Emerging therapeutic targets for neurofibromatosis type 1

References

• Upadhyaya M, Cooper DN. Molecular and Cellular Biology of Neurofibromatosis Type 1. Upadhyaya M, Cooper DN, Eds. Springer Verlag, Heidelberg; 2012.
   Google Scholar
• Upadhyaya M. Neurofibromatosis type 1: diagnosis and recent advances. Expert Opin Med Diagn. 2010 Jul;4(4):307–322.
   PubMedGoogle Scholar
• Evans DG, Baser ME, McGaughran J, et al. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. 2002 May;39(5):311–314.
   PubMed Web of Science ®Google Scholar
• Farid M, Demicco EG, Garcia R, et al. Malignant peripheral nerve sheath tumors. Oncologist. 2014 Feb;19(2):193–201.
   PubMed Web of Science ®Google Scholar
• Gutmann DH, Ferner RE, Listernick RH, et al. Neurofibromatosis type 1. Nat Rev Dis Primers. 2017 Feb 23;3:17004.
   PubMed Web of Science ®Google Scholar
• Tidyman WE, Rauen KA. Pathogenetics of the RASopathies. Hum Mol Genet. 2016 Oct 1; 25(R2):R123–R32.
   PubMed Web of Science ®Google Scholar
• Mautner VF, Asuagbor FA, Dombi E, et al. Assessment of benign tumor burden by whole-body MRI in patients with neurofibromatosis 1. Neuro Oncol. 2008 Aug;10(4):593–598.
   PubMed Web of Science ®Google Scholar
• Miettinen MM, Antonescu CR, Fletcher CDM, et al. Histopathologic evaluation of atypical neurofibromatous tumors and their transformation into malignant peripheral nerve sheath tumor in patients with neurofibromatosis 1-a consensus overview. Hum Pathol. 2017;67:1–10.
   PubMed Web of Science ®Google Scholar
• Beert E, Brems H, Daniels B, et al. Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors. Genes Chromosomes Cancer. 2011 Dec;50(12):1021–1032.
   PubMed Web of Science ®Google Scholar
• Acosta MT, Gioia GA, Silva AJ. Neurofibromatosis type 1: new insights into neurocognitive issues. Curr Neurol Neurosci Rep. 2006 Mar;6(2):136–143.
   PubMed Web of Science ®Google Scholar
• Mautner VF, Kluwe L, Thakker SD, et al. Treatment of ADHD in neurofibromatosis type 1. Dev Med Child Neurol. 2002 Mar;44(3):164–170.
   PubMed Web of Science ®Google Scholar
• Thomas PK, King RH, Chiang TR, et al. Neurofibromatous neuropathy. Muscle Nerve. 1990 Feb;13(2):93–101.
   PubMed Web of Science ®Google Scholar
• Brems H, Legius E. Legius syndrome, an Update Molecular pathology of mutations in SPRED1. Keio J Med. 2013;62(4):107–112.
   PubMedGoogle Scholar
• Garcia-Romero MT, Parkin P. Lara-Corrales I. Mosaic Neurofibromatosis Type 1: A Systematic Review. Pediatr Dermatol. 2016 Jan-Feb;33(1):9–17.
   PubMed Web of Science ®Google Scholar
• Messiaen LM, Callens T, Mortier G, et al. Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Hum Mutat. 2000;15(6):541–555.
   PubMed Web of Science ®Google Scholar
• Messiaen LM, Wimmer K. NF1 Mutational Spectrum. In: Kaufmann D, Edited by. Neurofibromatoses. Karger, Basel; 2008. p. 63–77.
   Google Scholar
• Legius E, Dierick H, Wu R, et al. TP53 mutations are frequent in malignant NF1 tumors. Genes Chromosomes Cancer. 1994 Aug;10(4):250–255.
   PubMed Web of Science ®Google Scholar
• De Raedt T, Beert E, Pasmant E, et al. PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct 9;514(7521):247–251.
   PubMed Web of Science ®Google Scholar
• Lee W, Teckie S, Wiesner T, et al. PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nat Genet. 2014 Nov;46(11):1227–1232.
   PubMed Web of Science ®Google Scholar
• Philpott C, Tovell H, Frayling IM, et al. The NF1 somatic mutational landscape in sporadic human cancers. Hum Genomics. 2017 Jun 21;11(1):13.
   PubMedGoogle Scholar
• Pasmant E, Sabbagh A, Spurlock G, et al. NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype. Hum Mutat. 2010 Jun;31(6):E1506E1518.
   Web of Science ®Google Scholar
• Zhang M, Wang Y, Jones S, et al. Somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors. Nat Genet. 2014 Nov;46(11):1170–1172.
   PubMed Web of Science ®Google Scholar
• Pinna V, Lanari V, Daniele P, et al. p.Arg1809Cys substitution in neurofibromin is associated with a distinctive NF1 phenotype without neurofibromas. Eur J Hum Genet. 2015 Aug;23(8):1068–1071.
   PubMed Web of Science ®Google Scholar
• Upadhyaya M, Huson SM, Davies M, et al. An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.29702972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation. Am J Hum Genet. 2007 Jan;80(1):140–151.
   PubMed Web of Science ®Google Scholar
• Rojnueangnit K, Xie J, Gomes A, et al. High incidence of Noonan syndrome features including short stature and pulmonic stenosis in patients carrying NF1 missense mutations affecting p.Arg1809: genotype-phenotype correlation. Hum Mutat. 2015 Nov;36(11):1052–1063.
   PubMed Web of Science ®Google Scholar
• Koczkowska M, Chen Y, Callens T, et al. Genotype-phenotype correlation in NF1: evidence for a more severe phenotype associated with missense mutations affecting NF1 Codons 844848. Am J Hum Genet. 2018 Jan 4;102(1):69–87.
   PubMed Web of Science ®Google Scholar
• Easton DF, Ponder MA, Huson SM, et al. An analysis of variation in expression of neurofibromatosis (NF) type 1 (NF1): evidence for modifying genes. Am J Hum Genet. 1993 Aug;53(2):305–313.
   PubMed Web of Science ®Google Scholar
• Rieley MB, Stevenson DA, Viskochil DH, et al. Variable expression of neurofibromatosis 1 in monozygotic twins. Am J Med Genet A. 2011 Mar;155A(3):478–485.
   PubMed Web of Science ®Google Scholar
• Sabbagh A, Pasmant E, Laurendeau I, et al. Unravelling the genetic basis of variable clinical expression in neurofibromatosis 1. Hum Mol Genet. 2009 Aug 1;18(15):2768–2778.
   PubMed Web of Science ®Google Scholar
• Martin GA, Viskochil D, Bollag G, et al. The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell. 1990 Nov 16;63(4):843–849.
   PubMed Web of Science ®Google Scholar
• Simanshu DK, Nissley DV, McCormick F, et al. Their regulators in human disease. Cell. 2017 Jun 29;170(1):17–33.
   PubMed Web of Science ®Google Scholar
• Ohba Y, Mochizuki N, Yamashita S, et al. Regulatory proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3. J Biol Chem. 2000 Jun 30;275(26):20020–20026.
   PubMed Web of Science ®Google Scholar
• Johannessen CM, Reczek EE, James MF, et al. The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8573–8578.
   PubMed Web of Science ®Google Scholar
• Shilyansky C, Lee YS, Silva AJ. Molecular and cellular mechanisms of learning disabilities: a focus on NF1. Annu Rev Neurosci. 2010;33:221–243.
   PubMed Web of Science ®Google Scholar
• Dunzendorfer-Matt T, Mercado EL, Maly K, et al. The neurofibromin recruitment factor Spred1 binds to the GAP related domain without affecting Ras inactivation. Proc Natl Acad Sci U S A. 2016 Jul 5;113(27):7497–7502.
   PubMed Web of Science ®Google Scholar
• Keeling KM, Xue X, Gunn G, et al. Therapeutics based on stop codon readthrough. Annu Rev Genomics Hum Genet. 2014;15:371–394.
   PubMed Web of Science ®Google Scholar
• Lee HL, Dougherty JP. Pharmaceutical therapies to recode nonsense mutations in inherited diseases. Pharmacol Ther. 2012 Nov;136(2):227–266.
   PubMed Web of Science ®Google Scholar
• Pros E, Fernandez-Rodriguez J, Canet B, et al. Antisense therapeutics for neurofibromatosis type 1 caused by deep intronic mutations. Hum Mutat. 2009 Mar;30(3):454–462.
   PubMed Web of Science ®Google Scholar
• Nelson CE, Gersbach CA. Engineering delivery vehicles for genome editing. Annu Rev Chem Biomol Eng. 2016 Jun;7(7):637–662.
   PubMedGoogle Scholar
• Liang XH, Sun H, Shen W, et al. Antisense oligonucleotides targeting translation inhibitory elements in 5ʹ UTRs can selectively increase protein levels. Nucleic Acids Res. 2016 Sep 19;45(16):9528–9546.
   Web of Science ®Google Scholar
• Gori JL, Hsu PD, Maeder ML, et al. Delivery and specificity of CRISPR-Cas9 genome editing technologies for human gene therapy. Hum Gene Ther. 2015 Jul;26(7):443–451.
   PubMed Web of Science ®Google Scholar
• Hanemann CO, Blakeley JO, Nunes FP, et al. Current status and recommendations for biomarkers and biobanking in neurofibromatosis. Neurology. 2016 Aug 16;87(7 Suppl 1):S40S48.
   Google Scholar
• Jones RE, Grimstead JW, Sedani A, et al. Telomere erosion in NF1 tumorigenesis. Oncotarget. 2017 Jun 20;8(25):40132–40139.
   PubMedGoogle Scholar
• Mantripragada KK, Caley M, Stephens P, et al. Telomerase activity is a biomarker for high grade malignant peripheral nerve sheath tumors in neurofibromatosis type 1 individuals. Genes Chromosomes Cancer. 2008 Mar;47(3):238–246.
   PubMed Web of Science ®Google Scholar
• Klochkov SG, Neganova ME, Yarla NS, et al. Implications of farnesyltransferase and its inhibitors as a promising strategy for cancer therapy. Semin Cancer Biol. 2017 Oct 31, pii: S1044-579X (17)30044-5. doi: 10.1016/j.semcancer.2017.10.010.
   PubMedGoogle Scholar
• Baines AT, Xu D, Der CJ. Inhibition of Ras for cancer treatment: the search continues. Future Med Chem. 2011 Oct;3(14):1787–1808.
   PubMed Web of Science ®Google Scholar
• Bakker AC, La Rosa S, Sherman LS, et al. Neurofibromatosis as a gateway to better treatment for a variety of malignancies. Prog Neurobiol. 2017;152:149–165.
   PubMed Web of Science ®Google Scholar
• Ostrem JM, Shokat KM. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat Rev Drug Discov. 2016 Nov;15(11):771–785.
   PubMed Web of Science ®Google Scholar
• Holderfield M. Efforts to Develop KRAS Inhibitors. Cold Spring Harb Perspect Med. 2017 Nov 3.
   PubMedGoogle Scholar
• Athuluri-Divakar SK, Vasquez-Del Carpio R, Dutta K, et al. A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling. Cell. 2016 Apr 21;165(3):643–655.
   PubMed Web of Science ®Google Scholar
• Dombi E, Baldwin A, Marcus LJ, et al. Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas. N Engl J Med. 2016 Dec 29;375(26):2550–2560.
   PubMed Web of Science ®Google Scholar
• Jessen WJ, Miller SJ, Jousma E, et al. MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors. J Clin Invest. 2013 Jan;123(1):340–347.
   PubMed Web of Science ®Google Scholar
• Jousma E, Rizvi TA, Wu J, et al. Preclinical assessments of the MEK inhibitor PD-0325901 in a mouse model of Neurofibromatosis type 1. Pediatr Blood Cancer. 2015 Oct;62(10):1709–1716.
   PubMed Web of Science ®Google Scholar
• Chang T, Krisman K, Theobald EH, et al. Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice. J Clin Invest. 2013 Jan;123(1):335–339.
   PubMed Web of Science ®Google Scholar
• Lake D, Correa SA, Muller J. Negative feedback regulation of the ERK1/2 MAPK pathway. Cell Mol Life Sci. 2016 Dec;73(23):4397–4413.
   PubMed Web of Science ®Google Scholar
• Nissan MH, Rosen N, Solit DB. ERK pathway inhibitors: how low should we go? Cancer Discov. 2013 Jul;3(7):719–721.
   PubMed Web of Science ®Google Scholar
• Johannessen CM, Johnson BW, Williams SM, et al. TORC1 is essential for NF1-associated malignancies. Curr Biol. 2008 Jan 8;18(1):56–62.
   PubMed Web of Science ®Google Scholar
• Hegedus B, Banerjee D, Yeh TH, et al. Preclinical cancer therapy in a mouse model of neurofibromatosis-1 optic glioma. Cancer Res. 2008 Mar 1;68(5):1520–1528.
   PubMed Web of Science ®Google Scholar
• Watson AL, Anderson LK, Greeley AD, et al. Co-targeting the MAPK and PI3K/AKT/mTOR pathways in two genetically engineered mouse models of schwann cell tumors reduces tumor grade and multiplicity. Oncotarget. 2014 Mar 30;5(6):1502–1514.
   PubMedGoogle Scholar
• Malone CF, Fromm JA, Maertens O, et al. Defining key signaling nodes and therapeutic biomarkers in NF1-mutant cancers. Cancer Discov. 2014 Sep;4(9):1062–1073.
   PubMed Web of Science ®Google Scholar
• Massacesi C, Di Tomaso E, Urban P, et al. PI3K inhibitors as new cancer therapeutics: implications for clinical trial design. Onco Targets Ther. 2016;9:203–210.
   PubMed Web of Science ®Google Scholar
• Upadhyaya M, Spurlock G, Thomas L, et al. Microarray-based copy number analysis of neurofibromatosis type-1 (NF1)-associated malignant peripheral nerve sheath tumors reveals a role for Rho-GTPase pathway genes in NF1 tumorigenesis. Hum Mutat. 2012 Apr;33(4):763–776.
   PubMed Web of Science ®Google Scholar
• Yang FC, Ingram DA, Chen S, et al. Nf1-dependent tumors require a microenvironment containing Nf1+/– and c-kit-dependent bone marrow. Cell. 2008 Oct 31;135(3):437–448.
   PubMed Web of Science ®Google Scholar
• Demestre M, Herzberg J, Holtkamp N, et al. Imatinib mesylate (Glivec) inhibits Schwann cell viability and reduces the size of human plexiform neurofibroma in a xenograft model. J Neurooncol. 2010 May;98(1):11–19.
   PubMed Web of Science ®Google Scholar
• Robertson KA, Nalepa G, Yang FC, et al. Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial. Lancet Oncol. 2012 Dec;13(12):1218–1224.
   PubMed Web of Science ®Google Scholar
• Gesundheit B, Parkin P, Greenberg M, et al. The role of angiogenesis in the transformation of plexiform neurofibroma into malignant peripheral nerve sheath tumors in children with neurofibromatosis type 1. J Pediatr Hematol Oncol. 2010 Oct;32(7):548–553.
   PubMed Web of Science ®Google Scholar
• Rad E, Dodd K, Thomas L, et al. STAT3 and HIF1alpha signaling drives oncogenic cellular phenotypes in malignant peripheral nerve sheath tumors. Mol Cancer Res. 2015 Jul;13(7):1149–1160.
   PubMed Web of Science ®Google Scholar
• Luscan A, Shackleford G, Masliah-Planchon J, et al. The activation of the WNT signaling pathway is a Hallmark in neurofibromatosis type 1 tumorigenesis. Clin Cancer Res. 2013 Jan 15;20(2):358–371.
   PubMed Web of Science ®Google Scholar
• Mo W, Chen J, Patel A, et al. CXCR4/CXCL12 mediate autocrine cell- cycle progression in NF1-associated malignant peripheral nerve sheath tumors. Cell. 2013 Feb 28;152(5):1077–1090.
   PubMed Web of Science ®Google Scholar
• Wu J, Keng VW, Patmore DM, et al. Insertional mutagenesis identifies a STAT3/Arid1b/beta-catenin pathway driving neurofibroma initiation. Cell Rep. 2016 Mar 1;14(8):1979–1990.
   PubMed Web of Science ®Google Scholar
• Reilly KM, Kim A, Blakely J, et al. Neurofibromatosis type 1-associated MPNST state of the science: outlining a research agenda for the future. J Natl Cancer Inst. 2017 1;109(8):Aug.
   Google Scholar
• Kim A, Pratilas CA. The promise of signal transduction in genetically driven sarcomas of the nerve. Exp Neurol. 2018 Jan;299(Pt B):317–325.
   PubMedGoogle Scholar
• De Raedt T, Walton Z, Yecies JL, et al. Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors. Cancer Cell. 2011 Sep 13;20(3):400–413.
   PubMed Web of Science ®Google Scholar
• Malone CF, Emerson C, Ingraham R, et al. mTOR and HDAC inhibitors converge on the TXNIP/Thioredoxin pathway to cause catastrophic oxidative stress and regression of RAS-driven tumors. Cancer Discov. 2017 Dec;7(12):1450–1463.
   PubMed Web of Science ®Google Scholar
• Patel AJ, Liao CP, Chen Z, et al. BET bromodomain inhibition triggers apoptosis of NF1-associated malignant peripheral nerve sheath tumors through Bim induction. Cell Rep. 2014 Jan 16;6(1):81–92.
   PubMed Web of Science ®Google Scholar
• Varin J, Poulain L, Hivelin M, et al. Dual mTORC1/2 inhibition induces anti-proliferative effect in NF1-associated plexiform neurofibroma and malignant peripheral nerve sheath tumor cells. Oncotarget. 2016 Jun 14;7(24):35753–35767.
   PubMedGoogle Scholar
• Patel AV, Eaves D, Jessen WJ, et al. Ras-driven transcriptome analysis identifies aurora kinase A as a potential malignant peripheral nerve sheath tumor therapeutic target. Clin Cancer Res. 2012 Sep 15;18(18):5020–5030.
   PubMed Web of Science ®Google Scholar
• Patel AV, Chaney KE, Choi K, et al. An ShRNA screen identifies MEIS1 as a driver of malignant peripheral nerve sheath tumors. EBioMedicine. 2016 Jul;9:110–119.
   PubMed Web of Science ®Google Scholar
• Radu M, Semenova G, Kosoff R, et al. PAK signalling during the development and progression of cancer. Nat Rev Cancer. 2014 Jan;14(1):13–25.
   PubMed Web of Science ®Google Scholar
• Semenova G, Stepanova DS, Dubyk C, et al. Targeting group I p21-activated kinases to control malignant peripheral nerve sheath tumor growth and metastasis. Oncogene. 2017 Sep 21;36(38):5421–5431.
   PubMed Web of Science ®Google Scholar
• Fischer-Huchzermeyer S, Dombrowski A, Hagel C, et al. The cellular retinoic acid binding protein 2 promotes survival of malignant peripheral nerve sheath tumor cells. Am J Pathol. 2017 Jul;187(7):1623–1632.
   PubMed Web of Science ®Google Scholar
• Fischer-Huchzermeyer S, Dombrowski A, Wilke G, et al. MEK inhibitors enhance therapeutic response towards ATRA in NF1 associated malignant peripheral nerve sheath tumors (MPNST) in-vitro. PLoS One. 2017;12(11):e0187700.
   PubMed Web of Science ®Google Scholar
• Kobayashi D, Hirayama M, Komohara Y, et al. Translationally controlled tumor protein is a novel biological target for neurofibromatosis type 1-associated tumors. J Biol Chem. 2014 Sep 19;289(38):26314–26326.
   PubMed Web of Science ®Google Scholar
• Varelas X. The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease. Development. 2014 Apr;141(8):1614–1626.
   PubMed Web of Science ®Google Scholar
• Kim YH, Ohta T, Oh JE, et al. TP53, MSH4, and LATS1 germline mutations in a family with clustering of nervous system tumors. Am J Pathol. 2014 Sep;184(9):2374–2381.
   PubMed Web of Science ®Google Scholar
• Oh JE, Ohta T, Satomi K, et al. Alterations in the NF2/LATS1/LATS2/YAP pathway in schwannomas. J Neuropathol Exp Neurol. 2015 Oct;74(10):952–959.
   PubMed Web of Science ®Google Scholar
• Wu LMN, Deng Y, Wang J, et al. Programming of schwann cells by lats1/2-TAZ/YAP signaling drives malignant peripheral nerve sheath tumorigenesis. Cancer Cell. 2018 Feb 12;33(2):292–308 e7.
   PubMed Web of Science ®Google Scholar
• Chau V, Lim SK, Mo W, et al. Preclinical therapeutic efficacy of a novel pharmacologic inducer of apoptosis in malignant peripheral nerve sheath tumors. Cancer Res. 2014 Jan 15;74(2):586–597.
   PubMed Web of Science ®Google Scholar
• Oblinger JL, Burns SS, Akhmametyeva EM, et al. Components of the eIF4F complex are potential therapeutic targets for malignant peripheral nerve sheath tumors and vestibular schwannomas. Neuro Oncol. 2016 Sep;18(9):1265–1277.
   PubMed Web of Science ®Google Scholar
• Lee MJ, Cho JH, Galas DJ, et al. The systems biology of neurofibromatosis type 1–critical roles for microRNA. Exp Neurol. 2012 Jun;235(2):464–468.
   PubMed Web of Science ®Google Scholar
• Subramanian S, Thayanithy V, West RB, et al. Genome-wide transcriptome analyses reveal p53 inactivation mediated loss of miR-34a expression in malignant peripheral nerve sheath tumours. J Pathol. 2010 Jan;220(1):58–70.
   PubMed Web of Science ®Google Scholar
• Gong M, Ma J, Li M, et al. MicroRNA-204 critically regulates carcinogenesis in malignant peripheral nerve sheath tumors. Neuro Oncol. 2012 Aug;14(8):1007–1017.
   PubMed Web of Science ®Google Scholar
• Presneau N, Eskandarpour M, Shemais T, et al. MicroRNA profiling of peripheral nerve sheath tumours identifies miR-29c as a tumour suppressor gene involved in tumour progression. Br J Cancer. 2013 Mar 5;108(4):964–972.
   PubMed Web of Science ®Google Scholar
• Masliah-Planchon J, Pasmant E, Luscan A, et al. MicroRNAome profiling in benign and malignant neurofibromatosis type 1-associated nerve sheath tumors: evidences of PTEN pathway alterations in early NF1 tumorigenesis. BMC Genomics. 2013 Jul 13;14:473.
   PubMed Web of Science ®Google Scholar
• Staser K, Yang FC, Clapp DW. Pathogenesis of plexiform neurofibroma: tumor-stromal/hematopoietic interactions in tumor progression. Annu Rev Pathol. 2012;7:469–495.
   PubMed Web of Science ®Google Scholar
• Staser K, Yang FC, Clapp DW. Mast cells and the neurofibroma microenvironment. Blood. 2010 Jul 15;116(2):157–164.
   PubMed Web of Science ®Google Scholar
• Patwardhan PP, Surriga O, Beckman MJ, et al. Sustained inhibition of receptor tyrosine kinases and macrophage depletion by PLX3397 and rapamycin as a potential new approach for the treatment of MPNSTs. Clin Cancer Res. 2014 Jun 15;20(12):3146–3158.
   PubMed Web of Science ®Google Scholar
• Ribeiro S, Napoli I, White IJ, et al. Injury signals cooperate with Nf1 loss to relieve the tumor-suppressive environment of adult peripheral nerve. Cell Rep. 2013 Oct 17;5(1):126–136.
   PubMed Web of Science ®Google Scholar
• Pong WW, Higer SB, Gianino SM, et al. Reduced microglial CX3CR1 expression delays neurofibromatosis-1 glioma formation. Ann Neurol. 2013 Feb;73(2):303–308.
   PubMed Web of Science ®Google Scholar
• Choi K, Komurov K, Fletcher JS, et al. An inflammatory gene signature distinguishes neurofibroma Schwann cells and macrophages from cells in the normal peripheral nervous system. Sci Rep. 2017 Mar 3;7:43315.
   PubMed Web of Science ®Google Scholar
• Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018 Mar 23;359(6382):1350–1355.
   PubMed Web of Science ®Google Scholar
• Wang S, Liechty B, Patel S, et al. Programmed death ligand 1 expression and tumor infiltrating lymphocytes in neurofibromatosis type 1 and 2 associated tumors. J Neurooncol. 2018 Feb 9.
   Google Scholar
• Torres KC, Lima G, Simoes ESAC, et al. Immune markers in the RASopathy neurofibromatosis type 1. J Neuroimmunol. 2016 Jun 15;295296:122–129.
   Google Scholar
• Haworth KB, Arnold MA, Pierson CR, et al. Immune profiling of NF1-associated tumors reveals histologic subtype distinctions and heterogeneity: implications for immunotherapy. Oncotarget. 2017 Oct 10;8(47):82037–82048.
   PubMedGoogle Scholar
• Schulz A, Grafe P, Hagel C, et al. Neuropathies in the setting of Neurofibromatosis tumor syndromes: complexities and opportunities. Exp Neurol. 2018 Jan;299(Pt B):334–344.
   PubMedGoogle Scholar
• Moutal A, Wang Y, Yang X, et al. Dissecting the role of the CRMP2-neurofibromin complex on pain behaviors. Pain. 2017 Nov;158(11):2203–2221.
   PubMed Web of Science ®Google Scholar
• Moutal A, Yang X, Li W, et al. CRISPR/Cas9 editing of Nf1 gene identifies CRMP2 as a therapeutic target in neurofibromatosis type 1-related pain that is reversed by (S)-Lacosamide. Pain. 2017 Dec;158(12):2301–2319.
   PubMed Web of Science ®Google Scholar
• Stansfield BK, Bessler WK, Mali R, et al. Heterozygous inactivation of the Nf1 gene in myeloid cells enhances neointima formation via a rosuvastatin-sensitive cellular pathway. Hum Mol Genet. 2013 Mar 1;22(5):977–988.
   PubMed Web of Science ®Google Scholar
• Bessler WK, Kim G, Hudson FZ, et al. Nf1+/- monocytes/macrophages induce neointima formation via CCR2 activation. Hum Mol Genet. 2016 Mar 15;25(6):1129–1139.
   PubMed Web of Science ®Google Scholar
• Stevenson DA, Elefteriou F. Molecular Basis of Bone Abnormalities in NF1. In: Upadhyaya M, Cooper DN, Eds. Molecular and Cellular Biology of Neurofibromatosis Type 1. Springer Verlag, Heidelberg; 2012.
   Google Scholar
• El-Hoss J, Cheng T, Carpenter EC, et al. A Combination of rhBMP-2 (Recombinant Human Bone Morphogenetic Protein-2) and MEK (MAP Kinase/ERK Kinase) Inhibitor PD0325901 Increases Bone Formation in a Murine Model of Neurofibromatosis Type I Pseudarthrosis. J Bone Joint Surg Am. 2014 Jul 16;96(14):e117.
   PubMedGoogle Scholar
• Sullivan K, El-Hoss J, Little DG, et al. JNK inhibitors increase osteogenesis in Nf1-deficient cells. Bone. 2011 Dec;49(6):1311–1316.
   PubMed Web of Science ®Google Scholar
• Rhodes SD, Wu X, He Y, et al. Hyperactive transforming growth factor-beta1 signaling potentiates skeletal defects in a neurofibromatosis type 1 mouse model. J Bone Miner Res. 2013 Dec;28(12):2476–2489.
   PubMed Web of Science ®Google Scholar
• Karolak MR, Yang X, Elefteriou F. FGFR1 signaling in hypertrophic chondrocytes is attenuated by the Ras-GAP neurofibromin during endochondral bone formation. Hum Mol Genet. 2015 May 1;24(9):2552–2564.
   PubMed Web of Science ®Google Scholar
• Ghadakzadeh S, Kannu P, Whetstone H, et al. beta-Catenin modulation in neurofibromatosis type 1 bone repair: therapeutic implications. FASEB J. 2016 Sep;30(9):3227–3237.
   PubMed Web of Science ®Google Scholar
• Baht GS, Nadesan P, Silkstone D, et al. Pharmacologically targeting beta-catenin for NF1 associated deficiencies in fracture repair. Bone. 2017 May;98:31–36.
   PubMed Web of Science ®Google Scholar
• Gutmann DH, Parada LF, Silva AJ, et al. Neurofibromatosis type 1: modeling CNS dysfunction. J Neurosci. 2012 Oct 10;32(41):14087–14093.
   PubMed Web of Science ®Google Scholar
• Cui Y, Costa RM, Murphy GG, et al. Neurofibromin regulation of ERK signaling modulates GABA release and learning. Cell. 2008 Oct 31;135(3):549–560.
   PubMed Web of Science ®Google Scholar
• Brown JA, Gianino SM, Gutmann DH. Defective cAMP generation underlies the sensitivity of CNS neurons to neurofibromatosis-1 heterozygosity. J Neurosci. 2010 Apr 21;30(16):5579–5589.
   PubMed Web of Science ®Google Scholar
• Payne JM, Barton B, Ullrich NJ, et al. Randomized placebo-controlled study of lovastatin in children with neurofibromatosis type 1. Neurology. 2016 Dec 13;87(24):2575–2584.
   PubMed Web of Science ®Google Scholar
• Brown JA, Emnett RJ, White CR, et al. Reduced striatal dopamine underlies the attention system dysfunction in neurofibromatosis-1 mutant mice. Hum Mol Genet. 2010 Nov 15;19(22):4515–4528.
   PubMed Web of Science ®Google Scholar
• Diggs-Andrews KA, Tokuda K, Izumi Y, et al. Dopamine deficiency underlies learning deficits in neurofibromatosis-1 mice. Ann Neurol. 2013 Feb;73(2):309–315.
   PubMed Web of Science ®Google Scholar
• Omrani A, van Der Vaart T, Mientjes E, et al. HCN channels are a novel therapeutic target for cognitive dysfunction in Neurofibromatosis type 1. Mol Psychiatry. 2015 Nov;20(11):1311–1321.
   PubMed Web of Science ®Google Scholar
• Gouzi JY, Moressis A, Walker JA, et al. The receptor tyrosine kinase Alk controls neurofibromin functions in Drosophila growth and learning. PLoS Genet. 2011 Sep;7(9):e1002281.
   PubMed Web of Science ®Google Scholar
• Walker JA, Gouzi JY, Long JB, et al. Genetic and functional studies implicate synaptic overgrowth and ring gland cAMP/PKA signaling defects in the Drosophila melanogaster neurofibromatosis-1 growth deficiency. PLoS Genet. 2013 Nov;9(11):e1003958.
   PubMed Web of Science ®Google Scholar
• Weiss JB, Weber S, Marzulla T, et al. Pharmacological inhibition of Anaplastic Lymphoma Kinase rescues spatial memory impairments in Neurofibromatosis 1 mutant mice. Behav Brain Res. 2017 Aug 14;332:337–342.
   PubMed Web of Science ®Google Scholar
• Wu J, Liu W, Williams JP, et al. EGFR-Stat3 signalling in nerve glial cells modifies neurofibroma initiation. Oncogene. 2017 Mar 23;36(12):1669–1677.
   PubMed Web of Science ®Google Scholar
• Kraniak JM, Chalasani A, Wallace MR, et al. Development of 3D culture models of plexiform neurofibroma and initial application for phenotypic characterization and drug screening. Exp Neurol. 2018 Jan;299(Pt B):289–298.
   PubMedGoogle Scholar
• Castellsague J, Gel B, Fernandez-Rodriguez J, et al. Comprehensive establishment and characterization of orthoxenograft mouse models of malignant peripheral nerve sheath tumors for personalized medicine. EMBO Mol Med. 2015 May;7(5):608–627.
   PubMed Web of Science ®Google Scholar
• Wegscheid ML, Anastasaki C, Gutmann DH. Human stem cell modeling in neurofibromatosis type 1 (NF1). Exp Neurol. 2018 Jan;299(Pt B):270–280.
   PubMedGoogle Scholar
• Gutmann DH, Blakeley JO, Korf BR, et al. Optimizing biologically targeted clinical trials for neurofibromatosis. Expert Opin Investig Drugs. 2013 Apr;22(4):443–462.
   PubMed Web of Science ®Google Scholar
• Maertens O, McCurrach ME, Braun BS, et al. A Collaborative Model for Accelerating the Discovery and Translation of Cancer Therapies. Cancer Res. 2017 Nov 1;77(21):5706–5711.
   PubMed Web of Science ®Google Scholar
• Weiss B, Widemann BC, Wolters P, et al. Sirolimus for progressive neurofibromatosis type 1-associated plexiform neurofibromas: a neurofibromatosis Clinical Trials Consortium phase II study. Neuro Oncol. 2015 Apr;17(4):596–603.
   PubMed Web of Science ®Google Scholar
• Babovic-Vuksanovic D, Ballman K, Michels V, et al. Phase II trial of pirfenidone in adults with neurofibromatosis type 1. Neurology. 2006 Nov 28;67(10):1860–1862.
   PubMed Web of Science ®Google Scholar
• Widemann BC, Babovic-Vuksanovic D, Dombi E, et al. Phase II trial of pirfenidone in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas. Pediatr Blood Cancer. 2014 Sep;61(9):1598–1602.
   PubMed Web of Science ®Google Scholar
• Kim A, Dombi E, Tepas K, et al. 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.
   PubMed Web of Science ®Google Scholar
• Widemann BC, Dombi E, Gillespie A, et al. Phase 2 randomized, flexible crossover, double-blinded, placebo-controlled trial of the farnesyltransferase inhibitor tipifarnib in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas. Neuro Oncol. 2014 May;16(5):707–718.
   PubMed Web of Science ®Google Scholar
• Albritton KH, Rankin C, Coffin CM, et al. Phase II study of erlotinib in metastatic or unresectable malignant peripheral nerve sheath tumors (MPNST). J Clin Oncol. 2006;24(18_suppl):9518.
   Web of Science ®Google Scholar
• Chugh R, Wathen JK, Maki RG, et al. Phase II Multicenter Trial of Imatinib in 10 Histologic Subtypes of Sarcoma Using a Bayesian Hierarchical Statistical Model. J Clin Oncol. 2009;27(19):3148–3153.
   PubMed Web of Science ®Google Scholar
• Maki RG, D’Adamo DR, Keohan ML, et al. Phase II study of sorafenib in patients with metastatic or recurrent sarcomas. J Clin Oncol. 2009 Jul 1;27(19):3133–3140.
   PubMed Web of Science ®Google Scholar
• Schuetze SM, Wathen JK, Lucas DR, et al. SARC009: phase 2 study of dasatinib in patients with previously treated, high-grade, advanced sarcoma. Cancer. 2016 Mar 15;122(6):868–874.
   PubMed Web of Science ®Google Scholar
• Dickson MA, Mahoney MR, Tap WD, et al. Phase II study of MLN8237 (Alisertib) in advanced/metastatic sarcoma. Ann Oncol. 2016 Oct;27(10):1855–1860.
   PubMed Web of Science ®Google Scholar
• Widemann BC, Meyer CF, Cote GM, et al. SARC016: phase II study of everolimus in combination with bevacizumab in sporadic and neurofibromatosis type 1 (NF1) related refractory malignant peripheral nerve sheath tumors (MPNST). J Clin Oncol. 2016;34(15_suppl):11053.
   Web of Science ®Google Scholar
• Karajannis MA, Legault G, Fisher MJ, et al. Phase II study of sorafenib in children with recurrent or progressive low-grade astrocytomas. Neuro Oncol. 2014 Oct;16(10):1408–1416.
   PubMed Web of Science ®Google Scholar
• Ater JL, Xia C, Mazewski CM, et al. Nonrandomized comparison of neurofibromatosis type 1 and non-neurofibromatosis type 1 children who received carboplatin and vincristine for progressive low-grade glioma: a report from the Children’s Oncology Group. Cancer. 2016 Jun 15;122(12):1928–1936.
   PubMed Web of Science ®Google Scholar
• Lion-Francois L, Gueyffier F, Mercier C, et al. The effect of methylphenidate on neurofibromatosis type 1: a randomised, double-blind, placebo-controlled, crossover trial. Orphanet J Rare Dis. 2014 Sep 10;9:142.
   PubMed Web of Science ®Google Scholar
• van Der Vaart T, Rietman AB, Plasschaert E, et al. Behavioral and cognitive outcomes for clinical trials in children with neurofibromatosis type 1. Neurology. 2016 Jan 12;86(2):154–160.
   PubMed Web of Science ®Google Scholar
• van Der Vaart T, Plasschaert E, Rietman AB, et al. Simvastatin for cognitive deficits and behavioural problems in patients with neurofibromatosis type 1 (NF1-SIMCODA): a randomised, placebo-controlled trial. Lancet Neurol. 2013 Nov;12(11):1076–1083.
   PubMed Web of Science ®Google Scholar
• Stivaros S, Garg S, Tziraki M, et al. Randomised controlled trial of simvastatin treatment for autism in young children with neurofibromatosis type 1 (SANTA). Mol Autism. 2018;9:12.
   PubMed Web of Science ®Google Scholar