Giordano
- Pathology Unit, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Domenico Corradi
- Pathology Unit, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Enrico Maria Silini
- Pathology Unit, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Valentina Zanatta
- Cytogenetics, Molecular Genetics and Medical Genetics Unit, Toma Advanced Biomedical Assays, 21052 Busto Arsizio, Italy
| | - Federica Cennamo
- Pediatric Hematology Oncology Unit, University Hospital of Parma, 43126 Parma, Italy
| | - Patrizia Bertolini
- Pediatric Hematology Oncology Unit, University Hospital of Parma, 43126 Parma, Italy
| | | | - Davide Martorana
- Medical Genetics, University Hospital of Parma, 43126 Parma, Italy
| | - Vera Uliana
- Medical Genetics, University Hospital of Parma, 43126 Parma, Italy
| | - Antonio Percesepe
- Medical Genetics, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
- Medical Genetics, University Hospital of Parma, 43126 Parma, Italy
| | - Valeria Barili
- Medical Genetics, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
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6
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Seres R, Hameed H, McCabe MG, Russell D, Lee ATJ. The Multimodality Management of Malignant Peripheral Nerve Sheath Tumours. Cancers (Basel) 2024; 16:3266. [PMID: 39409887 PMCID: PMC11475700 DOI: 10.3390/cancers16193266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 09/10/2024] [Accepted: 09/10/2024] [Indexed: 10/20/2024] Open
Abstract
Malignant peripheral nerve sheath tumours (MPNST) are aggressive sarcomas that have nerve sheath differentiation and can present at any anatomical site. They can arise from precursor neurofibroma in the context of neurofibromatosis type 1 (NF1) or as de novo and sporadic tumours in the absence of an underlying genetic predisposition. The primary therapeutic approach is most often radical surgery, with non-surgical modalities playing an important role, especially in locally advanced or metastatic cases. The aim of multimodality approaches is to optimize both local and systemic control while keeping to a minimum acute and late treatment morbidity. Advances in the understanding of the underlying biology of MPNSTs in both sporadic and NF-1-related contexts are essential for the management and implementation of novel therapeutic approaches.
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Affiliation(s)
- Remus Seres
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK
| | - Hassan Hameed
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK
| | - Martin G. McCabe
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK
- Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK
| | - David Russell
- Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK
- Department of Radiology, Lancashire Teaching Hospitals NHS Trust, Chorley PR7 1PP, UK
| | - Alexander T. J. Lee
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK
- NHS England Highly Specialised Service for Complex Neurofibromatosis Type 1: Manchester, Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester M13 9WL, UK
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7
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Somaiah N, Paudyal B, Winkler RE, Van Tine BA, Hirbe AC. Malignant Peripheral Nerve Sheath Tumor, a Heterogeneous, Aggressive Cancer with Diverse Biomarkers and No Targeted Standard of Care: Review of the Literature and Ongoing Investigational Agents. Target Oncol 2024; 19:665-678. [PMID: 38954182 PMCID: PMC11392982 DOI: 10.1007/s11523-024-01078-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/30/2024] [Indexed: 07/04/2024]
Abstract
BACKGROUND Malignant peripheral sheath tumor (MPNST) is a rare, aggressive form of soft-tissue sarcoma that presents a unique set of diagnostic and treatment challenges and is associated with major unmet treatment medical needs. OBJECTIVE The chief aim of this review is to consider the epidemiology, histology, anatomic distribution, pathologic signaling pathways, diagnosis, and management of MPNST, with a focus on potential targeted therapies. A subordinate objective was to establish benchmarks for the antitumor activity of such treatments. RESULTS MPNST has an incidence of 1:100,000 in the general population and 1:3500 among patients with the inherited condition of neurofibromatosis-1. Spindle-cell sarcomas of neural-crest origin, MPNSTs are frequently situated in the extremities and pelvis/trunk, often at the confluence of large nerve roots and bundles. Highly copy-number aberrant and enriched in chromosome 8, MPNSTs have a complex molecular pathogenesis that likely involves the interplay of multiple signaling pathways, including Ras/AKT/mTOR/MAPK, EGFR, p53, PTEN, and PRC2, as well as factors in the tumor microenvironment. A combination of magnetic resonance imaging (MRI) and positron emission tomography with 18F-fluorodeoxyglucose (FDG-PET) enables comprehensive assessment of both morphology and metabolism, while MRI- and ultrasound-guided core needle biopsy can confirm histopathology. Although surgery with wide excisional margins is now the chief curative approach to localized disease, MPNST-specific survival has not improved in decades. For advanced and metastatic MPNST, radiation and chemotherapy (chiefly with anthracyclines plus ifosfamide) have somewhat promising but still largely uncertain treatment roles, chiefly in local control, downstaging, and palliation. No single druggable target has emerged, no objective responses have been observed with a number of targeted therapies (cumulative disease control rate in our review = 22.9-34.8%), and combinatorial approaches directed toward multiple signal transduction mechanisms are hallmarks of ongoing clinical trials. CONCLUSIONS Despite advances in our understanding of the genetics and molecular biology of MPNST, further research is warranted to: (1) unravel the complex pathogenesis of this condition; (2) improve diagnostic yield; (3) delineate the appropriate roles of chemotherapy and radiation; and (4) develop a targeted therapy (or combination of such treatments) that is well tolerated and prolongs survival.
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Affiliation(s)
- Neeta Somaiah
- Chair of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | | | - Brian A Van Tine
- Medicine and of Pediatrics, Developmental Therapeutics (Phase 1) Program, Sarcoma Program, Washington University School of Medicine, Barnes and Jewish Hospital, Siteman Cancer Center, St. Louis, MO, USA
| | - Angela C Hirbe
- Medicine and Pediatrics, Adult Neurofibromatosis Clinical Program, Division of Oncology, Sarcoma Section, Couch Building, Room 3304, Washington University School of Medicine, Barnes Jewish Hospital, Siteman Cancer Center, 660 S. Euclid Avenue, Campus, Box 8076, St. Louis, MO, 63110-1010, USA.
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8
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Paudel SN, Hutzen BJ, Miller KE, Garfinkle EAR, Chen CY, Wang PY, Glaspell AM, Currier MA, Ringwalt EM, Boon L, Mardis ER, Cairo MS, Ratner N, Dodd RD, Cassady KA, Cripe TP. Myelomodulatory treatments augment the therapeutic benefit of oncolytic viroimmunotherapy in murine models of malignant peripheral nerve sheath tumors. Front Immunol 2024; 15:1384623. [PMID: 39044819 PMCID: PMC11263800 DOI: 10.3389/fimmu.2024.1384623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Accepted: 06/10/2024] [Indexed: 07/25/2024] Open
Abstract
Introduction Malignant peripheral nerve sheath tumors (MPNST) pose a significant therapeutic challenge due to high recurrence rates after surgical resection and a largely ineffective response to traditional chemotherapy. An alternative treatment strategy is oncolytic viroimmunotherapy, which can elicit a durable and systemic antitumor immune response and is Food and Drug Administration (FDA)-approved for the treatment of melanoma. Unfortunately, only a subset of patients responds completely, underscoring the need to address barriers hindering viroimmunotherapy effectiveness. Methods Here we investigated the therapeutic utility of targeting key components of the MPNST immunosuppressive microenvironment to enhance viroimmunotherapy's antitumor efficacy in three murine models, one of which showed more immunogenic characteristics than the others. Results Myelomodulatory therapy with pexidartinib, a small molecule inhibitor of CSF1R tyrosine kinase, and the oncolytic herpes simplex virus T-VEC exhibited the most significant increase in median survival time in the highly immunogenic model. Additionally, targeting myeloid cells with the myelomodulatory therapy trabectedin, a small molecule activator of caspase-8 dependent apoptosis, augmented the survival benefit of T-VEC in a less immunogenic MPNST model. However, tumor regressions or shrinkages were not observed. Depletion experiments confirmed that the enhanced survival benefit relied on a T cell response. Furthermore, flow cytometry analysis following combination viroimmunotherapy revealed decreased M2 macrophages and myeloid-derived suppressor cells and increased tumor-specific gp70+ CD8 T cells within the tumor microenvironment. Discussion In summary, our findings provide compelling evidence for the potential to leverage viroimmunotherapy with myeloid cell targeting against MPNST and warrant further investigation.
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Affiliation(s)
- Siddhi N. Paudel
- Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
| | - Brian J. Hutzen
- Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
| | - Katherine E. Miller
- Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
- Department of Pediatrics, The Ohio State University Wexner College of Medicine, Columbus, OH, United States
| | - Elizabeth A. R. Garfinkle
- Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
| | - Chun-Yu Chen
- Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
| | - Pin-Yi Wang
- Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
| | - Andrea M. Glaspell
- Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
| | - Mark A. Currier
- Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
| | - Emily M. Ringwalt
- Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
| | | | - Elaine R. Mardis
- Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
- Department of Pediatrics, The Ohio State University Wexner College of Medicine, Columbus, OH, United States
| | - Mitchell S. Cairo
- Department of Pediatrics, Medicine, Pathology, Microbiology and Immunology, and Cell Biology, New York Medical College, Valhalla, NY, United States
| | - Nancy Ratner
- Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Rebecca D. Dodd
- Department of Internal Medicine, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, United States
| | - Kevin A. Cassady
- Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
- Department of Pediatrics, The Ohio State University Wexner College of Medicine, Columbus, OH, United States
| | - Timothy P. Cripe
- Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
- Department of Pediatrics, The Ohio State University Wexner College of Medicine, Columbus, OH, United States
- Division of Pediatric Hematology/Oncology/BMT, Nationwide Children’s Hospital, Columbus, OH, United States
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9
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Huang Y, Che X, Wang PW, Qu X. p53/MDM2 signaling pathway in aging, senescence and tumorigenesis. Semin Cancer Biol 2024; 101:44-57. [PMID: 38762096 DOI: 10.1016/j.semcancer.2024.05.001] [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: 04/16/2024] [Revised: 05/10/2024] [Accepted: 05/14/2024] [Indexed: 05/20/2024]
Abstract
A wealth of evidence has emerged that there is an association between aging, senescence and tumorigenesis. Senescence, a biological process by which cells cease to divide and enter a status of permanent cell cycle arrest, contributes to aging and aging-related diseases, including cancer. Aging populations have the higher incidence of cancer due to a lifetime of exposure to cancer-causing agents, reduction of repairing DNA damage, accumulated genetic mutations, and decreased immune system efficiency. Cancer patients undergoing cytotoxic therapies, such as chemotherapy and radiotherapy, accelerate aging. There is growing evidence that p53/MDM2 (murine double minute 2) axis is critically involved in regulation of aging, senescence and oncogenesis. Therefore, in this review, we describe the functions and mechanisms of p53/MDM2-mediated senescence, aging and carcinogenesis. Moreover, we highlight the small molecular inhibitors, natural compounds and PROTACs (proteolysis targeting chimeras) that target p53/MDM2 pathway to influence aging and cancer. Modification of p53/MDM2 could be a potential strategy for treatment of aging, senescence and tumorigenesis.
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Affiliation(s)
- Youyi Huang
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, Liaoning Province 110001, China; Provincial key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, Liaoning Province 110001, China; Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, Liaoning Province 110001, China
| | - Xiaofang Che
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, Liaoning Province 110001, China; Provincial key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, Liaoning Province 110001, China; Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, Liaoning Province 110001, China
| | - Peter W Wang
- Department of Medicine, Oasis Medical Research Center, Watertown, MA 02472, USA.
| | - Xiujuan Qu
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, Liaoning Province 110001, China; Provincial key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, Liaoning Province 110001, China; Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, Liaoning Province 110001, China.
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10
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Murphy KC, Ruscetti M. Advances in Making Cancer Mouse Models More Accessible and Informative through Non-Germline Genetic Engineering. Cold Spring Harb Perspect Med 2024; 14:a041348. [PMID: 37277206 PMCID: PMC10982712 DOI: 10.1101/cshperspect.a041348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Genetically engineered mouse models (GEMMs) allow for modeling of spontaneous tumorigenesis within its native microenvironment in mice and have provided invaluable insights into mechanisms of tumorigenesis and therapeutic strategies to treat human disease. However, as their generation requires germline manipulation and extensive animal breeding that is time-, labor-, and cost-intensive, traditional GEMMs are not accessible to most researchers, and fail to model the full breadth of cancer-associated genetic alterations and therapeutic targets. Recent advances in genome-editing technologies and their implementation in somatic tissues of mice have ushered in a new class of mouse models: non-germline GEMMs (nGEMMs). nGEMM approaches can be leveraged to generate somatic tumors de novo harboring virtually any individual or group of genetic alterations found in human cancer in a mouse through simple procedures that do not require breeding, greatly increasing the accessibility and speed and scale on which GEMMs can be produced. Here we describe the technologies and delivery systems used to create nGEMMs and highlight new biological insights derived from these models that have rapidly informed functional cancer genomics, precision medicine, and immune oncology.
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Affiliation(s)
- Katherine C Murphy
- Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01605, USA
| | - Marcus Ruscetti
- Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01605, USA;
- Immunology and Microbiology Program, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01605, USA
- Cancer Center, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01605, USA
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11
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Somatilaka BN, Madana L, Sadek A, Chen Z, Chandrasekaran S, McKay RM, Le LQ. STING activation reprograms the microenvironment to sensitize NF1-related malignant peripheral nerve sheath tumors for immunotherapy. J Clin Invest 2024; 134:e176748. [PMID: 38502231 PMCID: PMC11093615 DOI: 10.1172/jci176748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 03/12/2024] [Indexed: 03/21/2024] Open
Abstract
Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene that encodes neurofibromin, a RAS GTPase-activating protein. Inactivating NF1 mutations cause hyperactivation of RAS-mediated signaling, resulting in the development of multiple neoplasms, including malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are an aggressive tumor and the main cause of mortality in patients with NF1. MPNSTs are difficult to resect and refractory to chemo- and radiotherapy, and no molecular therapies currently exist. Immune checkpoint blockade (ICB) is an approach to treat inoperable, undruggable cancers like MPNST, but successful outcomes require an immune cell-rich tumor microenvironment. While MPNSTs are noninflamed "cold" tumors, here, we converted MPNSTs into T cell-inflamed "hot" tumors by activating stimulator of IFN genes (STING) signaling. Mouse genetic and human xenograft MPNST models treated with a STING agonist plus ICB exhibited growth delay via increased apoptotic cell death. This strategy offers a potential treatment regimen for MPNSTs.
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Affiliation(s)
| | | | | | | | - Sanjay Chandrasekaran
- Simmons Comprehensive Cancer Center
- Department of Internal Medicine, Division of Hematology/Oncology
| | | | - Lu Q. Le
- Department of Dermatology
- Simmons Comprehensive Cancer Center
- University of Texas Southwestern Comprehensive Neurofibromatosis Clinic
- Hamon Center for Regenerative Science and Medicine, and
- O’Donnell Brain Institute, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
- Department of Dermatology, University of Virginia School of Medicine, Charlottesville, Virginia, USA
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12
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White EE, Rhodes SD. The NF1+/- Immune Microenvironment: Dueling Roles in Neurofibroma Development and Malignant Transformation. Cancers (Basel) 2024; 16:994. [PMID: 38473354 PMCID: PMC10930863 DOI: 10.3390/cancers16050994] [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: 01/15/2024] [Revised: 02/12/2024] [Accepted: 02/16/2024] [Indexed: 03/14/2024] Open
Abstract
Neurofibromatosis type 1 (NF1) is a common genetic disorder resulting in the development of both benign and malignant tumors of the peripheral nervous system. NF1 is caused by germline pathogenic variants or deletions of the NF1 tumor suppressor gene, which encodes the protein neurofibromin that functions as negative regulator of p21 RAS. Loss of NF1 heterozygosity in Schwann cells (SCs), the cells of origin for these nerve sheath-derived tumors, leads to the formation of plexiform neurofibromas (PNF)-benign yet complex neoplasms involving multiple nerve fascicles and comprised of a myriad of infiltrating stromal and immune cells. PNF development and progression are shaped by dynamic interactions between SCs and immune cells, including mast cells, macrophages, and T cells. In this review, we explore the current state of the field and critical knowledge gaps regarding the role of NF1(Nf1) haploinsufficiency on immune cell function, as well as the putative impact of Schwann cell lineage states on immune cell recruitment and function within the tumor field. Furthermore, we review emerging evidence suggesting a dueling role of Nf1+/- immune cells along the neurofibroma to MPNST continuum, on one hand propitiating PNF initiation, while on the other, potentially impeding the malignant transformation of plexiform and atypical neurofibroma precursor lesions. Finally, we underscore the potential implications of these discoveries and advocate for further research directed at illuminating the contributions of various immune cells subsets in discrete stages of tumor initiation, progression, and malignant transformation to facilitate the discovery and translation of innovative diagnostic and therapeutic approaches to transform risk-adapted care.
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Affiliation(s)
- Emily E. White
- Medical Scientist Training Program, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Steven D. Rhodes
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Division of Pediatric Hematology/Oncology/Stem Cell Transplant, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- IU Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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13
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Lemberg KM, Ali ES, Krecmerova M, Aguilar JMH, Alt J, Peters DE, Zhao L, Wu Y, Nuha N, Asara JM, Staedtke V, Pratilas CA, Majer P, Rais R, Ben-Sahra I, Slusher BS. Pro-905, a Novel Purine Antimetabolite, Combines with Glutamine Amidotransferase Inhibition to Suppress Growth of Malignant Peripheral Nerve Sheath Tumor. Mol Cancer Ther 2023; 22:1390-1403. [PMID: 37616542 PMCID: PMC10690047 DOI: 10.1158/1535-7163.mct-23-0258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 07/21/2023] [Accepted: 08/21/2023] [Indexed: 08/26/2023]
Abstract
Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft-tissue sarcomas that arise from neural tissues and carry a poor prognosis. Previously, we found that the glutamine amidotransferase inhibitor JHU395 partially impeded tumor growth in preclinical models of MPNST. JHU395 inhibits de novo purine synthesis in human MPNST cells and murine tumors with partial decreases in purine monophosphates. On the basis of prior studies showing enhanced efficacy when glutamine amidotransferase inhibition was combined with the antimetabolite 6-mercaptopurine (6-MP), we hypothesized that such a combination would be efficacious in MPNST. Given the known toxicity associated with 6-MP, we set out to develop a more efficient and well-tolerated drug that targets the purine salvage pathway. Here, we report the discovery of Pro-905, a phosphoramidate protide that delivered the active nucleotide antimetabolite thioguanosine monophosphate (TGMP) to tumors over 2.5 times better than equimolar 6-MP. Pro-905 effectively prevented the incorporation of purine salvage substrates into nucleic acids and inhibited colony formation of human MPNST cells in a dose-dependent manner. In addition, Pro-905 inhibited MPNST growth and was well-tolerated in both human patient-derived xenograft (PDX) and murine flank MPNST models. When combined with JHU395, Pro-905 enhanced the colony formation inhibitory potency of JHU395 in human MPNST cells and augmented the antitumor efficacy of JHU395 in mice. In summary, the dual inhibition of the de novo and purine salvage pathways in preclinical models may safely be used to enhance therapeutic efficacy against MPNST.
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Affiliation(s)
- Kathryn M. Lemberg
- Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, Maryland
- Johns Hopkins Drug Discovery, Baltimore, Maryland
| | - Eunus S. Ali
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Marcela Krecmerova
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic
| | | | - Jesse Alt
- Johns Hopkins Drug Discovery, Baltimore, Maryland
| | - Diane E. Peters
- Johns Hopkins Drug Discovery, Baltimore, Maryland
- Department of Pharmacology and Molecular Sciences, School of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Liang Zhao
- Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Ying Wu
- Johns Hopkins Drug Discovery, Baltimore, Maryland
| | - Naziba Nuha
- Johns Hopkins Drug Discovery, Baltimore, Maryland
| | - John M. Asara
- Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard University School of Medicine, Boston, Massachusetts
| | - Verena Staedtke
- Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Christine A. Pratilas
- Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Pavel Majer
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic
| | - Rana Rais
- Johns Hopkins Drug Discovery, Baltimore, Maryland
- Department of Pharmacology and Molecular Sciences, School of Medicine, Johns Hopkins University, Baltimore, Maryland
- Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Issam Ben-Sahra
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Barbara S. Slusher
- Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, Maryland
- Johns Hopkins Drug Discovery, Baltimore, Maryland
- Department of Pharmacology and Molecular Sciences, School of Medicine, Johns Hopkins University, Baltimore, Maryland
- Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, Maryland
- Departments of Medicine, Neuroscience, Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, Maryland
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14
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Larsson AT, Bhatia H, Calizo A, Pollard K, Zhang X, Conniff E, Tibbitts JF, Rono E, Cummins K, Osum SH, Williams KB, Crampton AL, Jubenville T, Schefer D, Yang K, Lyu Y, Pino JC, Bade J, Gross JM, Lisok A, Dehner CA, Chrisinger JSA, He K, Gosline SJC, Pratilas CA, Largaespada DA, Wood DK, Hirbe AC. Ex vivo to in vivo model of malignant peripheral nerve sheath tumors for precision oncology. Neuro Oncol 2023; 25:2044-2057. [PMID: 37246765 PMCID: PMC10628938 DOI: 10.1093/neuonc/noad097] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Indexed: 05/30/2023] Open
Abstract
BACKGROUND Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that often develop in patients with neurofibromatosis type 1 (NF1). To address the critical need for novel therapeutics in MPNST, we aimed to establish an ex vivo 3D platform that accurately captured the genomic diversity of MPNST and could be utilized in a medium-throughput manner for drug screening studies to be validated in vivo using patient-derived xenografts (PDX). METHODS Genomic analysis was performed on all PDX-tumor pairs. Selected PDX were harvested for assembly into 3D microtissues. Based on prior work in our labs, we evaluated drugs (trabectedin, olaparib, and mirdametinib) ex vivo and in vivo. For 3D microtissue studies, cell viability was the endpoint as assessed by Zeiss Axio Observer. For PDX drug studies, tumor volume was measured twice weekly. Bulk RNA sequencing was performed to identify pathways enriched in cells. RESULTS We developed 13 NF1-associated MPNST-PDX and identified mutations or structural abnormalities in NF1 (100%), SUZ12 (85%), EED (15%), TP53 (15%), CDKN2A (85%), and chromosome 8 gain (77%). We successfully assembled PDX into 3D microtissues, categorized as robust (>90% viability at 48 h), good (>50%), or unusable (<50%). We evaluated drug response to "robust" or "good" microtissues, namely MN-2, JH-2-002, JH-2-079-c, and WU-225. Drug response ex vivo predicted drug response in vivo, and enhanced drug effects were observed in select models. CONCLUSIONS These data support the successful establishment of a novel 3D platform for drug discovery and MPNST biology exploration in a system representative of the human condition.
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Affiliation(s)
- Alex T Larsson
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Himanshi Bhatia
- Division of Oncology, Department of Internal Medicine, Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Ana Calizo
- Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Department of Oncology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Kai Pollard
- Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Department of Oncology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Xiaochun Zhang
- Division of Oncology, Department of Internal Medicine, Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Eric Conniff
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA
| | - Justin F Tibbitts
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Elizabeth Rono
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA
| | - Katherine Cummins
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA
| | - Sara H Osum
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Kyle B Williams
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Alexandra L Crampton
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA
| | - Tyler Jubenville
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Daniel Schefer
- Division of Oncology, Department of Internal Medicine, Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Kuangying Yang
- Division of Oncology, Department of Internal Medicine, Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Yang Lyu
- Division of Oncology, Department of Internal Medicine, Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, USA
| | - James C Pino
- Pacific Northwest National Laboratory, Seattle, Washington, USA
| | - Jessica Bade
- Pacific Northwest National Laboratory, Seattle, Washington, USA
| | - John M Gross
- Department of Pathology, Division of Surgical Pathology, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Alla Lisok
- Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Department of Oncology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Carina A Dehner
- Department of Pathology and Immunology, Washington University in St. Louis, Missouri, USA
| | - John S A Chrisinger
- Department of Pathology and Immunology, Washington University in St. Louis, Missouri, USA
| | - Kevin He
- Division of Oncology, Department of Internal Medicine, Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, USA
| | | | - Christine A Pratilas
- Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Department of Oncology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - David A Largaespada
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - David K Wood
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA
| | - Angela C Hirbe
- Division of Oncology, Department of Internal Medicine, Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, USA
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15
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Gross AM, Dombi E, Wolters PL, Baldwin A, Dufek A, Herrera K, Martin S, Derdak J, Heisey KS, Whitcomb PM, Steinberg SM, Venzon DJ, Fisher MJ, Kim A, Bornhorst M, Weiss BD, Blakeley JO, Smith MA, Widemann BC. Long-term safety and efficacy of selumetinib in children with neurofibromatosis type 1 on a phase 1/2 trial for inoperable plexiform neurofibromas. Neuro Oncol 2023; 25:1883-1894. [PMID: 37115514 PMCID: PMC10547508 DOI: 10.1093/neuonc/noad086] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Indexed: 04/29/2023] Open
Abstract
BACKGROUND Selumetinib shrank inoperable symptomatic plexiform neurofibromas (PN) in children with neurofibromatosis type 1 (NF1) and provided clinical benefit for many in our previously published phase 1/2 clinical trials (SPRINT, NCT01362803). At the data cutoff (DCO) of the prior publications, 65% of participants were still receiving treatment. This report presents up to 5 years of additional safety and efficacy data from these studies. METHODS This manuscript includes data from the phase 1 and phase 2, stratum 1 study which included participants with clinically significant PN-related morbidity. Participants received continuous selumetinib dosing (1 cycle = 28 days). Safety and efficacy data through February 27, 2021 are included. PN response assessed by volumetric magnetic resonance imaging analysis: Confirmed partial response (cPR) ≥20% decrease from baseline on 2 consecutive evaluations. Phase 2 participants completed patient-reported outcome measures assessing tumor pain intensity (Numeric Rating Scale-11) and interference of pain in daily life (pain interference index). RESULTS For the 74 children (median age 10.3 years; range 3-18.5) enrolled, overall cPR rate was 70% (52/74); median duration of treatment was 57.5 cycles (range 1-100). Responses were generally sustained with 59% (44) lasting ≥ 12 cycles. Tumor pain intensity (n = 19, P = .015) and pain interference (n = 18, P = .0059) showed durable improvement from baseline to 48 cycles. No new safety signals were identified; however, some developed known selumetinib-related adverse events (AEs) for the first time after several years of treatment. CONCLUSIONS With up to 5 years of additional selumetinib treatment, most children with NF1-related PN had durable tumor shrinkage and sustained improvement in pain beyond that previously reported at 1 year. No new safety signals were identified; however, ongoing monitoring for known selumetinib-related AEs is needed while treatment continues.
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Affiliation(s)
- Andrea M Gross
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Eva Dombi
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Pamela L Wolters
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Andrea Baldwin
- Leidos, Clinical Research Directorate (CRD), Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
| | - Anne Dufek
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Kailey Herrera
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Staci Martin
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Joanne Derdak
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Kara S Heisey
- Leidos, Clinical Research Directorate (CRD), Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
| | - Patricia M Whitcomb
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Seth M Steinberg
- Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA
| | - David J Venzon
- Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA
| | - Michael J Fisher
- Children’s Hospital of Philadelphia, Section of Neuro-Oncology, Philadelphia, Pennsylvania, USA
| | - AeRang Kim
- Children’s National Hospital, Center for Cancer and Blood Disorders, Washington, District of Columbia, USA
| | - Miriam Bornhorst
- Children’s National Hospital, Center for Cancer and Blood Disorders, Washington, District of Columbia, USA
| | - Brian D Weiss
- Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
| | - Jaishri O Blakeley
- Johns Hopkins University, Division of Neurology, Baltimore, Maryland, USA
| | - Malcolm A Smith
- Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland, USA
| | - Brigitte C Widemann
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
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16
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Pillay-Smiley N, Fletcher JS, de Blank P, Ratner N. Shedding New Light: Novel Therapies for Common Disorders in Children with Neurofibromatosis Type I. Pediatr Clin North Am 2023; 70:937-950. [PMID: 37704352 DOI: 10.1016/j.pcl.2023.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/15/2023]
Abstract
Neurofibromatosis type I (NF1) is a common dominantly inherited disorder, and one of the most common of the RASopathies. Most individuals with NF1 develop plexiform neurofibromas and cutaneous neurofibromas, nerve tumors caused by NF1 loss of function in Schwann cells. Cell culture models and mouse models of NF1 are being used to test drug efficacy in preclinical trials, which led to Food and Drug Administration approval for use of MEK inhibitors to shrink most inoperable plexiform neurofibromas. This article details methods used for testing in preclinical models, and outlines newer models that may identify additional, curative, strategies.
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Affiliation(s)
- Natasha Pillay-Smiley
- University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-0731, USA; Cancer and Blood Diseases Institute, The Cure Starts Now Foundation Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Jonathan S Fletcher
- Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-0731, USA; Cancer and Blood Diseases Institute, The Cure Starts Now Foundation Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Current Address: Division of Hematology-Oncology, University of Texas Southwestern, Dallas, TX, USA
| | - Peter de Blank
- University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-0731, USA; Cancer and Blood Diseases Institute, The Cure Starts Now Foundation Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Nancy Ratner
- Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-0731, USA; Cancer and Blood Diseases Institute, The Cure Starts Now Foundation Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
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17
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Tanaka M, Nakamura T. Targeting epigenetic aberrations of sarcoma in CRISPR era. Genes Chromosomes Cancer 2023; 62:510-525. [PMID: 36967299 DOI: 10.1002/gcc.23142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 03/21/2023] [Accepted: 03/22/2023] [Indexed: 03/29/2023] Open
Abstract
Sarcomas are rare malignancies that exhibit diverse biological, genetic, morphological, and clinical characteristics. Genetic alterations, such as gene fusions, mutations in transcriptional machinery components, histones, and DNA methylation regulatory molecules, play an essential role in sarcomagenesis. These mutations induce and/or cooperate with specific epigenetic aberrations required for the growth and maintenance of sarcomas. Appropriate mouse models have been developed to clarify the significance of genetic and epigenetic interactions in sarcomas. Studies using the mouse models for human sarcomas have demonstrated major advances in our understanding the developmental processes as well as tumor microenvironment of sarcomas. Recent technological progresses in epigenome editing will not only improve the studies using animal models but also provide a direct clue for epigenetic therapies. In this manuscript, we review important epigenetic aberrations in sarcomas and their representative mouse models, current methods of epigenetic editing using CRISPR/dCas9 systems, and potential applications in sarcoma studies and therapeutics.
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Affiliation(s)
- Miwa Tanaka
- Project for Cancer Epigenomics, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
- Department of Experimental Pathology, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan
| | - Takuro Nakamura
- Department of Experimental Pathology, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan
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18
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Jiang C, McKay RM, Lee SY, Romo CG, Blakeley JO, Haniffa M, Serra E, Steensma MR, Largaespada D, Le LQ. Cutaneous Neurofibroma Heterogeneity: Factors that Influence Tumor Burden in Neurofibromatosis Type 1. J Invest Dermatol 2023; 143:1369-1377. [PMID: 37318402 PMCID: PMC11173230 DOI: 10.1016/j.jid.2022.12.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 12/01/2022] [Accepted: 12/05/2022] [Indexed: 06/16/2023]
Abstract
Neurofibromatosis type 1 is one of the most common genetic disorders of the nervous system and predisposes patients to develop benign and malignant tumors. Cutaneous neurofibromas (cNFs) are NF1-associated benign tumors that affect nearly 100% of patients with NF1. cNFs dramatically reduce patients' QOL owing to their unaesthetic appearance, physical discomfort, and corresponding psychological burden. There is currently no effective drug therapy option, and treatment is restricted to surgical removal. One of the greatest hurdles for cNF management is the variability of clinical expressivity in NF1, resulting in intrapatient and interpatient cNF tumor burden heterogeneity, that is, the variability in the presentation and evolution of these tumors. There is growing evidence that a wide array of factors are involved in the regulation of cNF heterogeneity. Understanding the mechanisms underlying this heterogeneity of cNF at the molecular, cellular, and environmental levels can facilitate the development of innovative and personalized treatment regimens.
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Affiliation(s)
- Chunhui Jiang
- Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Renée M McKay
- Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Sang Y Lee
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Carlos G Romo
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jaishri O Blakeley
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Muzlifah Haniffa
- Biosciences Institute, Newcastle University, Newcastle Upon Tyne, United Kingdom; NIHR Newcastle Biomedical Research Center Dermatology, Newcastle University, Newcastle Upon Tyne, United Kingdom
| | - Eduard Serra
- Hereditary Cancer Group, Germans Trias i Pujol Research Institute (IGTP), Barcelona, Spain
| | - Matthew R Steensma
- Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan, USA
| | - David Largaespada
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA; Division of Hematology and Oncology, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Lu Q Le
- Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Comprehensive Neurofibromatosis Clinic, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA; O'Donnell Brain Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
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19
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Fareez F, Wang BH, Brain I, Lu JQ. Lymphomas in patients with neurofibromatosis type 1 (NF1): another malignancy in the NF1 syndrome? Pathology 2023; 55:302-314. [PMID: 36774237 DOI: 10.1016/j.pathol.2023.01.002] [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: 07/16/2022] [Revised: 12/22/2022] [Accepted: 01/06/2023] [Indexed: 01/21/2023]
Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant multisystem syndrome caused by mutations in the neurofibromin 1 (NF1) gene that encodes for the protein neurofibromin acting as a tumour suppressor. Neurofibromin functions primarily as a GTPase-activating protein for the Ras family of oncogenes, which activates many signalling pathways for cell proliferation and differentiation; without neurofibromin, Ras is constitutively activated, thereby turning on many downstream signalling pathways related to oncogenesis. Patients with NF1 have a well known predisposition for certain types of malignancies including malignant peripheral nerve sheath tumours, gliomas, and breast cancers, as well as a potential association of NF1 with lymphoproliferative disorders such as lymphomas. In this article, we review the pathophysiology and tumourigenesis of NF1, previously reported cases of cutaneous lymphomas in NF1 patients along with our case demonstration of a NF1-associated scalp B-cell lymphoma, and NF1-associated extra cutaneous lymphomas. The diagnosis of lymphomas particularly cutaneous lymphomas may be difficult in NF1 patients as they often have skin lesions and/or cutaneous/subcutaneous nodules or tumours like neurofibromas, which raises the possibility of underdiagnosed cutaneous lymphomas in NF1 patients. We also comprehensively discuss the association between NF1 and lymphomas. In summary, most studies support a potential association between NF1 and lymphomas. Further investigation is needed to clarify the association between NF1 and lymphomas in order to bring clinical awareness of possibly underdiagnosed NF1-associated lymphomas and individualised management of NF1 patients to practice.
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Affiliation(s)
- Faiha Fareez
- Department of Pathology and Molecular Medicine, Hamilton, Ontario, Canada
| | - Bill H Wang
- Department of Surgery/Neurosurgery, McMaster University, Hamilton, Ontario, Canada
| | - Ian Brain
- Department of Laboratory Medicine and Pathobiology/Hematopathology, University of Toronto, Toronto, Ontario, Canada
| | - Jian-Qiang Lu
- Department of Pathology and Molecular Medicine, Hamilton, Ontario, Canada; Department of Pathology and Molecular Medicine/Neuropathology, Hamilton General Hospital, Hamilton, Ontario, Canada.
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20
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Na Y, Hall A, Yu Y, Hu L, Choi K, Burgard JA, Szabo S, Huang G, Ratner N, Wu J. Runx1/3-driven adaptive endoplasmic reticulum stress pathways contribute to neurofibromagenesis. Oncogene 2023; 42:1038-1047. [PMID: 36759572 PMCID: PMC10194627 DOI: 10.1038/s41388-023-02620-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 01/28/2023] [Accepted: 01/31/2023] [Indexed: 02/11/2023]
Abstract
Neurofibromatosis type 1 (NF1) patients are predisposed to develop plexiform neurofibromas (PNFs). Three endoplasmic reticulum (ER) stress response pathways restore cellular homeostasis. The unfolded protein response (UPR) sensors contribute to tumor initiation in many cancers. We found that all three UPR pathways were activated in mouse and human PNFs, with protein kinase RNA [PKR]-like ER kinase (PERK) the most highly expressed. We tested if neurofibroma cells adapt to ER stress, leading to their growth. Pharmacological or genetic inhibition of PERK reduced mouse neurofibroma-sphere number, and genetic inhibition in PERK in Schwann cell precursors (SCPs) decreased tumor-like lesion numbers in a cell transplantation model. Further, in a PNF mouse model, deletion of PERK in Schwann cells (SCs) and SCPs reduced tumor size, number, and increased survival. Mechanistically, loss of Nf1 activated PERK-eIF2α-ATF4 signaling and increased ATF4 downstream target gene p21 translocation from nucleus to cytoplasm. This nucleus-cytoplasm translocation was mediated by exportin-1. Runx transcriptionally activated ribosome gene expression and increased protein synthesis to allow SCs to adapt to ER stress and tumor formation. We propose that targeting proteostasis might provide cytotoxic and/or potentially durable novel therapy for PNFs.
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Affiliation(s)
- Youjin Na
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
| | - Ashley Hall
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
| | - Yanan Yu
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
- College of Life Science, Xuzhou Medical University, 221004, Jiangsu, P. R. China
| | - Liang Hu
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
| | - Kwangmin Choi
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
| | - Jake A Burgard
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
| | - Sara Szabo
- Department of Pediatrics and Department of Pediatric Pathology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA
| | - Gang Huang
- Department of Cell Systems & Anatomy and Department of Pathology & Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health San Antonio, San Antonio, TX, USA
- Department of Pathology & Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health San Antonio, San Antonio, TX, 78229, USA
| | - Nancy Ratner
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
| | - Jianqiang Wu
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA.
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
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21
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Dougherty J, Harvey K, Liou A, Labella K, Moran D, Brosius S, De Raedt T. Identification of therapeutic sensitivities in a spheroid drug combination screen of Neurofibromatosis Type I associated High Grade Gliomas. PLoS One 2023; 18:e0277305. [PMID: 36730269 PMCID: PMC9894422 DOI: 10.1371/journal.pone.0277305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 10/22/2022] [Indexed: 02/03/2023] Open
Abstract
Neurofibromatosis Type 1 (NF1) patients develop an array of benign and malignant tumors, of which Malignant Peripheral Nerve Sheath Tumors (MPNST) and High Grade Gliomas (HGG) have a dismal prognosis. About 15-20% of individuals with NF1 develop brain tumors and one third of these occur outside of the optic pathway. These non-optic pathway gliomas are more likely to progress to malignancy, especially in adults. Despite their low frequency, high grade gliomas have a disproportional effect on the morbidity of NF1 patients. In vitro drug combination screens have not been performed on NF1-associated HGG, hindering our ability to develop informed clinical trials. Here we present the first in vitro drug combination screen (21 compounds alone or in combination with MEK or PI3K inhibitors) on the only human NF1 patient derived HGG cell line available and on three mouse glioma cell lines derived from the NF1-P53 genetically engineered mouse model, which sporadically develop HGG. These mouse glioma cell lines were never exposed to serum, grow as spheres and express markers that are consistent with an Oligodendrocyte Precursor Cell (OPC) lineage origin. Importantly, even though the true cell of origin for HGG remains elusive, they are thought to arise from the OPC lineage. We evaluated drug sensitivities of the three murine glioma cell lines in a 3D spheroid growth assay, which more accurately reflects drug sensitivities in vivo. Excitingly, we identified six compounds targeting HDACs, BRD4, CHEK1, BMI-1, CDK1/2/5/9, and the proteasome that potently induced cell death in our NF1-associated HGG. Moreover, several of these inhibitors work synergistically with either MEK or PI3K inhibitors. This study forms the basis for further pre-clinical evaluation of promising targets, with an eventual hope to translate these to the clinic.
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Affiliation(s)
- Jacquelyn Dougherty
- Department of Pediatrics, Children’s Hospital Philadelphia, Philadelphia, Pennsylvania, United States of America
- School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Kyra Harvey
- Department of Pediatrics, Children’s Hospital Philadelphia, Philadelphia, Pennsylvania, United States of America
- School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Angela Liou
- Department of Pediatrics, Children’s Hospital Philadelphia, Philadelphia, Pennsylvania, United States of America
- School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Katherine Labella
- Department of Pediatrics, Children’s Hospital Philadelphia, Philadelphia, Pennsylvania, United States of America
- School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Deborah Moran
- Department of Pediatrics, Children’s Hospital Philadelphia, Philadelphia, Pennsylvania, United States of America
- School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Stephanie Brosius
- Department of Pediatrics, Children’s Hospital Philadelphia, Philadelphia, Pennsylvania, United States of America
- School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
- Department or Neurology, Children’s Hospital Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - Thomas De Raedt
- Department of Pediatrics, Children’s Hospital Philadelphia, Philadelphia, Pennsylvania, United States of America
- School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
- * E-mail:
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22
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Patel AJ, Warda S, Maag JL, Misra R, Miranda-Román MA, Pachai MR, Lee CJ, Li D, Wang N, Bayshtok G, Fishinevich E, Meng Y, Wong EW, Yan J, Giff E, Pappalardi MB, McCabe MT, Fletcher JA, Rudin CM, Chandarlapaty S, Scandura JM, Koche RP, Glass JL, Antonescu CR, Zheng D, Chen Y, Chi P. PRC2-Inactivating Mutations in Cancer Enhance Cytotoxic Response to DNMT1-Targeted Therapy via Enhanced Viral Mimicry. Cancer Discov 2022; 12:2120-2139. [PMID: 35789380 PMCID: PMC9437570 DOI: 10.1158/2159-8290.cd-21-1671] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 05/19/2022] [Accepted: 06/29/2022] [Indexed: 02/01/2023]
Abstract
Polycomb repressive complex 2 (PRC2) has oncogenic and tumor-suppressive roles in cancer. There is clinical success of targeting this complex in PRC2-dependent cancers, but an unmet therapeutic need exists in PRC2-loss cancer. PRC2-inactivating mutations are a hallmark feature of high-grade malignant peripheral nerve sheath tumor (MPNST), an aggressive sarcoma with poor prognosis and no effective targeted therapy. Through RNAi screening in MPNST, we found that PRC2 inactivation increases sensitivity to genetic or small-molecule inhibition of DNA methyltransferase 1 (DNMT1), which results in enhanced cytotoxicity and antitumor response. Mechanistically, PRC2 inactivation amplifies DNMT inhibitor-mediated expression of retrotransposons, subsequent viral mimicry response, and robust cell death in part through a protein kinase R (PKR)-dependent double-stranded RNA sensor. Collectively, our observations posit DNA methylation as a safeguard against antitumorigenic cell-fate decisions in PRC2-loss cancer to promote cancer pathogenesis, which can be therapeutically exploited by DNMT1-targeted therapy. SIGNIFICANCE PRC2 inactivation drives oncogenesis in various cancers, but therapeutically targeting PRC2 loss has remained challenging. Here we show that PRC2-inactivating mutations set up a tumor context-specific liability for therapeutic intervention via DNMT1 inhibitors, which leads to innate immune signaling mediated by sensing of derepressed retrotransposons and accompanied by enhanced cytotoxicity. See related commentary by Guil and Esteller, p. 2020. This article is highlighted in the In This Issue feature, p. 2007.
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Affiliation(s)
- Amish J. Patel
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Sarah Warda
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jesper L.V. Maag
- Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Rohan Misra
- Department of Genetics, Albert Einstein College of Medicine, Bronx, New York
| | - Miguel A. Miranda-Román
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
- Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Mohini R. Pachai
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Cindy J. Lee
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Dan Li
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Naitao Wang
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Gabriella Bayshtok
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Eve Fishinevich
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Yinuo Meng
- Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York
| | - Elissa W.P. Wong
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Juan Yan
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Emily Giff
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Melissa B. Pappalardi
- Cancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, Pennsylvania
| | - Michael T. McCabe
- Cancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, Pennsylvania
| | - Jonathan A. Fletcher
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Charles M. Rudin
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Sarat Chandarlapaty
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
- Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- Weill Cornell Medical College, New York, New York
| | - Joseph M. Scandura
- Laboratory of Molecular Hematopoiesis, Hematology and Oncology, Weill Cornell Medicine, New York, New York
- Richard T. Silver MD Myeloproliferative Neoplasm Center, Weill Cornell Medicine, New York, New York
- Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York
| | - Richard P. Koche
- Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jacob L. Glass
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
- Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York
- Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | | | - Deyou Zheng
- The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, New York
- Department of Genetics, Albert Einstein College of Medicine, Bronx, New York
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York
| | - Yu Chen
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
- Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York
- Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Ping Chi
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
- Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York
- Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Medicine, Weill Cornell Medical College, New York, New York
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23
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Thiel JT, Daigeler A, Kolbenschlag J, Rachunek K, Hoffmann S. The Role of CDK Pathway Dysregulation and Its Therapeutic Potential in Soft Tissue Sarcoma. Cancers (Basel) 2022; 14:3380. [PMID: 35884441 PMCID: PMC9323700 DOI: 10.3390/cancers14143380] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 07/07/2022] [Accepted: 07/09/2022] [Indexed: 02/04/2023] Open
Abstract
Soft tissue sarcomas (STSs) are tumors that are challenging to treat due to their pathologic and molecular heterogeneity and their tumor biology that is not yet fully understood. Recent research indicates that dysregulation of cyclin-dependent kinase (CDK) signaling pathways can be a strong driver of sarcogenesis. CDKs are enzyme forms that play a crucial role in cell-cycle control and transcription. They belong to the protein kinases group and to the serine/threonine kinases subgroup. Recently identified CDK/cyclin complexes and established CDK/cyclin complexes that regulate the cell cycle are involved in the regulation of gene expression through phosphorylation of critical components of transcription and pre-mRNA processing mechanisms. The current and continually growing body of data shows that CDKs play a decisive role in tumor development and are involved in the proliferation and growth of sarcoma cells. Since the abnormal expression or activation of large numbers of CDKs is considered to be characteristic of cancer development and progression, dysregulation of the CDK signaling pathways occurs in many subtypes of STSs. This review discusses how reversal and regulation can be achieved with new therapeutics and summarizes the current evidence from studies regarding CDK modulation for STS treatment.
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Affiliation(s)
- Johannes Tobias Thiel
- Department of Hand, Plastic, Reconstructive and Burn Surgery, BG Unfallklinik Tuebingen, University of Tuebingen, 72076 Tuebingen, Germany; (A.D.); (J.K.); (K.R.); (S.H.)
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24
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Alnefaie N, Almutairi OT, Alturki AY, Bafaquh M. Bibliometric analysis of the top 100 most-cited articles in neurofibromatosis. Surg Neurol Int 2022; 13:282. [PMID: 35855179 PMCID: PMC9282785 DOI: 10.25259/sni_114_2022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 06/10/2022] [Indexed: 11/04/2022] Open
Abstract
Background:
Neurofibromatosis (NF) is an umbrella term that refers to three distinct disease entities: NF Type 1, Type 2, and schwannomatosis. Here, we reviewed the scientific performance and the most influential publications on NF.
Methods:
A keyword-based search was performed using the Scopus database. The top 100 articles were grouped based on NF types and the studied entities. The differences between the articles, authors, and journals were quantified based on certain parameters. Other parameters were collected for the complete citational analysis.
Results:
The top 100 articles were published between 1961 and 2020. The most trending period of research was in the 1990s and articles studying the clinical aspect and the underlying genetic correlation made up 84% of all articles from the list. The United States of America (USA) had the highest number of contributions (69 articles, 69%). The top institute of contribution to the list was the Howard Hughes Medical Institute, USA (14 articles, 14%). Author-based analysis reveals that the neurologist D. H. Gutmann from St. Louis Children’s Hospital, USA, was the most active and authored 11 articles (11%) on the list.
Conclusion:
The publication trends show that articles studying medical and surgical management were of little interest. The top 100 articles did not include any randomized control trials, and the highest level of evidence was obtained from reviews of pooled knowledge as well as population-based and longitudinal studies.
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25
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Tian H, Chen Z, Jie G, Wang Z, Yan H, Wu S, Zhang S, Lu D, Zhang X, Wu Y. Prognostic features and comprehensive genomic analysis of NF1 mutations in EGFR mutant lung cancer patients. Cancer Med 2022; 12:396-406. [PMID: 35702826 PMCID: PMC9844590 DOI: 10.1002/cam4.4925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 05/24/2022] [Indexed: 01/25/2023] Open
Abstract
OBJECTIVE NF1 is a tumor suppressor gene that encodes the neurofibromin protein and negatively regulates Ras signaling. This study was aimed to investigate the molecular, clinical characteristics, and prognostic features of NF1 gene in EGFR mutant lung cancer patients. METHOD The next-generation sequencing (NGS) was used to analyze the data from lung cancer patients in the Guangdong Lung Cancer Institute (GLCI) from June 2016 to December 2020. RESULTS Somatic NF1 mutations were present in 4.2% (135/3220) of Chinese lung cancer patients. NF1 mutations where clearly enriched in older (p < 0.001), male (p < 0.001), and smoking (p < 0.001) patients. Patients with NF1 mutations were more likely to have TP53 (p = 0.003), BRAF (p = 0.001) and RASA1 (p = 0.026) mutations and mutually exclusive with EGFR mutations (p = 0.006). TP53 mutation had worsen prognosis in cases of NF1 mutant (p = 0.026) or EGFR/NF1 co-mutant (p = 0.031) lung adenocarcinomas (LUAD) patients. There was no effect on overall survival (OS) in LUAD patients with and without NF1 mutations, even in LUAD driver-gene negative patients. NF1/EGFR co-mutation patients had a longer OS than a single mutation of either the EGFR gene (median OS: 47.7 m vs. 30.2 m, hazard ratio [95% CI], 0.47 [0.30-0.74], p = 0.004) or NF1 gene (47.7 m vs. 19.0 m, 0.44 [0.27-0.73], p = 0.003). Furthermore, NF1 mutations significantly prolonged OS in EGFR mutant/TP53 wild-type LUAD patients (106.5 m vs. 25.5 m, 0.28 [0.13-0.59], p = 0.003) but not in patients with EGFR/TP53 co-mutations (36.8 m vs. 30.2 m, 0.70 [0.39-1.26], p = 0.280). CONCLUSION Our results indicated NF1 mutations served as a good prognostic factor in EGFR mutant/TP53 wild-type lung cancer patients in this single-center study. TP53 mutation was obviously enriched in NF1 mutant patients and had shorter OS.
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Affiliation(s)
- Hong‐xia Tian
- Guangdong Lung Cancer Institute, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouChina,Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouChina
| | - Zhi‐hong Chen
- Guangdong Lung Cancer Institute, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouChina,Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouChina
| | - Guang‐Ling Jie
- Guangdong Lung Cancer Institute, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouChina
| | - Zhen Wang
- Guangdong Lung Cancer Institute, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouChina,Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouChina
| | - Hong‐hong Yan
- Guangdong Lung Cancer Institute, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouChina,Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouChina
| | - Si‐pei Wu
- Guangdong Lung Cancer Institute, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouChina,Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouChina
| | - Shui‐lian Zhang
- Guangdong Lung Cancer Institute, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouChina,Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouChina
| | - Dan‐xia Lu
- Guangdong Lung Cancer Institute, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouChina,Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouChina
| | - Xu‐chao Zhang
- Guangdong Lung Cancer Institute, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouChina,Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouChina
| | - Yi‐long Wu
- Guangdong Lung Cancer Institute, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouChina,Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouChina
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26
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Chaker-Margot M, Werten S, Dunzendorfer-Matt T, Lechner S, Ruepp A, Scheffzek K, Maier T. Structural basis of activation of the tumor suppressor protein neurofibromin. Mol Cell 2022; 82:1288-1296.e5. [PMID: 35353986 DOI: 10.1016/j.molcel.2022.03.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 01/14/2022] [Accepted: 03/03/2022] [Indexed: 12/15/2022]
Abstract
Mutations in the NF1 gene cause the familial genetic disease neurofibromatosis type I, as well as predisposition to cancer. The NF1 gene product, neurofibromin, is a GTPase-activating protein and acts as a tumor suppressor by negatively regulating the small GTPase, Ras. However, structural insights into neurofibromin activation remain incompletely defined. Here, we provide cryoelectron microscopy (cryo-EM) structures that reveal an extended neurofibromin homodimer in two functional states: an auto-inhibited state with occluded Ras-binding site and an asymmetric open state with an exposed Ras-binding site. Mechanistically, the transition to the active conformation is stimulated by nucleotide binding, which releases a lock that tethers the catalytic domain to an extended helical repeat scaffold in the occluded state. Structure-guided mutational analysis supports functional relevance of allosteric control. Disease-causing mutations are mapped and primarily impact neurofibromin stability. Our findings suggest a role for nucleotides in neurofibromin regulation and may lead to therapeutic modulation of Ras signaling.
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Affiliation(s)
| | - Sebastiaan Werten
- Institute of Biological Chemistry, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria
| | | | - Stefan Lechner
- Institute of Biological Chemistry, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria
| | - Angela Ruepp
- Institute of Biological Chemistry, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria
| | - Klaus Scheffzek
- Institute of Biological Chemistry, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria.
| | - Timm Maier
- Biozentrum, University of Basel, 4056 Basel, Switzerland.
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27
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Somatilaka BN, Sadek A, McKay RM, Le LQ. Malignant peripheral nerve sheath tumor: models, biology, and translation. Oncogene 2022; 41:2405-2421. [PMID: 35393544 PMCID: PMC9035132 DOI: 10.1038/s41388-022-02290-1] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 03/16/2022] [Accepted: 03/21/2022] [Indexed: 01/29/2023]
Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, invasive cancer that comprise around 10% of all soft tissue sarcomas and develop in about 8-13% of patients with Neurofibromatosis Type 1. They are associated with poor prognosis and are the leading cause of mortality in NF1 patients. MPNSTs can also develop sporadically or following exposure to radiation. There is currently no effective targeted therapy to treat MPNSTs and surgical removal remains the mainstay treatment. Unfortunately, surgery is not always possible due to the size and location of the tumor, thus, a better understanding of MPNST initiation and development is required to design novel therapeutics. Here, we provide an overview of MPNST biology and genetics, discuss findings regarding the developmental origin of MPNST, and summarize the various model systems employed to study MPNST. Finally, we discuss current management strategies for MPNST, as well as recent developments in translating basic research findings into potential therapies.
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Affiliation(s)
- Bandarigoda N. Somatilaka
- Department of Dermatology, University of Texas Southwestern
Medical Center at Dallas, Dallas, Texas, 75390-9069, USA
| | - Ali Sadek
- Department of Dermatology, University of Texas Southwestern
Medical Center at Dallas, Dallas, Texas, 75390-9069, USA
| | - Renee M. McKay
- Department of Dermatology, University of Texas Southwestern
Medical Center at Dallas, Dallas, Texas, 75390-9069, USA
| | - Lu Q. Le
- Department of Dermatology, University of Texas Southwestern
Medical Center at Dallas, Dallas, Texas, 75390-9069, USA,Simmons Comprehensive Cancer Center, University of Texas
Southwestern Medical Center at Dallas, Dallas, Texas, 75390-9069, USA,UTSW Comprehensive Neurofibromatosis Clinic, University of
Texas Southwestern Medical Center at Dallas, Dallas, Texas, 75390-9069, USA,Hamon Center for Regenerative Science and Medicine,
University of Texas Southwestern Medical Center at Dallas, Dallas, Texas,
75390-9069, USA,O’Donnell Brain Institute, University of Texas
Southwestern Medical Center at Dallas, Dallas, Texas, 75390-9069, USA
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28
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Mattox AK, Douville C, Silliman N, Ptak J, Dobbyn L, Schaefer J, Popoli M, Blair C, Judge K, Pollard K, Pratilas C, Blakeley J, Rodriguez F, Papadopoulos N, Belzberg A, Bettegowda C. Detection of malignant peripheral nerve sheath tumors in patients with neurofibromatosis using aneuploidy and mutation identification in plasma. eLife 2022; 11:e74238. [PMID: 35244537 PMCID: PMC9094745 DOI: 10.7554/elife.74238] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 02/01/2022] [Indexed: 11/28/2022] Open
Abstract
Malignant peripheral nerve sheath tumors (MPNST) are the deadliest cancer that arises in individuals diagnosed with neurofibromatosis and account for nearly 5% of the 15,000 soft tissue sarcomas diagnosed in the United States each year. Comprised of neoplastic Schwann cells, primary risk factors for developing MPNST include existing plexiform neurofibromas (PN), prior radiotherapy treatment, and expansive germline mutations involving the entire NF1 gene and surrounding genes. PN develop in nearly 30-50% of patients with neurofibromatosis type 1 (NF1) and most often grow rapidly in the first decade of life. One of the most important aspects of clinical care for NF1 patients is monitoring PN for signs of malignant transformation to MPNST that occurs in 10-15% of patients. We perform aneuploidy analysis on ctDNA from 883 ostensibly healthy individuals and 28 patients with neurofibromas, including 7 patients with benign neurofibroma, 9 patients with PN and 12 patients with MPNST. Overall sensitivity for detecting MPNST using genome wide aneuploidy scoring was 33%, and analysis of sub-chromosomal copy number alterations (CNAs) improved sensitivity to 50% while retaining a high specificity of 97%. In addition, we performed mutation analysis on plasma cfDNA for a subset of patients and identified mutations in NF1, NF2, RB1, TP53BP2, and GOLGA2. Given the high throughput and relatively low sequencing coverage required by our assay, liquid biopsy represents a promising technology to identify incipient MPNST.
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Affiliation(s)
- Austin K Mattox
- Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Christopher Douville
- Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Natalie Silliman
- Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Janine Ptak
- Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Lisa Dobbyn
- Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Joy Schaefer
- Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Maria Popoli
- Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Cherie Blair
- Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Kathy Judge
- Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Kai Pollard
- Department of Pediatrics, Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Oncology, Sidney Kimmel Comprehensive Cancer, Johns Hopkins UniversityBaltimoreUnited States
| | - Christine Pratilas
- Department of Pediatrics, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Jaishri Blakeley
- Department of Neurology, Johns Hopkins University School of Medicine, MD School of MedicineBaltimoreUnited States
| | - Fausto Rodriguez
- Department of Pathology, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Nickolas Papadopoulos
- Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Oncology, Sidney Kimmel Comprehensive Cancer, Johns Hopkins UniversityBaltimoreUnited States
- Department of Pathology, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Allan Belzberg
- Department of Neurosurgery, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Chetan Bettegowda
- Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Oncology, Sidney Kimmel Comprehensive Cancer, Johns Hopkins UniversityBaltimoreUnited States
- Department of Neurosurgery, Johns Hopkins University School of MedicineBaltimoreUnited States
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29
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Kohlmeyer JL, Kaemmer CA, Lingo JJ, Voigt E, Leidinger MR, McGivney GR, Scherer A, Koppenhafer SL, Gordon DJ, Breheny P, Meyerholz DK, Tanas MR, Dodd RD, Quelle DE. Oncogenic RABL6A promotes NF1-associated MPNST progression in vivo. Neurooncol Adv 2022; 4:vdac047. [PMID: 35571990 PMCID: PMC9092646 DOI: 10.1093/noajnl/vdac047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Background Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with complex molecular and genetic alterations. Powerful tumor suppressors CDKN2A and TP53 are commonly disrupted along with NF1, a gene that encodes a negative regulator of Ras. Many additional factors have been implicated in MPNST pathogenesis. A greater understanding of critical drivers of MPNSTs is needed to guide more informed targeted therapies for patients. RABL6A is a newly identified driver of MPNST cell survival and proliferation whose in vivo role in the disease is unknown. Methods Using CRISPR-Cas9 targeting of Nf1 + Cdkn2a or Nf1 + Tp53 in the mouse sciatic nerve to form de novo MPNSTs, we investigated the biological significance of RABL6A in MPNST development. Terminal tumors were evaluated by western blot, qRT-PCR, and immunohistochemistry. Results Mice lacking Rabl6 displayed slower tumor progression and extended survival relative to wildtype animals in both genetic contexts. YAP oncogenic activity was selectively downregulated in Rabl6-null, Nf1 + Cdkn2a lesions whereas loss of RABL6A caused upregulation of the CDK inhibitor, p27, in all tumors. Paradoxically, both models displayed elevated Myc protein and Ki67 staining in terminal tumors lacking RABL6A. In Nf1 + p53 tumors, cellular atypia and polyploidy were evident and increased by RABL6A loss. Conclusions These findings demonstrate that RABL6A is required for optimal progression of NF1 mutant MPNSTs in vivo in both Cdkn2a and p53 inactivated settings. However, sustained RABL6A loss may provide selective pressure for unwanted alterations, including increased Myc, cellular atypia, and polyploidy, that ultimately promote a hyper-proliferative tumor phenotype akin to drug-resistant lesions.
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Affiliation(s)
- Jordan L Kohlmeyer
- Molecular Medicine Graduate Program, The University of Iowa, Iowa City, Iowa, USA
- The Department of Neuroscience and Pharmacology, The University of Iowa, Iowa City, Iowa, USA
| | - Courtney A Kaemmer
- The Department of Neuroscience and Pharmacology, The University of Iowa, Iowa City, Iowa, USA
| | - Joshua J Lingo
- Cancer Biology Graduate Program, The University of Iowa, Iowa City, Iowa, USA
| | - Ellen Voigt
- Cancer Biology Graduate Program, The University of Iowa, Iowa City, Iowa, USA
- Medical Scientist Training Program, The University of Iowa, Iowa City, Iowa, USA
| | - Mariah R Leidinger
- The Department of Pathology, The University of Iowa, Iowa City, Iowa, USA
| | - Gavin R McGivney
- Cancer Biology Graduate Program, The University of Iowa, Iowa City, Iowa, USA
| | - Amanda Scherer
- The Department of Internal Medicine, The University of Iowa, Iowa City, Iowa, USA
| | | | - David J Gordon
- Molecular Medicine Graduate Program, The University of Iowa, Iowa City, Iowa, USA
- Cancer Biology Graduate Program, The University of Iowa, Iowa City, Iowa, USA
- Medical Scientist Training Program, The University of Iowa, Iowa City, Iowa, USA
- The Department of Pediatrics, The University of Iowa, Iowa City, Iowa, USA
- The Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa, USA
| | - Patrick Breheny
- Department of Biostatistics, The University of Iowa, Iowa City, Iowa, USA
- The Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa, USA
| | - David K Meyerholz
- The Department of Pathology, The University of Iowa, Iowa City, Iowa, USA
| | - Munir R Tanas
- Molecular Medicine Graduate Program, The University of Iowa, Iowa City, Iowa, USA
- Cancer Biology Graduate Program, The University of Iowa, Iowa City, Iowa, USA
- The Department of Pathology, The University of Iowa, Iowa City, Iowa, USA
- The Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa, USA
| | - Rebecca D Dodd
- Molecular Medicine Graduate Program, The University of Iowa, Iowa City, Iowa, USA
- Cancer Biology Graduate Program, The University of Iowa, Iowa City, Iowa, USA
- Medical Scientist Training Program, The University of Iowa, Iowa City, Iowa, USA
- The Department of Internal Medicine, The University of Iowa, Iowa City, Iowa, USA
- The Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa, USA
| | - Dawn E Quelle
- Molecular Medicine Graduate Program, The University of Iowa, Iowa City, Iowa, USA
- Cancer Biology Graduate Program, The University of Iowa, Iowa City, Iowa, USA
- Medical Scientist Training Program, The University of Iowa, Iowa City, Iowa, USA
- The Department of Neuroscience and Pharmacology, The University of Iowa, Iowa City, Iowa, USA
- The Department of Pathology, The University of Iowa, Iowa City, Iowa, USA
- The Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa, USA
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30
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Cohen-Barak E, Toledano-Alhadef H, Danial-Farran N, Livneh I, Mwassi B, Hriesh M, Zagairy F, Gafni-Amsalem C, Bashir H, Khayat M, Warrour N, Sher O, Marom D, Postovsky S, Dujovny T, Ziv M, Shalev SA. Concomitant variants in NF1, LZTR1 and GNAZ genes probably contribute to the aggressiveness of plexiform neurofibroma and warrant treatment with MEK inhibitor. Exp Dermatol 2021; 31:775-780. [PMID: 34913528 DOI: 10.1111/exd.14514] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 11/17/2021] [Accepted: 12/12/2021] [Indexed: 12/25/2022]
Abstract
Neurofibromatosis 1 (NF1) is caused by germline mutations in the NF1 gene and manifests as proliferation of various tissues, including plexiform neurofibromas. The plexiform neurofibroma phenotype varies from indolent to locally aggressive, suggesting contributions of other modifiers in addition to somatic loss of NF1. In this study, we investigated a life-threatening plexiform neurofibroma in a 9-month-old female infant with NF1. Germline mutations in two RASopathy-associated genes were identified using whole-exome sequencing-a de novo pathogenic variant in the NF1 gene, and a known pathogenic variant in the LZTR1 gene. Somatic analysis of the plexiform neurofibroma revealed NF1 loss of heterozygosity and a variant in GNAZ, a gene encoding a G protein-coupled receptor. Cells expressing mutant GNAZ exhibited increased ERK 1/2 activation compared to those expressing wild-type GNAZ. Taken together, we suggest the variants in NF1, LZRT1 and GNAZ act synergistically in our patient, leading to MAPK pathway activation and contributing to the severity of the patient's plexiform neurofibromatosis. After treatment with the MEK inhibitor, trametinib, a prominent clinical improvement was observed in this patient. This case study contributes to the knowledge of germline and somatic non-NF1 variants affecting the NF1 clinical phenotype and supports use of personalized, targeted therapy.
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Affiliation(s)
- Eran Cohen-Barak
- Department of Dermatology, "Emek" Medical Center, Afula, Israel.,Bruce and Ruth Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Hagit Toledano-Alhadef
- Pediatric Neurology and Child Development Center, Gilbert Israeli and International Neurofibromatosis Center, Dana-Dwek Children Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | | | - Ido Livneh
- Bruce and Ruth Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Banan Mwassi
- Department of Dermatology, "Emek" Medical Center, Afula, Israel.,Bruce and Ruth Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Maysa Hriesh
- Department of Dermatology, "Emek" Medical Center, Afula, Israel
| | - Fadia Zagairy
- Department of Dermatology, "Emek" Medical Center, Afula, Israel
| | | | - Husam Bashir
- The Genetic Institute, "Emek" Medical Center, Afula, Israel
| | - Morad Khayat
- The Genetic Institute, "Emek" Medical Center, Afula, Israel
| | - Nassim Warrour
- The Genetic Institute, "Emek" Medical Center, Afula, Israel
| | - Osnat Sher
- Bone&Soft Tissue Pathology Service, Department of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Daphna Marom
- Human Genetics Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Sergey Postovsky
- Department of Pediatric Oncology, "Emek" Medical Center, Afula, Israel
| | - Tal Dujovny
- Department of Pediatric Oncology, "Emek" Medical Center, Afula, Israel
| | - Michael Ziv
- Department of Dermatology, "Emek" Medical Center, Afula, Israel
| | - Stavit A Shalev
- Bruce and Ruth Rappaport Faculty of Medicine, Technion, Haifa, Israel.,The Genetic Institute, "Emek" Medical Center, Afula, Israel
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31
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Abstract
Neurofibromatosis type 1 (NF1) is one of the most common neurocutaneous genetic disorders, presenting with different cutaneous features such as café-au-lait macules, intertriginous skin freckling, and neurofibromas. Although most of the disease manifestations are benign, patients are at risk for a variety of malignancies, including malignant transformation of plexiform neurofibromas. Numerous studies have investigated the mechanisms by which these characteristic neurofibromas develop, with progress made toward unraveling the various players involved in their complex pathogenesis. In this review, we summarize the current understanding of the cells that give rise to NF1 neoplasms as well as the molecular mechanisms and cellular changes that confer tumorigenic potential. We also discuss the role of the tumor microenvironment and the key aspects of its various cell types that contribute to NF1-associated tumorigenesis. An increased understanding of these intrinsic and extrinsic components is critical for developing novel therapeutic approaches for affected patients.
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Affiliation(s)
- Ashley Bui
- Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Chunhui Jiang
- Department of Dermatology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Renee M McKay
- Department of Dermatology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Laura J Klesse
- Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.,Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.,Comprehensive Neurofibromatosis Clinic, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Lu Q Le
- Department of Dermatology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.,Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.,Comprehensive Neurofibromatosis Clinic, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.,Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
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32
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Wang W, Wei CJ, Cui XW, Li YH, Gu YH, Gu B, Li QF, Wang ZC. Impacts of NF1 Gene Mutations and Genetic Modifiers in Neurofibromatosis Type 1. Front Neurol 2021; 12:704639. [PMID: 34566848 PMCID: PMC8455870 DOI: 10.3389/fneur.2021.704639] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 07/15/2021] [Indexed: 12/26/2022] Open
Abstract
Neurofibromatosis type 1 (NF1) is a tumor predisposition genetic disorder that directly affects more than 1 in 3,000 individuals worldwide. It results from mutations of the NF1 gene and shows almost complete penetrance. NF1 patients show high phenotypic variabilities, including cafe-au-lait macules, freckling, or other neoplastic or non-neoplastic features. Understanding the underlying mechanisms of the diversities of clinical symptoms might contribute to the development of personalized healthcare for NF1 patients. Currently, studies have shown that the different types of mutations in the NF1 gene might correlate with this phenomenon. In addition, genetic modifiers are responsible for the different clinical features. In this review, we summarize different genetic mutations of the NF1 gene and related genetic modifiers. More importantly, we focus on the genotype–phenotype correlation. This review suggests a novel aspect to explain the underlying mechanisms of phenotypic heterogeneity of NF1 and provides suggestions for possible novel therapeutic targets to prevent or delay the onset and development of different manifestations of NF1.
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Affiliation(s)
- Wei Wang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Cheng-Jiang Wei
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xi-Wei Cui
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yue-Hua Li
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yi-Hui Gu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bin Gu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qing-Feng Li
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhi-Chao Wang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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33
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Martin TD, Patel RS, Cook DR, Choi MY, Patil A, Liang AC, Li MZ, Haigis KM, Elledge SJ. The adaptive immune system is a major driver of selection for tumor suppressor gene inactivation. Science 2021; 373:1327-1335. [PMID: 34529489 DOI: 10.1126/science.abg5784] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
During tumorigenesis, tumors must evolve to evade the immune system and do so by disrupting the genes involved in antigen processing and presentation or up-regulating inhibitory immune checkpoint genes. We performed in vivo CRISPR screens in syngeneic mouse tumor models to examine requirements for tumorigenesis both with and without adaptive immune selective pressure. In each tumor type tested, we found a marked enrichment for the loss of tumor suppressor genes (TSGs) in the presence of an adaptive immune system relative to immunocompromised mice. Nearly one-third of TSGs showed preferential enrichment, often in a cancer- and tissue-specific manner. These results suggest that clonal selection of recurrent mutations found in cancer is driven largely by the tumor’s requirement to avoid the adaptive immune system.
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MESH Headings
- Animals
- CRISPR-Cas Systems
- Carcinogenesis
- Cell Line, Tumor
- Chemokine CCL2/metabolism
- Female
- GTP-Binding Protein alpha Subunits, G12-G13/genetics
- GTP-Binding Protein alpha Subunits, G12-G13/metabolism
- Gene Silencing
- Genes, Tumor Suppressor
- Humans
- Immune Evasion/genetics
- Mammary Neoplasms, Experimental/genetics
- Mammary Neoplasms, Experimental/immunology
- Mammary Neoplasms, Experimental/pathology
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, SCID
- Neoplasm Transplantation
- Neoplasms, Experimental/genetics
- Neoplasms, Experimental/immunology
- Neoplasms, Experimental/pathology
- Selection, Genetic
- Tumor Microenvironment
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Affiliation(s)
- Timothy D Martin
- Division of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Rupesh S Patel
- Division of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Danielle R Cook
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Mei Yuk Choi
- Division of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Ajinkya Patil
- Division of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Anthony C Liang
- Division of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Mamie Z Li
- Division of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Kevin M Haigis
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Stephen J Elledge
- Division of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
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34
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Mo J, Anastasaki C, Chen Z, Shipman T, Papke J, Yin K, Gutmann DH, Le LQ. Humanized neurofibroma model from induced pluripotent stem cells delineates tumor pathogenesis and developmental origins. J Clin Invest 2021; 131:139807. [PMID: 33108355 DOI: 10.1172/jci139807] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 10/21/2020] [Indexed: 02/06/2023] Open
Abstract
Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome caused by NF1 gene mutation, in which affected patients develop Schwann cell lineage peripheral nerve sheath tumors (neurofibromas). To investigate human neurofibroma pathogenesis, we differentiated a series of isogenic, patient-specific NF1-mutant human induced pluripotent stem cells (hiPSCs) into Schwannian lineage cells (SLCs). We found that, although WT and heterozygous NF1-mutant hiPSCs-SLCs did not form tumors following mouse sciatic nerve implantation, NF1-null SLCs formed bona fide neurofibromas with high levels of SOX10 expression. To confirm that SOX10+ SLCs contained the cells of origin for neurofibromas, both Nf1 alleles were inactivated in mouse Sox10+ cells, leading to classic nodular cutaneous and plexiform neurofibroma formation that completely recapitulated their human counterparts. Moreover, we discovered that NF1 loss impaired Schwann cell differentiation by inducing a persistent stem-like state to expand the pool of progenitors required to initiate tumor formation, indicating that, in addition to regulating MAPK-mediated cell growth, NF1 loss also altered Schwann cell differentiation to promote neurofibroma development. Taken together, we established a complementary humanized neurofibroma explant and, to our knowledge, first-in-kind genetically engineered nodular cutaneous neurofibroma mouse models that delineate neurofibroma pathogenesis amenable to future therapeutic target discovery and evaluation.
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Affiliation(s)
- Juan Mo
- Department of Dermatology, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Corina Anastasaki
- Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA
| | - Zhiguo Chen
- Department of Dermatology, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Tracey Shipman
- Department of Dermatology, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Jason Papke
- Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA
| | - Kevin Yin
- Department of Dermatology, UT Southwestern Medical Center, Dallas, Texas, USA
| | - David H Gutmann
- Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA
| | - Lu Q Le
- Department of Dermatology, UT Southwestern Medical Center, Dallas, Texas, USA.,Simmons Comprehensive Cancer Center and.,Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
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35
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Mohamad T, Plante C, Brosseau JP. Toward Understanding the Mechanisms of Malignant Peripheral Nerve Sheath Tumor Development. Int J Mol Sci 2021; 22:ijms22168620. [PMID: 34445326 PMCID: PMC8395254 DOI: 10.3390/ijms22168620] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 08/03/2021] [Accepted: 08/05/2021] [Indexed: 12/12/2022] Open
Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) originate from the neural crest lineage and are associated with the neurofibromatosis type I syndrome. MPNST is an unmet clinical need. In this review article, we summarize the knowledge and discuss research perspectives related to (1) the natural history of MPNST development; (2) the mouse models recapitulating the progression from precursor lesions to MPNST; (3) the role of the tumor microenvironment in MPNST development, and (4) the signaling pathways linked to MPNST development.
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Affiliation(s)
- Teddy Mohamad
- Department of Biochemistry and Functional Genomics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada; (T.M.); (C.P.)
| | - Camille Plante
- Department of Biochemistry and Functional Genomics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada; (T.M.); (C.P.)
| | - Jean-Philippe Brosseau
- Department of Biochemistry and Functional Genomics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada; (T.M.); (C.P.)
- Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada
- Correspondence: ; Tel.: +1-819-821-8000 (ext. 72477)
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36
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Sun D, Xie XP, Zhang X, Wang Z, Sait SF, Iyer SV, Chen YJ, Brown R, Laks DR, Chipman ME, Shern JF, Parada LF. Stem-like cells drive NF1-associated MPNST functional heterogeneity and tumor progression. Cell Stem Cell 2021; 28:1397-1410.e4. [PMID: 34010628 PMCID: PMC8349880 DOI: 10.1016/j.stem.2021.04.029] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 02/18/2021] [Accepted: 04/26/2021] [Indexed: 12/15/2022]
Abstract
NF1-associated malignant peripheral nerve sheath tumors (MPNSTs) are the major cause of mortality in neurofibromatosis. MPNSTs arise from benign peripheral nerve plexiform neurofibromas that originate in the embryonic neural crest cell lineage. Using reporter transgenes that label early neural crest lineage cells in multiple NF1 MPNST mouse models, we discover and characterize a rare MPNST cell population with stem-cell-like properties, including quiescence, that is essential for tumor initiation and relapse. Following isolation of these cells, we derive a cancer-stem-cell-specific gene expression signature that includes consensus embryonic neural crest genes and identify Nestin as a marker for the MPNST cell of origin. Combined targeting of cancer stem cells along with antimitotic chemotherapy yields effective tumor inhibition and prolongs survival. Enrichment of the cancer stem cell signature in cognate human tumors supports the generality and relevance of cancer stem cells to MPNST therapy development.
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Affiliation(s)
- Daochun Sun
- Brain Tumor Center, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
| | - Xuanhua P Xie
- Brain Tumor Center, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Xiyuan Zhang
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Zilai Wang
- Brain Tumor Center, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Sameer Farouk Sait
- Brain Tumor Center, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Swathi V Iyer
- Brain Tumor Center, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Yu-Jung Chen
- Brain Tumor Center, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Rebecca Brown
- Brain Tumor Center, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Dan R Laks
- Brain Tumor Center, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Mollie E Chipman
- Brain Tumor Center, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Jack F Shern
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Luis F Parada
- Brain Tumor Center, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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Pitsava G, Stratakis CA, Faucz FR. PRKAR1A and Thyroid Tumors. Cancers (Basel) 2021; 13:cancers13153834. [PMID: 34359735 PMCID: PMC8345073 DOI: 10.3390/cancers13153834] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/24/2021] [Accepted: 07/27/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary In 2021 it is estimated that there will be 44,280 new cases of thyroid cancer in the United States and the incidence rate is higher in women than in men by almost 3 times. Well-differentiated thyroid cancer is the most common subtype of thyroid cancer and includes follicular (FTC) and papillary (PTC) carcinomas. Over the last decade, researchers have been able to better understand the molecular mechanisms involved in thyroid carcinogenesis, identifying genes including but not limited to RAS, BRAF, PAX8/PPARγ chromosomal rearrangements and others, as well as several tumor genes involved in major signaling pathways regulating cell cycle, differentiation, growth, or proliferation. Patients with Carney complex (CNC) have increased incidence of thyroid tumors, including cancer, yet little is known about this association. CNC is a familial multiple neoplasia and lentiginosis syndrome cause by inactivating mutations in the PRKAR1A gene which encodes the regulatory subunit type 1α of protein kinase A. This work summarizes what we know today about PRKAR1A defects in humans and mice and their role in thyroid tumor development, as the first such review on this issue. Abstract Thyroid cancer is the most common type of endocrine malignancy and the incidence is rapidly increasing. Follicular (FTC) and papillary thyroid (PTC) carcinomas comprise the well-differentiated subtype and they are the two most common thyroid carcinomas. Multiple molecular genetic and epigenetic alterations have been identified in various types of thyroid tumors over the years. Point mutations in BRAF, RAS as well as RET/PTC and PAX8/PPARγ chromosomal rearrangements are common. Thyroid cancer, including both FTC and PTC, has been observed in patients with Carney Complex (CNC), a syndrome that is inherited in an autosomal dominant manner and predisposes to various tumors. CNC is caused by inactivating mutations in the tumor-suppressor gene encoding the cyclic AMP (cAMP)-dependent protein kinase A (PKA) type 1α regulatory subunit (PRKAR1A) mapped in chromosome 17 (17q22–24). Growth of the thyroid is driven by the TSH/cAMP/PKA signaling pathway and it has been shown in mouse models that PKA activation through genetic ablation of the regulatory subunit Prkar1a can cause FTC. In this review, we provide an overview of the molecular mechanisms contributing to thyroid tumorigenesis associated with inactivation of the RRKAR1A gene.
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Affiliation(s)
- Georgia Pitsava
- Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA;
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA;
| | - Constantine A. Stratakis
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA;
| | - Fabio R. Faucz
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA;
- Correspondence: ; Tel.: +1-301-451-7177
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38
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Vasudevan HN, Lucas CHG, Villanueva-Meyer JE, Theodosopoulos PV, Raleigh DR. Genetic Events and Signaling Mechanisms Underlying Schwann Cell Fate in Development and Cancer. Neurosurgery 2021; 88:234-245. [PMID: 33094349 DOI: 10.1093/neuros/nyaa455] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 08/08/2020] [Indexed: 01/08/2023] Open
Abstract
In this review, we describe Schwann cell development from embryonic neural crest cells to terminally differentiated myelinated and nonmyelinated mature Schwann cells. We focus on the genetic drivers and signaling mechanisms mediating decisions to proliferate versus differentiate during Schwann cell development, highlighting pathways that overlap with Schwann cell development and are dysregulated in tumorigenesis. We conclude by considering how our knowledge of the events underlying Schwann cell development and mouse models of schwannoma, neurofibroma, and malignant peripheral nerve sheath tumor can inform novel therapeutic strategies for patients with cancers derived from Schwann cell lineages.
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Affiliation(s)
- Harish N Vasudevan
- Department of Radiation Oncology, University of California, San Francisco, San Francisco, California.,Department of Neurological Surgery, University of California, San Francisco, San Francisco, California
| | - Calixto-Hope G Lucas
- Department of Anatomic Pathology, University of California, San Francisco, San Francisco, California
| | - Javier E Villanueva-Meyer
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California
| | - Philip V Theodosopoulos
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, California
| | - David R Raleigh
- Department of Radiation Oncology, University of California, San Francisco, San Francisco, California.,Department of Neurological Surgery, University of California, San Francisco, San Francisco, California
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Preclinical In Vivo Modeling of Pediatric Sarcoma-Promises and Limitations. J Clin Med 2021; 10:jcm10081578. [PMID: 33918045 PMCID: PMC8069549 DOI: 10.3390/jcm10081578] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 04/05/2021] [Accepted: 04/06/2021] [Indexed: 02/07/2023] Open
Abstract
Pediatric sarcomas are an extremely heterogeneous group of genetically distinct diseases. Despite the increasing knowledge on their molecular makeup in recent years, true therapeutic advancements are largely lacking and prognosis often remains dim, particularly for relapsed and metastasized patients. Since this is largely due to the lack of suitable model systems as a prerequisite to develop and assess novel therapeutics, we here review the available approaches to model sarcoma in vivo. We focused on genetically engineered and patient-derived mouse models, compared strengths and weaknesses, and finally explored possibilities and limitations to utilize these models to advance both biological understanding as well as clinical diagnosis and therapy.
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40
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Osum SH, Watson AL, Largaespada DA. Spontaneous and Engineered Large Animal Models of Neurofibromatosis Type 1. Int J Mol Sci 2021; 22:1954. [PMID: 33669386 PMCID: PMC7920315 DOI: 10.3390/ijms22041954] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 02/02/2021] [Accepted: 02/04/2021] [Indexed: 12/13/2022] Open
Abstract
Animal models are crucial to understanding human disease biology and developing new therapies. By far the most common animal used to investigate prevailing questions about human disease is the mouse. Mouse models are powerful tools for research as their small size, limited lifespan, and defined genetic background allow researchers to easily manipulate their genome and maintain large numbers of animals in general laboratory spaces. However, it is precisely these attributes that make them so different from humans and explains, in part, why these models do not accurately predict drug responses in human patients. This is particularly true of the neurofibromatoses (NFs), a group of genetic diseases that predispose individuals to tumors of the nervous system, the most common of which is Neurofibromatosis type 1 (NF1). Despite years of research, there are still many unanswered questions and few effective treatments for NF1. Genetically engineered mice have drastically improved our understanding of many aspects of NF1, but they do not exemplify the overall complexity of the disease and some findings do not translate well to humans due to differences in body size and physiology. Moreover, NF1 mouse models are heavily reliant on the Cre-Lox system, which does not accurately reflect the molecular mechanism of spontaneous loss of heterozygosity that accompanies human tumor development. Spontaneous and genetically engineered large animal models may provide a valuable supplement to rodent studies for NF1. Naturally occurring comparative models of disease are an attractive prospect because they occur on heterogeneous genetic backgrounds and are due to spontaneous rather than engineered mutations. The use of animals with naturally occurring disease has been effective for studying osteosarcoma, lymphoma, and diabetes. Spontaneous NF-like symptoms including neurofibromas and malignant peripheral nerve sheath tumors (MPNST) have been documented in several large animal species and share biological and clinical similarities with human NF1. These animals could provide additional insight into the complex biology of NF1 and potentially provide a platform for pre-clinical trials. Additionally, genetically engineered porcine models of NF1 have recently been developed and display a variety of clinical features similar to those seen in NF1 patients. Their large size and relatively long lifespan allow for longitudinal imaging studies and evaluation of innovative surgical techniques using human equipment. Greater genetic, anatomic, and physiologic similarities to humans enable the engineering of precise disease alleles found in human patients and make them ideal for preclinical pharmacokinetic and pharmacodynamic studies of small molecule, cellular, and gene therapies prior to clinical trials in patients. Comparative genomic studies between humans and animals with naturally occurring disease, as well as preclinical studies in large animal disease models, may help identify new targets for therapeutic intervention and expedite the translation of new therapies. In this review, we discuss new genetically engineered large animal models of NF1 and cases of spontaneous NF-like manifestations in large animals, with a special emphasis on how these comparative models could act as a crucial translational intermediary between specialized murine models and NF1 patients.
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Affiliation(s)
- Sara H. Osum
- Masonic Cancer Center, Department of Pediatrics, Division of Hematology and Oncology, University of Minnesota, Minneapolis, MN 55455, USA;
| | | | - David A. Largaespada
- Masonic Cancer Center, Department of Pediatrics, Division of Hematology and Oncology, University of Minnesota, Minneapolis, MN 55455, USA;
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41
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Kohlmeyer JL, Gordon DJ, Tanas MR, Dodd RD, Monga V, Darbro BW, Quelle DE. Combination therapies for MPNSTs targeting RABL6A-RB1 signaling. Oncotarget 2021; 12:10-14. [PMID: 33456709 PMCID: PMC7800773 DOI: 10.18632/oncotarget.27862] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 01/15/2023] Open
Abstract
Precision medicine relies on a detailed molecular understanding of disease pathogenesis. Here, we consider urgently needed therapeutic options for malignant peripheral nerve sheath tumors (MPNSTs) based on emerging insights into druggable pathway alterations found to drive this deadly cancer. Recent observations demonstrate an essential role for an oncogenic GTPase, RABL6A, in promoting MPNST progression through hyperactivation of cyclin-dependent kinases (CDKs) and inactivation of the retinoblastoma (RB1) tumor suppressor. Monotherapies with CDK4/6 inhibitors have shown limited efficacy and durability in pre-clinical studies of MPNSTs and in clinical studies of other tumors. Therefore, we discuss the rationale and clinical benefits of inhibiting multiple RABL6A effectors, particularly CDK4/6 and MEK kinases, in targeted combination therapies suitable for MPNSTs and other Ras-driven malignancies.
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Affiliation(s)
- Jordan L Kohlmeyer
- Molecular Medicine Graduate Program, University of Iowa, Iowa City, Iowa, USA.,Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, Iowa, USA
| | - David J Gordon
- Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA.,Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa, USA
| | - Munir R Tanas
- Molecular Medicine Graduate Program, University of Iowa, Iowa City, Iowa, USA.,Department of Pathology, University of Iowa, Iowa City, Iowa, USA.,Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa, USA
| | - Rebecca D Dodd
- Molecular Medicine Graduate Program, University of Iowa, Iowa City, Iowa, USA.,Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.,Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa, USA
| | - Varun Monga
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.,Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa, USA
| | - Benjamin W Darbro
- Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA.,Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa, USA
| | - Dawn E Quelle
- Molecular Medicine Graduate Program, University of Iowa, Iowa City, Iowa, USA.,Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, Iowa, USA.,Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA.,Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa, USA
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42
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Inoue A, Janke LJ, Gudenas BL, Jin H, Fan Y, Paré J, Clay MR, Northcott PA, Hirbe AC, Cao X. A genetic mouse model with postnatal Nf1 and p53 loss recapitulates the histology and transcriptome of human malignant peripheral nerve sheath tumor. Neurooncol Adv 2021; 3:vdab129. [PMID: 34647023 PMCID: PMC8500687 DOI: 10.1093/noajnl/vdab129] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas. Somatic inactivation of NF1 and cooperating tumor suppressors, including CDKN2A/B, PRC2, and p53, is found in most MPNST. Inactivation of LATS1/2 of the Hippo pathway was recently shown to cause tumors resembling MPNST histologically, although Hippo pathway mutations are rarely found in MPNST. Because existing genetically engineered mouse (GEM) models of MPNST do not recapitulate some of the key genetic features of human MPNST, we aimed to establish a GEM-MPNST model that recapitulated the human disease genetically, histologically, and molecularly. METHODS We combined 2 genetically modified alleles, an Nf1;Trp53 cis-conditional allele and an inducible Plp-CreER allele (NP-Plp), to model the somatic, possibly postnatal, mutational events in human MPNST. We also generated conditional Lats1;Lats2 knockout mice. We performed histopathologic analyses of mouse MPNST models and transcriptomic comparison of mouse models and human nerve sheath tumors. RESULTS Postnatal Nf1;Trp53 cis-deletion resulted in GEM-MPNST that were histologically more similar to human MPNST than the widely used germline Nf1;Trp53 cis-heterozygous (NPcis) model and showed partial loss of H3K27me3. At the transcriptome level, Nf1;p53-driven GEM-MPNST were distinct from Lats-driven GEM-MPNST and resembled human MPNST more closely than do Lats-driven tumors. CONCLUSIONS The NP-Plp model recapitulates human MPNST genetically, histologically, and molecularly.
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Affiliation(s)
- Akira Inoue
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Laura J Janke
- Department of Pathology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Brian L Gudenas
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Hongjian Jin
- Center for Applied Bioinformatics, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Yiping Fan
- Center for Applied Bioinformatics, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Joshua Paré
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Michael R Clay
- Department of Pathology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Paul A Northcott
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Angela C Hirbe
- Division of Medical Oncology, Washington University, St. Louis, Missouri, USA
| | - Xinwei Cao
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
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Butler E, Schwettmann B, Geboers S, Hao G, Kim J, Nham K, Sun X, Laetsch TW, Xu L, Williams NS, Skapek SX. Functional imaging of RAS pathway targeting in malignant peripheral nerve sheath tumor cells and xenografts. Pediatr Blood Cancer 2020; 67:e28639. [PMID: 32975370 DOI: 10.1002/pbc.28639] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 07/21/2020] [Accepted: 07/22/2020] [Indexed: 11/10/2022]
Abstract
BACKGROUND Malignant peripheral nerve sheath tumor (MPNST) is an aggressive form of soft-tissue sarcoma (STS) in children. Despite intensive therapy, relatively few children with metastatic and unresectable disease survive beyond three years. RAS pathway activation is common in MPNST, suggesting MEK pathway inhibition as a targeted therapy, but the impact on clinical outcome has been small to date. PROCEDURE We conducted preclinical pharmacokinetic (PK) and pharmacodynamic studies of two MEK inhibitors, trametinib and selumetinib, in two MPNST models and analyzed tumors for intratumor drug levels. We then investigated 3'-deoxy-3'-[18 F]fluorothymidine (18 F-FLT) PET imaging followed by 18 F-FDG PET/CT imaging of MPNST xenografts coupled to short-term or longer-term treatment with selumetinib focusing on PET-based imaging as a biomarker of MEK inhibition. RESULTS Trametinib decreased pERK expression in MPNST xenografts but did not prolong survival or decrease Ki67 expression. In contrast, selumetinib prolonged survival of animals bearing MPNST xenografts, and this correlated with decreased pERK and Ki67 staining. PK studies revealed a significantly higher fraction of unbound selumetinib within a responsive MPNST xenograft model. Thymidine uptake, assessed by 18 F-FLT PET/CT, positively correlated with Ki67 expression in different xenograft models and in response to selumetinib. CONCLUSION The ability of MEK inhibitors to control MPNST growth cannot simply be predicted by serum drug levels or drug-induced changes in pERK expression. Tumor cell proliferation assessed by 18 F-FLT PET imaging might be useful as an early response marker to targeted therapies, including MEK inhibition, where a primary effect is cell-cycle arrest.
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Affiliation(s)
- Erin Butler
- Department of Pediatrics Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Blake Schwettmann
- Department of Pediatrics Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Sophie Geboers
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Guiyang Hao
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jiwoong Kim
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Kien Nham
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Xiankai Sun
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas.,The Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Theodore W Laetsch
- Department of Pediatrics Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, Texas.,The Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Lin Xu
- Department of Pediatrics Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, Texas.,Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, Texas.,The Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Noelle S Williams
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Stephen X Skapek
- Department of Pediatrics Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, Texas
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Zhao XF, Shen YM, Chen J. Multiple recurrent neurofibromas in the abdominal wall: A case report. World J Clin Cases 2020; 8:4223-4227. [PMID: 33024782 PMCID: PMC7520774 DOI: 10.12998/wjcc.v8.i18.4223] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 08/10/2020] [Accepted: 08/21/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Neurofibroma can be a clinical manifestation of neurofibromatosis, which is a benign neurogenic tumor that occurs sporadically. Neurofibromas in the abdomen usually appear in the retroperitoneal space. Reports on neurofibromas in the abdominal wall are rare, and multiple recurrent neurofibromas in this area have not yet been reported.
CASE SUMMARY This is a case of a 73-year-old man who suffered from multiple recurrent neurofibromas in the abdominal wall for 16 years and received 13 surgical treatments.
CONCLUSION We need to pay due attention to its treatment, and primary surgery should be designed thoroughly.
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Affiliation(s)
- Xue-Fei Zhao
- Department of Hernia and Abdominal Wall Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Ying-Mo Shen
- Department of Hernia and Abdominal Wall Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Jie Chen
- Department of Hernia and Abdominal Wall Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
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45
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Special Issue: "Genomics and Models of Nerve Sheath Tumors". Genes (Basel) 2020; 11:genes11091024. [PMID: 32882803 PMCID: PMC7563428 DOI: 10.3390/genes11091024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 08/28/2020] [Indexed: 12/26/2022] Open
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Armstrong AE, Rhodes SD, Smith A, Chen S, Bessler W, Ferguson MJ, Jiang L, Li X, Yuan J, Yang X, Yang FC, Robertson KA, Ingram DA, Blakeley JO, Clapp DW. Early administration of imatinib mesylate reduces plexiform neurofibroma tumor burden with durable results after drug discontinuation in a mouse model of neurofibromatosis type 1. Pediatr Blood Cancer 2020; 67:e28372. [PMID: 32459399 PMCID: PMC7516834 DOI: 10.1002/pbc.28372] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 03/26/2020] [Accepted: 04/13/2020] [Indexed: 01/12/2023]
Abstract
BACKGROUND Neurofibromatosis type 1 (NF1) is a common genetic disorder characterized by plexiform neurofibromas (pNF), which are thought to be congenital tumors that arise in utero and enlarge throughout life. Genetic studies in murine models delineated an indispensable role for the stem cell factor (SCF)/c-kit pathway in pNF initiation and progression. A subsequent phase 2 clinical trial using imatinib mesylate to inhibit SCF/c-kit demonstrated tumor shrinkage in a subset of preexisting pNF; however, imatinib's role on preventing pNF development has yet to be explored. PROCEDURE We evaluated the effect of imatinib dosed at 10-100 mg/kg/day for 12 weeks to one-month-old Nf1flox/flox ;PostnCre(+) mice, prior to onset of pNF formation. To determine durability of response, we then monitored for pNF growth at later time points, comparing imatinib- with vehicle-treated mice. We assessed gross and histopathological analysis of tumor burden. RESULTS Imatinib administered preventatively led to a significant decrease in pNF number, even at doses as low as 10 mg/kg/day. Tumor development continued to be significantly inhibited after cessation of imatinib dosed at 50 and 100 mg/kg/day. In the cohort of treated mice that underwent prolonged follow-up, the size of residual tumors was significantly reduced as compared with age-matched littermates that received vehicle control. CONCLUSIONS Early administration of imatinib inhibits pNF genesis in vivo, and effects are sustained after discontinuation of therapy. These findings may guide clinical use of imatinib in young NF1 patients prior to the substantial development of pNF.
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Affiliation(s)
- Amy E. Armstrong
- Division of Pediatric Hematology/Oncology, Riley Hospital for Children, Indianapolis, Indiana,Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana
| | - Steven D. Rhodes
- Division of Pediatric Hematology/Oncology, Riley Hospital for Children, Indianapolis, Indiana,Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana
| | - Abbi Smith
- Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana
| | - Shi Chen
- Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana
| | - Waylan Bessler
- Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana
| | - Michael J. Ferguson
- Division of Pediatric Hematology/Oncology, Riley Hospital for Children, Indianapolis, Indiana,Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana
| | - Li Jiang
- Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana
| | - Xiaohong Li
- Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana
| | - Jin Yuan
- Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana
| | - Xianlin Yang
- Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana
| | - Feng-Chun Yang
- Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana,Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Kent A. Robertson
- Division of Pediatric Hematology/Oncology, Riley Hospital for Children, Indianapolis, Indiana,Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana
| | - David A. Ingram
- Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana
| | - Jaishri O. Blakeley
- Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - D. Wade Clapp
- Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana,Correspondence should be addressed to: D. Wade Clapp, M.D., Richard L. Schreiner Professor and Chairman, Department of Pediatrics, Indiana University School of Medicine, Riley Hospital for Children at Indiana University Health, 705 Riley Hospital Dr., Room 5900, Indianapolis, IN 46202, Phone: (317) 944-7810 Office,
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Preventative Effect of Mebendazole against Malignancies in Neurofibromatosis 1. Genes (Basel) 2020; 11:genes11070762. [PMID: 32650362 PMCID: PMC7397152 DOI: 10.3390/genes11070762] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/28/2020] [Accepted: 06/30/2020] [Indexed: 12/23/2022] Open
Abstract
Patients with RASopathy Neurofibromatosis 1 (NF1) are at a markedly increased risk of the development of benign and malignant tumors. Malignant tumors are often recalcitrant to treatments and associated with poor survival; however, no chemopreventative strategies currently exist. We thus evaluated the effect of mebendazole, alone or in combination with cyclooxygenase-2 (COX-2) inhibitors, on the prevention of NF1-related malignancies in a cisNf1+/−;Tp53+/− (NPcis) mouse model of NF1. Our in vitro findings showed that mebendazole (MBZ) inhibits the growth of NF1-related malignant peripheral nerve sheath tumors (MPNSTs) through a reduction in activated guanosine triphosphate (GTP)-bound Ras. The daily MBZ treatment of NPcis mice dosed at 195 mg/kg daily, initiated 60 days after birth, substantially delayed the formation of solid malignancies and increased median survival (p < 0.0001). Compared to placebo-treated mice, phosphorylated extracellular signal-regulated kinase (pERK) levels were decreased in the malignancies of MBZ-treated mice. The combination of MBZ with COX-2 inhibitor celecoxib (CXB) further enhanced the chemopreventative effect in female mice beyond each drug alone. These findings demonstrate the feasibility of a prevention strategy for malignancy development in high-risk NF1 individuals.
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Abdel Al S, Abou Chaar MK, Asha W, Al-Najjar H, Al-Hussaini M. Fungating malignant peripheral nerve sheath tumor arising from a slow-growing mass in the forearm: a case report and review of the literature. J Med Case Rep 2020; 14:91. [PMID: 32631436 PMCID: PMC7339469 DOI: 10.1186/s13256-020-02427-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 06/02/2020] [Indexed: 12/16/2022] Open
Abstract
Background Malignant peripheral nerve sheath tumor is a rare and aggressive form of sarcoma that arises from a peripheral nerve, mostly in association with neurofibromatosis type 1. Half of the cases were reported in the extremities, with the lungs being the most common site of metastasis. We report a rare case of successful limb salvage surgery performed for a large exophytic malignant peripheral nerve sheath tumor of the right forearm with wide surgical margins followed by split-thickness skin graft and later a flexor carpi radialis tendon transfer to extensor digitorum communis tendon. Case presentation A 51-year-old Bedouin Arabic man presented to our institution with an incompletely excised, large, fungating, malignant peripheral nerve sheath tumor occupying most of his right forearm. Staging imaging showed multiple lung nodules. He underwent wide local excision followed by skin graft and tendon transfer as a palliative measure to preserve the function of his dominant limb. The operation was performed without any complications, and the patient had an excellent postoperative result. Afterward, he was started on multiple lines of chemotherapy that failed because of disease progression, and the patient died 7 months after the operation. Conclusion Clinicians must consider the possibility of soft tissue sarcoma even in a patient with a small, slow-growing, superficial mass. Furthermore, a wrong open biopsy or nononcological surgical procedure may lead to possible contamination and ultimately a more radical procedure than would have originally been necessary, where this can be prevented by an early referral to a highly specialized sarcoma center.
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Affiliation(s)
- Samer Abdel Al
- Department of Orthopedic Oncology, King Hussein Cancer Center, Amman, 11941, Jordan.
| | | | - Wafa Asha
- Department of Radiation Oncology, King Hussein Cancer Center, Amman, Jordan
| | - Hani Al-Najjar
- Department of Surgery, King Hussein Cancer Center, Amman, Jordan
| | - Maysa Al-Hussaini
- Department of Pathology and Laboratory Medicine, King Hussein Cancer Center, Amman, Jordan
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Prudner BC, Ball T, Rathore R, Hirbe AC. Diagnosis and management of malignant peripheral nerve sheath tumors: Current practice and future perspectives. Neurooncol Adv 2020; 2:i40-i49. [PMID: 32642731 PMCID: PMC7317062 DOI: 10.1093/noajnl/vdz047] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
One of the most common malignancies affecting adults with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome is the malignant peripheral nerve sheath tumor (MPNST), a highly aggressive sarcoma that typically develops from benign plexiform neurofibromas. Approximately 8-13% of individuals with NF1 will develop MPNST during young adulthood. There are few therapeutic options, and the vast majority of people with these cancers will die within 5 years of diagnosis. Despite efforts to understand the pathogenesis of these aggressive tumors, the overall prognosis remains dismal. This manuscript will review the current understanding of the cellular and molecular progression of MPNST, diagnostic workup of patients with these tumors, current treatment paradigms, and investigational treatment options. Additionally, we highlight novel areas of preclinical research, which may lead to future clinical trials. In summary, MPNST remains a diagnostic and therapeutic challenge, and future work is needed to develop novel and rational combinational therapy for these tumors.
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Affiliation(s)
- Bethany C Prudner
- Division of Medical Oncology, Department of Medicine, Washington University, St. Louis
| | - Tyler Ball
- Division of Medical Oncology, Department of Medicine, Washington University, St. Louis
| | - Richa Rathore
- Division of Medical Oncology, Department of Medicine, Washington University, St. Louis
| | - Angela C Hirbe
- Division of Medical Oncology, Department of Medicine, Washington University, St. Louis
- Neurofibromatosis Center, Washington University, St. Louis MO
- Siteman Cancer Center, Washington University, St. Louis
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Brosseau JP, Liao CP, Le LQ. Translating current basic research into future therapies for neurofibromatosis type 1. Br J Cancer 2020; 123:178-186. [PMID: 32439933 PMCID: PMC7374719 DOI: 10.1038/s41416-020-0903-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 03/25/2020] [Accepted: 05/01/2020] [Indexed: 12/12/2022] Open
Abstract
Neurofibromatosis type 1 (NF1) is a hereditary tumour syndrome that predisposes to benign and malignant tumours originating from neural crest cells. Biallelic inactivation of the tumour-suppressor gene NF1 in glial cells in the skin, along a nerve plexus or in the brain results in the development of benign tumours: cutaneous neurofibroma, plexiform neurofibroma and glioma, respectively. Despite more than 40 years of research, only one medication was recently approved for treatment of plexiform neurofibroma and no drugs have been specifically approved for the management of other tumours. Work carried out over the past several years indicates that inhibiting different cellular signalling pathways (such as Hippo, Janus kinase/signal transducer and activator of transcription, mitogen-activated protein kinase and those mediated by sex hormones) in tumour cells or targeting cells in the microenvironment (nerve cells, macrophages, mast cells and T cells) might benefit NF1 patients. In this review, we outline previous strategies aimed at targeting these signalling pathways or cells in the microenvironment, agents that are currently in clinical trials, and the latest advances in basic research that could culminate in the development of novel therapeutics for patients with NF1.
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Affiliation(s)
- Jean-Philippe Brosseau
- Department of Dermatology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390-9069, USA.
- Department of Biochemistry and Functional Genomics, University of Sherbrooke, Sherbrooke, QC, J1E 4K8, Canada.
| | - Chung-Ping Liao
- Department of Dermatology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390-9069, USA
| | - Lu Q Le
- Department of Dermatology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390-9069, USA.
- Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390-9069, USA.
- UTSW Comprehensive Neurofibromatosis Clinic, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390-9069, USA.
- Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390-9069, USA.
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