MEK inhibitors for neurofibromatosis type 1 manifestations: Clinical evidence and consensus

Author:

de Blank Peter M K1ORCID,Gross Andrea M2ORCID,Akshintala Srivandana2,Blakeley Jaishri O3ORCID,Bollag Gideon4,Cannon Ashley5,Dombi Eva2ORCID,Fangusaro Jason6,Gelb Bruce D7,Hargrave Darren8,Kim AeRang9ORCID,Klesse Laura J10,Loh Mignon11,Martin Staci2,Moertel Christopher12,Packer Roger9,Payne Jonathan M13,Rauen Katherine A14,Rios Jonathan J15,Robison Nathan16,Schorry Elizabeth K1,Shannon Kevin11,Stevenson David A17,Stieglitz Elliot11,Ullrich Nicole J18,Walsh Karin S9,Weiss Brian D1,Wolters Pamela L2,Yohay Kaleb19,Yohe Marielle E2,Widemann Brigitte C2,Fisher Michael J20

Affiliation:

1. Department of Pediatrics, University of Cincinnati and Cincinnati Children’s Hospital Medical Center , Cincinnati, Ohio , USA

2. Pediatric Oncology Branch, National Cancer Institute , Bethesda, Maryland , USA

3. Department of Neurology, Johns Hopkins University , Baltimore, Maryland , USA

4. Plexxikon Inc. , Berkeley, California , USA

5. Department of Genetics, University of Alabama at Birmingham , Birmingham, Alabama , USA

6. Children’s Hospital of Atlanta, Emory University and the Aflac Cancer Center , Atlanta, Georgia , USA

7. Department of Pediatrics and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai , New York, New York , USA

8. Department of Oncology, Great Ormond Street Hospital for Children , London , UK

9. Center for Neuroscience and Behavioral Medicine and Center for Cancer and Blood Disorders, Children’s National Hospital , Washington, DC , USA

10. Department of Pediatrics, Division of Hematology/Oncology, UT Southwestern Medical Center , Dallas, Texas , USA

11. Benioff Children’s Hospital, University of California San Francisco , San Francisco, California , USA

12. Department of Pediatrics, University of Minnesota , Minneapolis, Minnesota , USA

13. Murdoch Children’s Research Institute, The Royal Children’s Hospital , Parkville, Victoria , Australia

14. Department of Pediatrics, University of California Davis , Sacramento, California , USA

15. Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children , Dallas, Texas , USA

16. Children’s Center for Cancer and Blood Diseases, Children’s Hospital Los Angeles , Los Angeles, California , USA

17. Department of Pediatrics, Division of Medical Genetics, Stanford University , Stanford, California , USA

18. Department of Neurology, Boston Children’s Hospital , Boston, Massachusetts , USA

19. Department of Neurology and Pediatrics, New York University Grossman School of Medicine , New York, New York , USA

20. Division of Oncology, The Children’s Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine , Philadelphia, Pennsylvania , USA

Abstract

Abstract The wide variety of clinical manifestations of the genetic syndrome neurofibromatosis type 1 (NF1) are driven by overactivation of the RAS pathway. Mitogen-activated protein kinase kinase inhibitors (MEKi) block downstream targets of RAS. The recent regulatory approvals of the MEKi selumetinib for inoperable symptomatic plexiform neurofibromas in children with NF1 have made it the first medical therapy approved for this indication in the United States, the European Union, and elsewhere. Several recently published and ongoing clinical trials have demonstrated that MEKi may have potential benefits for a variety of other NF1 manifestations, and there is broad interest in the field regarding the appropriate clinical use of these agents. In this review, we present the current evidence regarding the use of existing MEKi for a variety of NF1-related manifestations, including tumor (neurofibromas, malignant peripheral nerve sheath tumors, low-grade glioma, and juvenile myelomonocytic leukemia) and non-tumor (bone, pain, and neurocognitive) manifestations. We discuss the potential utility of MEKi in related genetic conditions characterized by overactivation of the RAS pathway (RASopathies). In addition, we review practical treatment considerations for the use of MEKi as well as provide consensus recommendations regarding their clinical use from a panel of experts.

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Neurology (clinical),Oncology

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