المصدر: Phase II Trial of the MEK1/2 Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate in Adults With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas
Curry BP, Alvarez R, Widemann BC, Johnson M, Agarwal PK, Lehky T, Valera V, Chittiboina P. Robotic Nerve Sheath Tumor Resection With Intraoperative Neuromonitoring: Case Series and Systematic Review. Oper Neurosurg (Hagerstown). 2022 Feb 1;22(2):44-50. doi: 10.1227/ONS.0000000000000051.
Herrick WG, Kilpatrick CL, Hollingshead MG, Esposito D, O'Sullivan Coyne G, Gross AM, Johnson BC, Chen AP, Widemann BC, Doroshow JH, Parchment RE, Srivastava AK. Isoform- and Phosphorylation-specific Multiplexed Quantitative Pharmacodynamics of Drugs Targeting PI3K and MAPK Signaling in Xenograft Models and Clinical Biopsies. Mol Cancer Ther. 2021 Apr;20(4):749-760. doi: 10.1158/1535-7163.MCT-20-0566. Epub 2021 Feb 3.

المصدر: A Phase I/II Study of the Mitogen Activated Protein Kinase Kinase (MEK) 1 Inhibitor Selumetinib (AZD6244; Hydrogen Sulfate in Children With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (PN)
Gross AM, Glassberg B, Wolters PL, Dombi E, Baldwin A, Fisher MJ, Kim A, Bornhorst M, Weiss BD, Blakeley JO, Whitcomb P, Paul SM, Steinberg SM, Venzon DJ, Martin S, Carbonell A, Heisey K, Therrien J, Kapustina O, Dufek A, Derdak J, Smith MA, Widemann BC. Selumetinib in children with neurofibromatosis type 1 and asymptomatic inoperable plexiform neurofibroma at risk for developing tumor-related morbidity. Neuro Oncol. 2022 Nov 2;24(11):1978-1988. doi: 10.1093/neuonc/noac109.
Gross AM, Wolters PL, Dombi E, Baldwin A, Whitcomb P, Fisher MJ, Weiss B, Kim A, Bornhorst M, Shah AC, Martin S, Roderick MC, Pichard DC, Carbonell A, Paul SM, Therrien J, Kapustina O, Heisey K, Clapp DW, Zhang C, Peer CJ, Figg WD, Smith M, Glod J, Blakeley JO, Steinberg SM, Venzon DJ, Doyle LA, Widemann BC. Selumetinib in Children with Inoperable Plexiform Neurofibromas. N Engl J Med. 2020 Apr 9;382(15):1430-1442. doi: 10.1056/NEJMoa1912735. Epub 2020 Mar 18. Erratum In: N Engl J Med. 2020 Sep 24;383(13):1290. doi: 10.1056/NEJMx200013.
Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, Whitcomb P, Martin S, Aschbacher-Smith LE, Rizvi TA, Wu J, Ershler R, Wolters P, Therrien J, Glod J, Belasco JB, Schorry E, Brofferio A, Starosta AJ, Gillespie A, Doyle AL, Ratner N, Widemann BC. Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas. N Engl J Med. 2016 Dec 29;375(26):2550-2560. doi: 10.1056/NEJMoa1605943.

المؤلفون: Children's Hospital of Philadelphia, Indiana University, United States Department of Defense

المساهمون: Girish Dhall, MD, Professor

المصدر: A Phase 1/1b/2 Study of Cabozantinib in Combination with Selumetinib for Plexiform Neurofibroma in Adults and Adolescents with Neurofibromatosis Type 1

المؤلفون: Array BioPharma, Pacific Pediatric Neuro-Oncology Consortium

المساهمون: Bruce Korf, MD, Principal Investigator

المصدر: A Phase II Study of Binimetinib in Children and Adults with NF1 Associated Plexiform Neurofibromas (PNOC010)
Wu J, Williams JP, Rizvi TA, Kordich JJ, Witte D, Meijer D, Stemmer-Rachamimov AO, Cancelas JA, Ratner N. Plexiform and dermal neurofibromas and pigmentation are caused by Nf1 loss in desert hedgehog-expressing cells. Cancer Cell. 2008 Feb;13(2):105-16. doi: 10.1016/j.ccr.2007.12.027.
Kebudi R, Cakir FB, Gorgun O. Interferon-alpha for unresectable progressive and symptomatic plexiform neurofibromas. J Pediatr Hematol Oncol. 2013 Apr;35(3):e115-7. doi: 10.1097/MPH.0b013e318270cd24.
Citak EC, Oguz A, Karadeniz C, Okur A, Memis L, Boyunaga O. Management of plexiform neurofibroma with interferon alpha. Pediatr Hematol Oncol. 2008 Sep;25(7):673-8. doi: 10.1080/08880010802315983.
Jakacki RI, Dombi E, Potter DM, Goldman S, Allen JC, Pollack IF, Widemann BC. Phase I trial of pegylated interferon-alpha-2b in young patients with plexiform neurofibromas. Neurology. 2011 Jan 18;76(3):265-72. doi: 10.1212/WNL.0b013e318207b031.
Widemann BC, Arceci RJ, Jayaprakash N, Fox E, Zannikos P, Goodspeed W, Goodwin A, Wright JJ, Blaney SM, Adamson PC, Balis FM. Phase 1 trial and pharmacokinetic study of the farnesyl transferase inhibitor tipifarnib in children and adolescents with refractory leukemias: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2011 Feb;56(2):226-33. doi: 10.1002/pbc.22775. Epub 2010 Sep 21.
Widemann BC, Salzer WL, Arceci RJ, Blaney SM, Fox E, End D, Gillespie A, Whitcomb P, Palumbo JS, Pitney A, Jayaprakash N, Zannikos P, Balis FM. Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitor tipifarnib in children with refractory solid tumors or neurofibromatosis type I and plexiform neurofibromas. J Clin Oncol. 2006 Jan 20;24(3):507-16. doi: 10.1200/JCO.2005.03.8638.
Babovic-Vuksanovic D, Widemann BC, Dombi E, Gillespie A, Wolters PL, Toledo-Tamula MA, O'Neill BP, Fox E, MacDonald T, Beck H, Packer RJ. Phase I trial of pirfenidone in children with neurofibromatosis 1 and plexiform neurofibromas. Pediatr Neurol. 2007 May;36(5):293-300. doi: 10.1016/j.pediatrneurol.2007.01.009.
Babovic-Vuksanovic D, Ballman K, Michels V, McGrann P, Lindor N, King B, Camp J, Micic V, Babovic N, Carrero X, Spinner R, O'Neill B. Phase II trial of pirfenidone in adults with neurofibromatosis type 1. Neurology. 2006 Nov 28;67(10):1860-2. doi: 10.1212/01.wnl.0000243231.12248.67. Epub 2006 Oct 11.
Kim A, Dombi E, Tepas K, Fox E, Martin S, Wolters P, Balis FM, Jayaprakash N, Turkbey B, Muradyan N, Choyke PL, Reddy A, Korf B, Widemann BC. Phase I trial and pharmacokinetic study of sorafenib in children with neurofibromatosis type I and plexiform neurofibromas. Pediatr Blood Cancer. 2013 Mar;60(3):396-401. doi: 10.1002/pbc.24281. Epub 2012 Sep 7.
Lasater EA, Bessler WK, Mead LE, Horn WE, Clapp DW, Conway SJ, Ingram DA, Li F. Nf1+/- mice have increased neointima formation via hyperactivation of a Gleevec sensitive molecular pathway. Hum Mol Genet. 2008 Aug 1;17(15):2336-44. doi: 10.1093/hmg/ddn134. Epub 2008 Apr 28.
McCormick F. Ras signaling and NF1. Curr Opin Genet Dev. 1995 Feb;5(1):51-5. doi: 10.1016/s0959-437x(95)90053-5.
Sherman LS, Atit R, Rosenbaum T, Cox AD, Ratner N. Single cell Ras-GTP analysis reveals altered Ras activity in a subpopulation of neurofibroma Schwann cells but not fibroblasts. J Biol Chem. 2000 Sep 29;275(39):30740-5. doi: 10.1074/jbc.M001702200.
Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003 Jan;3(1):11-22. doi: 10.1038/nrc969.
Weiss B, Bollag G, Shannon K. Hyperactive Ras as a therapeutic target in neurofibromatosis type 1. Am J Med Genet. 1999 Mar 26;89(1):14-22.
Wu J, Dombi E, Jousma E, Scott Dunn R, Lindquist D, Schnell BM, Kim MO, Kim A, Widemann BC, Cripe TP, Ratner N. Preclincial testing of sorafenib and RAD001 in the Nf(flox/flox) ;DhhCre mouse model of plexiform neurofibroma using magnetic resonance imaging. Pediatr Blood Cancer. 2012 Feb;58(2):173-80. doi: 10.1002/pbc.23015. Epub 2011 Feb 11.
Kissil JL, Blakeley JO, Ferner RE, Huson SM, Kalamarides M, Mautner VF, McCormick F, Morrison H, Packer R, Ramesh V, Ratner N, Rauen KA, Stevenson DA, Hunter-Schaedle K, North K. What's new in neurofibromatosis? Proceedings from the 2009 NF Conference: new frontiers. Am J Med Genet A. 2010 Feb;152A(2):269-83. doi: 10.1002/ajmg.a.33189.
Yang FC, Ingram DA, Chen S, Zhu Y, Yuan J, Li X, Yang X, Knowles S, Horn W, Li Y, Zhang S, Yang Y, Vakili ST, Yu M, Burns D, Robertson K, Hutchins G, Parada LF, Clapp DW. Nf1-dependent tumors require a microenvironment containing Nf1+/-- and c-kit-dependent bone marrow. Cell. 2008 Oct 31;135(3):437-48. doi: 10.1016/j.cell.2008.08.041.
Jessen WJ, Miller SJ, Jousma E, Wu J, Rizvi TA, Brundage ME, Eaves D, Widemann B, Kim MO, Dombi E, Sabo J, Hardiman Dudley A, Niwa-Kawakita M, Page GP, Giovannini M, Aronow BJ, Cripe TP, Ratner N. MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors. J Clin Invest. 2013 Jan;123(1):340-7. doi: 10.1172/JCI60578. Epub 2012 Dec 10.
Chang T, Krisman K, Theobald EH, Xu J, Akutagawa J, Lauchle JO, Kogan S, Braun BS, Shannon K. Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice. J Clin Invest. 2013 Jan;123(1):335-9. doi: 10.1172/JCI63193. Epub 2012 Dec 10. Erratum In: J Clin Invest. 2016 Jan;126(1):404. doi: 10.1172/JCI85325.
Nutakki K, Hingtgen CM, Monahan P, Varni JW, Swigonski NL. Development of the adult PedsQL neurofibromatosis type 1 module: initial feasibility, reliability and validity. Health Qual Life Outcomes. 2013 Feb 21;11:21. doi: 10.1186/1477-7525-11-21.
Rosser T, Packer RJ. Neurofibromas in children with neurofibromatosis 1. J Child Neurol. 2002 Aug;17(8):585-91; discussion 602-4, 646-51. doi: 10.1177/088307380201700808.
Le LQ, Parada LF. Tumor microenvironment and neurofibromatosis type I: connecting the GAPs. Oncogene. 2007 Jul 12;26(32):4609-16. doi: 10.1038/sj.onc.1210261. Epub 2007 Feb 12.
Prada CE, Jousma E, Rizvi TA, Wu J, Dunn RS, Mayes DA, Cancelas JA, Dombi E, Kim MO, West BL, Bollag G, Ratner N. Neurofibroma-associated macrophages play roles in tumor growth and response to pharmacological inhibition. Acta Neuropathol. 2013 Jan;125(1):159-68. doi: 10.1007/s00401-012-1056-7. Epub 2012 Oct 26.
Wolkenstein P, Zeller J, Revuz J, Ecosse E, Leplege A. Quality-of-life impairment in neurofibromatosis type 1: a cross-sectional study of 128 cases. Arch Dermatol. 2001 Nov;137(11):1421-5. doi: 10.1001/archderm.137.11.1421.

المصدر: Development and Validation of Patient Reported Outcome (PRO) Measures for Individuals With Neurofibromatosis 1 (NF1) and Plexiform Neurofibromas (pNFs)

المصدر: Transformation of Plexiform Neurofibromas to Malignant Peripheral Nerve Sheath Tumors in Neurofibromatosis Type 1: Clinical, Histopathologic, and Genomic Analysis
Benz MR, Czernin J, Dry SM, Tap WD, Allen-Auerbach MS, Elashoff D, Phelps ME, Weber WA, Eilber FC. Quantitative F18-fluorodeoxyglucose positron emission tomography accurately characterizes peripheral nerve sheath tumors as malignant or benign. Cancer. 2010 Jan 15;116(2):451-8. doi: 10.1002/cncr.24755. Erratum In: Cancer. 2010 Feb 1;116(3):775.
Meany H, Dombi E, Reynolds J, Whatley M, Kurwa A, Tsokos M, Salzer W, Gillespie A, Baldwin A, Derdak J, Widemann B. 18-fluorodeoxyglucose-positron emission tomography (FDG-PET) evaluation of nodular lesions in patients with Neurofibromatosis type 1 and plexiform neurofibromas (PN) or malignant peripheral nerve sheath tumors (MPNST). Pediatr Blood Cancer. 2013 Jan;60(1):59-64. doi: 10.1002/pbc.24212. Epub 2012 May 29.
Salskov A, Tammisetti VS, Grierson J, Vesselle H. FLT: measuring tumor cell proliferation in vivo with positron emission tomography and 3'-deoxy-3'-[18F]fluorothymidine. Semin Nucl Med. 2007 Nov;37(6):429-39. doi: 10.1053/j.semnuclmed.2007.08.001. Erratum In: Semin Nucl Med. 2008 Mar;38(2):148.

المصدر: Real-World Treatment Study of Koselugo (Selumetinib)

Other URLs: https://vivli.org/

المصدر: Observational Study of the Effectiveness and Safety of the MEK 1/2 Inhibitor (MEKi) Koselugo (Selumetinib) in Pediatric Patients With Symptomatic, Inoperable, Neurofibromatosis Type 1 (NF1)-Associated Plexiform Neurofibromas (PN)

Other URLs: https://vivli.org/

المؤلفون: Van Andel Research Institute

المساهمون: Matthew Steensma, Dr. Matthew Steensma

المصدر: Targeting the Mechanisms Underlying Cutaneous Neurofibroma Formation in NF1: a Clinical Translational Approach.

المساهمون: Yi Ji, Principal Investigator

المصدر: The Efficacy, Safety, and Long-Term Prognosis of Low-Dose Selumetinib in the Treatment of Neurofibromatosis Type 1 Associated Plexiform Neurofibromas in Chinese Children: a Multicenter Randomized Controlled Trial
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 Oct 3;25(10):1883-1894. doi: 10.1093/neuonc/noad086.
Kim H, Yoon HM, Kim EK, Ra YS, Kim HW, Yum MS, Kim MJ, Baek JS, Sung YS, Lee SM, Lim HS, Lee BJ, Lim HT, Kim D, Yoon J, Bae H, Hwang S, Choi YH, Kim KA, Choi IH, Lee SW, Park SJ, Lee BH. Safety and efficacy of selumetinib in pediatric and adult patients with neurofibromatosis type 1 and plexiform neurofibroma. Neuro Oncol. 2024 Dec 5;26(12):2352-2363. doi: 10.1093/neuonc/noae121.
Gross AM, Glassberg B, Wolters PL, Dombi E, Baldwin A, Fisher MJ, Kim A, Bornhorst M, Weiss BD, Blakeley JO, Whitcomb P, Paul SM, Steinberg SM, Venzon DJ, Martin S, Carbonell A, Heisey K, Therrien J, Kapustina O, Dufek A, Derdak J, Smith MA, Widemann BC. Selumetinib in children with neurofibromatosis type 1 and asymptomatic inoperable plexiform neurofibroma at risk for developing tumor-related morbidity. Neuro Oncol. 2022 Nov 2;24(11):1978-1988. doi: 10.1093/neuonc/noac109.
Yang X, Yoo HK, Amin S, Cheng WY, Sundaresan S, Zhang L, Duh MS. Clinical and humanistic burden among pediatric patients with neurofibromatosis type 1 and plexiform neurofibroma in the USA. Childs Nerv Syst. 2022 Aug;38(8):1513-1522. doi: 10.1007/s00381-022-05513-8. Epub 2022 May 17.
Gross AM, Wolters PL, Dombi E, Baldwin A, Whitcomb P, Fisher MJ, Weiss B, Kim A, Bornhorst M, Shah AC, Martin S, Roderick MC, Pichard DC, Carbonell A, Paul SM, Therrien J, Kapustina O, Heisey K, Clapp DW, Zhang C, Peer CJ, Figg WD, Smith M, Glod J, Blakeley JO, Steinberg SM, Venzon DJ, Doyle LA, Widemann BC. Selumetinib in Children with Inoperable Plexiform Neurofibromas. N Engl J Med. 2020 Apr 9;382(15):1430-1442. doi: 10.1056/NEJMoa1912735. Epub 2020 Mar 18. Erratum In: N Engl J Med. 2020 Sep 24;383(13):1290. doi: 10.1056/NEJMx200013.
Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, Whitcomb P, Martin S, Aschbacher-Smith LE, Rizvi TA, Wu J, Ershler R, Wolters P, Therrien J, Glod J, Belasco JB, Schorry E, Brofferio A, Starosta AJ, Gillespie A, Doyle AL, Ratner N, Widemann BC. Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas. N Engl J Med. 2016 Dec 29;375(26):2550-2560. doi: 10.1056/NEJMoa1605943.

المؤلفون: Children's Hospital of Philadelphia, Congressionally Directed Medical Research Programs

المساهمون: Girish Dhall, MD, Chair of NFCTC

المصدر: Phase 2 Trial of Selumetinib for the Prevention of Plexiform Neurofibroma Growth and Morbidity in Neurofibromatosis Type 1

المؤلفون: Merck Sharp & Dohme LLC

المصدر: A Phase I, Single-Arm, Sequential Study to Evaluate the Effect of Food on the Gastrointestinal Tolerability and Pharmacokinetics of Selumetinib After Multiple Doses in Adolescent Children With Neurofibromatosis Type 1 Related Plexiform Neurofibromas

Other URLs: https://astrazenecagroup-dt.pharmacm.com/DT/Home

المصدر: Natural History Study and Longitudinal Assessment of Children, Adolescents, and Adults With Neurofibromatosis Type 1
Ferner RE. Neurofibromatosis 1 and neurofibromatosis 2: a twenty first century perspective. Lancet Neurol. 2007 Apr;6(4):340-51. doi: 10.1016/S1474-4422(07)70075-3.
Korf BR. Clinical features and pathobiology of neurofibromatosis 1. J Child Neurol. 2002 Aug;17(8):573-7; discussion 602-4, 646-51. doi: 10.1177/088307380201700806.
Kim A, Gillespie A, Dombi E, Goodwin A, Goodspeed W, Fox E, Balis FM, Widemann BC. Characteristics of children enrolled in treatment trials for NF1-related plexiform neurofibromas. Neurology. 2009 Oct 20;73(16):1273-9. doi: 10.1212/WNL.0b013e3181bd1326.
Curry BP, Alvarez R, Widemann BC, Johnson M, Agarwal PK, Lehky T, Valera V, Chittiboina P. Robotic Nerve Sheath Tumor Resection With Intraoperative Neuromonitoring: Case Series and Systematic Review. Oper Neurosurg (Hagerstown). 2022 Feb 1;22(2):44-50. doi: 10.1227/ONS.0000000000000051.
Akshintala S, Baldwin A, Liewehr DJ, Goodwin A, Blakeley JO, Gross AM, Steinberg SM, Dombi E, Widemann BC. Longitudinal evaluation of peripheral nerve sheath tumors in neurofibromatosis type 1: growth analysis of plexiform neurofibromas and distinct nodular lesions. Neuro Oncol. 2020 Sep 29;22(9):1368-1378. doi: 10.1093/neuonc/noaa053.
Dagalakis U, Lodish M, Dombi E, Sinaii N, Sabo J, Baldwin A, Steinberg SM, Stratakis CA, Widemann BC. Puberty and plexiform neurofibroma tumor growth in patients with neurofibromatosis type I. J Pediatr. 2014 Mar;164(3):620-4. doi: 10.1016/j.jpeds.2013.10.081. Epub 2013 Dec 8.

المؤلفون: Merck Sharp & Dohme LLC

المصدر: A Phase III, Multicentre, International Study With a Parallel, Randomised, Double-blind, Placebo-controlled, 2 Arm Design to Assess the Efficacy and Safety of Selumetinib in Adult Participants With NF1 Who Have Symptomatic, Inoperable Plexiform Neurofibromas (KOMET)

Other URLs: https://astrazenecagroup-dt.pharmacm.com/DT/Home

المصدر: Phase I Trial of TURALIO (Pexidartinib, PLX3397) in Children and Young Adults With Refractory Leukemias and Refractory Solid Tumors Including Neurofibromatosis Type 1 (NF1) Associated Plexiform Neurofibromas (PN) and Tenosynovial Giant Cell Tumor (TGCT)

المؤلفون: Merck Sharp & Dohme LLC

المصدر: A Phase 1 Open Label Study to Assess the Safety, Tolerability, Pharmacokinetics and Clinical Efficacy of Selumetinib, a Selective Mitogen Activated Protein Kinase Kinase (MEK) 1 Inhibitor, in Chinese Paediatric and Adult Subjects With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (PN)

Other URLs: https://astrazenecagroup-dt.pharmacm.com/DT/Home

المصدر: A Multi-center, Open-label, Single-arm Phase I Dose-escalation and Phase II Dose-expansion Study to Evaluate the Safety, Tolerability, PK Characteristics and Anti-tumor Activity of FCN-159 in Adult and Pediatric Participants With Neurofibromatosis Type 1

المصدر: A Multi-Center Phase I Dose Escalation Study of Avutometinib, a RAF/MEK Clamp, in Pediatric Patients With Refractory or Recurrent Solid Tumors Harboring Activating MAPK Pathway Alterations

المصدر: A Phase 2b Trial of the MEK 1/2 Inhibitor (MEKi) PD-0325901 in Adult and Pediatric Patients With Neurofibromatosis Type 1 (NF1)-Associated Inoperable Plexiform Neurofibromas (PNs) That Are Causing Significant Morbidity

المصدر: US Selumetinib Registry