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

被引：56

作者：

de Blank, Peter M. K. ^{[1
,2
]}

Gross, Andrea M. ^{[3
]}

Akshintala, Srivandana ^{[3
]}

Blakeley, Jaishri O. ^{[4
]}

Bollag, Gideon ^{[5
]}

Cannon, Ashley ^{[6
]}

Dombi, Eva ^{[3
]}

Fangusaro, Jason ^{[7
,8
]}

Gelb, Bruce D. ^{[9
,10
]}

Hargrave, Darren ^{[11
]}

Kim, AeRang ^{[12
,13
]}

Klesse, Laura J. ^{[14
]}

Loh, Mignon ^{[15
]}

Martin, Staci ^{[3
]}

Moertel, Christopher ^{[16
]}

Packer, Roger ^{[12
,13
]}

Payne, Jonathan M. ^{[17
]}

Rauen, Katherine A. ^{[18
]}

Rios, Jonathan J. ^{[19
]}

Robison, Nathan ^{[20
]}

Schorry, Elizabeth K. ^{[1
,2
]}

Shannon, Kevin ^{[15
]}

Stevenson, David A. ^{[21
]}

Stieglitz, Elliot ^{[15
]}

Ullrich, Nicole J. ^{[22
]}

Walsh, Karin S. ^{[12
,13
]}

Weiss, Brian D. ^{[1
,2
]}

Wolters, Pamela L. ^{[3
]}

Yohay, Kaleb ^{[23
]}

Yohe, Marielle E. ^{[3
]}

Widemann, Brigitte C. ^{[3
]}

Fisher, Michael J. ^{[24
,25
]}

机构：

[1] Univ Cincinnati, Dept Pediat, Cincinnati, OH USA

[2] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA

[3] NCI, Pediat Oncol Branch, 10 Ctr Dr,Room 1-5742, Bethesda, MD 20892 USA

[4] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA

[5] Plexxikon Inc, Berkeley, CA USA

[6] Univ Alabama Birmingham, Birmingham, AL USA

[7] Emory Univ, Childrens Hosp Atlanta, Atlanta, GA 30322 USA

[8] Aflac Canc Ctr, Atlanta, GA USA

[9] Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY 10029 USA

[10] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[11] Great Ormond St Hosp Sick Children, Dept Oncol, London, England

[12] Childrens Natl Hosp, Ctr Neurosci & Behav Med, Washington, DC USA

[13] Childrens Natl Hosp, Ctr Canc & Blood Disorders, Washington, DC USA

[14] UT Southwestern Med Ctr, Dept Pediat, Div Hematol Oncol, Dallas, TX USA

[15] Univ Calif San Francisco, Benioff Childrens Hosp, San Francisco, CA 94143 USA

[16] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA

[17] Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic, Australia

[18] Univ Calif Davis, Dept Pediat, Sacramento, CA 95817 USA

[19] Scottish Rite Children, Ctr Pediat Bone Biol & Translat Res, Dallas, TX USA

[20] Childrens Hosp Los Angeles, Childrens Ctr Canc & Blood Dis, Los Angeles, CA 90027 USA

[21] Stanford Univ, Dept Pediat, Div Med Genet, Stanford, CA 94305 USA

[22] Boston Childrens Hosp, Dept Neurol, Boston, MA USA

[23] NYU, Grossman Sch Med, New York, NY USA

[24] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA

[25] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA

来源：

NEURO-ONCOLOGY | 2022年 / 24卷 / 11期

关键词：

low-grade glioma; MEK inhibitors; neurofibromatosis type 1; plexiform neurofibromas; RASopathy; NERVE SHEATH TUMORS; PHASE-II TRIAL; PLEXIFORM NEUROFIBROMAS; NOONAN SYNDROME; MOUSE MODELS; COSTELLO SYNDROME; DOSE-ESCALATION; P-GLYCOPROTEIN; CHILDREN; NF1;

D O I：

10.1093/neuonc/noac165

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：1845 / 1856

页数：12

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