Advances in the treatment of neurofibromatosis-associated tumours

Nature Reviews Clinical Oncology

Volumn 10, Issue 11, 2013, Pages 616-624

  Lin, Andrew L ^a   Gutmann, David H ^a  

^a WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BEVACIZUMAB; EVEROLIMUS; IMATINIB; LAPATINIB; SORAFENIB;

ACOUSTIC NEURINOMA; CANCER SUSCEPTIBILITY; CLINICAL FEATURE; DISEASE ASSOCIATION; DRUG RESPONSE; EYE CANCER; GENE FUNCTION; GENE LOCATION; GENE MUTATION; GENETIC ASSOCIATION; GLIOMA; HUMAN; MALIGNANT PERIPHERAL NERVE SHEATH TUMOR; MALIGNANT TRANSFORMATION; NEUROFIBROMA; NEUROFIBROMATOSIS; NONHUMAN; POSITRON EMISSION TOMOGRAPHY; PRIORITY JOURNAL; REVIEW; STEREOTACTIC RADIOSURGERY; TREATMENT OUTCOME; TUMOR SUPPRESSOR GENE;

ANIMALS; DISEASE MODELS, ANIMAL; GENES, NEUROFIBROMATOSIS 1; GENES, NEUROFIBROMATOSIS 2; GLIOMA; HUMANS; MAGNETIC RESONANCE IMAGING; MENINGIOMA; MICE; NERVE SHEATH NEOPLASMS; NEURILEMMOMA; NEUROFIBROMATOSIS 1; NEUROFIBROMATOSIS 2;

EID: 84887411846     PISSN: 17594774     EISSN: 17594782     Source Type: Journal    
DOI: 10.1038/nrclinonc.2013.144     Document Type: Review

References (142)

1. Ferner, R. E. The neurofibromatoses. Pract. Neurol. 10, 82-93 (2010
2. Houshmandi, S. S. & Gutmann, D. H. All in the family: Using inherited cancer syndromes to understand de-regulated cell signaling in brain tumors. J. Cell. Biochem. 102, 811-819 (2007
3. Stumpf, D. A. et al. Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch. Neurol. 45, 575-578 (1987
4. Baser, M. E. et al. Evaluation of clinical diagnostic criteria for neurofibromatosis 2. Neurology 59, 1759-1765 (2002
5. Rasmussen, S. A. & Friedman, J. M. NF1 gene and neurofibromatosis 1. Am. J. Epidemiol. 151, 33-40 (2000
6. Huson, S. M., Compston, D. A., Clark, P. & Harper, P. S. A genetic study of von Recklinghausen neurofibromatosis in south east Wales. I. Prevalence, fitness, mutation rate, and effect of parental transmission on severity. J. Med. Genet. 26, 704-711 (1989
7. Evans, D. G. et al. Incidence of vestibular schwannoma and neurofibromatosis 2 in the North West of England over a 10-year period: Higher incidence than previously thought. Otol. Neurotol. 26, 93-97 (2005
8. Evans, D. G. et al. Birth incidence and prevalence of tumor-prone syndromes: Estimates from a UK family genetic register service. Am. J. Med. Genet. A 152A, 327-332 (2010
9. De Luca, A. et al. Novel and recurrent mutations in the NF1 gene in Italian patients with neurofibromatosis type 1. Hum. Mutat. 23, 629 (2004
10. Evans, D. G. & Wallace, A. An update on age related mosaic and offspring risk in neurofibromatosis 2 (NF2). J. Med. Genet. 46, 792 (2009
11. Rasmussen, S. A., Yang, Q. & Friedman, J. M. Mortality in neurofibromatosis 1: An analysis using U. S. death certificates. Am. J. Hum. Genet. 68, 1110-1118 (2001
12. Wilding, A. et al. Life expectancy in hereditary cancer predisposing diseases: An observational study. J. Med. Genet. 49, 264-269 (2012
13. McGaughran, J. M. et al. A clinical study of type 1 neurofibromatosis in north west England. J. Med. Genet. 36, 197-203 (1999
14. Friedman, J. M. & Birch, P. H. Type 1 neurofibromatosis: A descriptive analysis of the disorder in 1,728 patients. Am. J. Med. Genet. 70, 138-143 (1997
15. Plotkin, S. R. et al. Quantitative assessment of whole-body tumor burden in adult patients with neurofibromatosis. PLoS ONE 7, e35711 (2012
16. Evans, D. G. et al. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J. Med. Genet. 39, 311-314 (2002
17. Listernick, R., Charrow, J., Greenwald, M. & Mets, M. Natural history of optic pathway tumors in children with neurofibromatosis type 1: A longitudinal study. J. Pediatr. 125, 63-66 (1994
18. Lewis, R. A., Gerson, L. P., Axelson, K. A., Riccardi, V. M. & Whitford, R. P. von Recklinghausen neurofibromatosis. II. Incidence of optic gliomata. Ophthalmology 91, 929-935 (1984
19. Gutmann, D. H. et al. Gliomas presenting after age 10 in individuals with neurofibromatosis type 1 (NF1). Neurology 59, 759-761 (2002
20. Matsui, I. et al. Neurofibromatosis type 1 and childhood cancer. Cancer 72, 2746-2754 (1993
21. Side, L. et al. Homozygous inactivation of the NF1 gene in bone marrow cells from children with neurofibromatosis type 1 and malignant myeloid disorders. N. Engl. J. Med. 336, 1713-1720 (1997
22. Stiller, C. A., Chessells, J. M. & Fitchett, M. Neurofibromatosis and childhood leukaemia/lymphoma: A population-based UKCCSG study. Br. J. Cancer 70, 969-972 (1994
23. Walther, M. M., Herring, J., Enquist, E., Keiser, H. R. & Linehan, W. M. von Recklinghausen's disease and pheochromocytomas. J. Urol. 162, 1582-1586 (1999
24. Vlenterie, M. et al. Pheochromocytoma and gastrointestinal stromal tumors in patients with neurofibromatosis type I. Am. J. Med. 126, 174-180 (2013
25. Sung, L. et al. Neurofibromatosis in children with Rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma study IV. J. Pediatr. 144, 666-668 (2004
26. Sharif, S. et al. Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening. J. Med. Genet. 44, 481-484 (2007
27. Jouhilahti, E. M. et al. The development of cutaneous neurofibromas. Am. J. Pathol. 178, 500-505 (2011
28. Boyd, K. P., Korf, B. R. & Theos, A. Neurofibromatosis type 1. J. Am. Acad. Dermatol. 61, 1-14 (2009
29. Rosser, T. & Packer, R. J. Neurofibromas in children with neurofibromatosis 1. J. Child. Neurol. 17, 585-591 (2002
30. Prada, C. E. et al. Pediatric plexiform neurofibromas: Impact on morbidity and mortality in neurofibromatosis type 1. J. Pediatr. 160, 461-467 (2012
31. Ducatman, B. S., Scheithauer, B. W., Piepgras, D. G., Reiman, H. M. & Ilstrup, D. M. Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases. Cancer 57, 2006-2021 (1986
32. Rodriguez, F. J. et al. Gliomas in neurofibromatosis type 1: A clinicopathologic study of 100 patients. J. Neuropathol. Exp. Neurol. 67, 240-249 (2008
33. Listernick, R., Charrow, J., Greenwald, M. J. & Esterly, N. B. Optic gliomas in children with neurofibromatosis type 1. J. Pediatr. 114, 788-792 (1989
34. Listernick, R., Darling, C., Greenwald, M., Strauss, L. & Charrow, J. Optic pathway tumors in children: The effect of neurofibromatosis type 1 on clinical manifestations and natural history. J. Pediatr. 127, 718-722 (1995
35. Listernick, R., Charrow, J. & Gutmann, D. H. Intracranial gliomas in neurofibromatosis type 1. Am. J. Med. Genet. 89, 38-44 (1999
36. Habiby, R., Silverman, B., Listernick, R. & Charrow, J. Precocious puberty in children with neurofibromatosis type 1. J. Pediatr. 126, 364-367 (1995
37. Molloy, P. T. et al. Brainstem tumors in patients with neurofibromatosis type 1: A distinct clinical entity. Neurology 45, 1897-1902 (1995
38. Ullrich, N. J., Raja, A. I., Irons, M. B., Kieran, M. W. & Goumnerova, L. Brainstem lesions in neurofibromatosis type 1. Neurosurgery 61, 762-767 (2007
39. Pollack, I. F., Shultz, B. & Mulvihill, J. J. The management of brainstem gliomas in patients with neurofibromatosis 1. Neurology 46, 1652-1660 (1996
40. Vinchon, M., Soto-Ares, G., Ruchoux, M. M. & Dhellemmes, P. Cerebellar gliomas in children with NF1: Pathology and surgery. Childs Nerv. Syst. 16, 417-420 (2000
41. Maris, J. M. et al. Monosomy 7 myelodysplastic syndrome and other second malignant neoplasms in children with neurofibromatosis type 1. Cancer 79, 1438-1446 (1997
42. Sharif, S. et al. Second primary tumors in neurofibromatosis 1 patients treated for optic glioma: Substantial risks after radiotherapy. J. Clin. Oncol. 24, 2570-2575 (2006
43. Parry, D. M. et al. Neurofibromatosis 2 (NF2): Clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity. Am. J. Med. Genet. 52, 450-461 (1994
44. Mautner, V. F. et al. The neuroimaging and clinical spectrum of neurofibromatosis 2. Neurosurgery 38, 880-886 (1996
45. National Institutes of Health Consensus Development Conference Statement on Acoustic Neuroma, December 11-13, 1991. The Consensus Development Panel. Arch. Neurol. 51, 201-207 (1994
46. Sobel, R. A. Vestibular (acoustic) schwannomas: Histologic features in neurofibromatosis 2 and in unilateral cases. J. Neuropathol. Exp. Neurol. 52, 106-113 (1993
47. Mautner, V. F., Tatagiba, M., Guthoff, R., Samii, M. & Pulst, S. M. Neurofibromatosis 2 in the pediatric age group. Neurosurgery 33, 92-96 (1993
48. Asthagiri, A. R. et al. Neurofibromatosis type 2. Lancet 373, 1974-1986 (2009
49. Evans, D. G. et al. A clinical study of type 2 neurofibromatosis. Q. J. Med. 84, 603-618 (1992
50. MacCollin, M. et al. Diagnostic criteria for schwannomatosis. Neurology 64, 1838-1845 (2005
51. Hulsebos, T. J. et al. Germline mutation of INI1/SMARCB1 in familial schwannomatosis. Am. J. Hum. Genet. 80, 805-810 (2007
52. Plotkin, S. R. et al. Update from the 2011 International Schwannomatosis Workshop: From genetics to diagnostic criteria. Am. J. Med. Genet. A 161, 405-416 (2013
53. Antinheimo, J. et al. Proliferation potential and histological features in neurofibromatosis 2 associated and sporadic meningiomas. J. Neurosurg. 87, 610-614 (1997
54. Mautner, V. F. et al. Spinal tumors in patients with neurofibromatosis type 2: MR imaging study of frequency, multiplicity, and variety. AJR Am. J. Roentgenol. 165, 951-955 (1995
55. Hagel, C. et al. Clinical presentation, immunohistochemistry and electron microscopy indicate neurofibromatosis type 2-associated gliomas to be spinal ependymomas. Neuropathology 32, 611-616 (2012
56. Plotkin, S. R. et al. Spinal ependymomas in neurofibromatosis Type 2: A retrospective analysis of 55 patients. J. Neurosurg. Spine 14, 543-547 (2011
57. Stemmer-Rachamimov, A. O. et al. Universal absence of merlin, but not other ERM family members, in schwannomas. Am. J. Pathol. 151, 1649-1654 (1997
58. Kimura, N. et al. Neurofibromin and NF1 gene analysis in composite pheochromocytoma and tumors associated with von Recklinghausen's disease. Mod. Pathol. 15, 183-188 (2002
59. Gutmann, DH., Cole, J. L., Stone, W. J., Ponder, B. A. & Collins, F. S. Loss of neurofibromin in adrenal gland tumors from patients with neurofibromatosis type I. Genes Chromosomes Cancer 10, 55-58 (1994
60. Xu, G. F. et al. The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 62, 599-608 (1990
61. Buchberg, A. M., Cleveland, L. S., Jenkins, N. A. & Copeland, N. G. Sequence homology shared by neurofibromatosis type 1 gene and IRA 1 and IRA 2 negative regulators of the RAS cyclic AMP pathway. Nature 347, 291-294 (1990
62. Basu, T. N. et al. Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients. Nature 356, 713-715 (1992
63. Pylayeva-Gupta, Y., Grabocka, E. & Bar-Sagi, D. RAS oncogenes: Weaving a tumorigenic web. Nat. Rev. Cancer 11, 761-774 (2011
64. Ballester, R. et al. The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 63, 851-859 (1990
65. Martin, G. A. et al. The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell 63, 843-849 (1990
66. DeClue, J. E. et al. Abnormal regulation of mammalian p21ras contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis. Cell 69, 265-273 (1992
67. Bollag, G. et al. Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells. Nat. Genet. 12, 144-148 (1996
68. Dasgupta, B., Yi, Y., Chen, D. Y., Weber, J. D. & Gutmann, D. H. Proteomic analysis reveals hyperactivation of the mammalian target of rapamycin pathway in neurofibromatosis 1 associated human and mouse brain tumors. Cancer Res. 65, 2755-2760 (2005
69. Jessen, W. J. et al. MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors. J. Clin. Invest. 123, 340-347 (2013
70. Tong, J., Hannan, F., Zhu, Y., Bernards, A. & Zhong, Y. Neurofibromin regulates G protein stimulated adenylyl cyclase activity. Nat. Neurosci. 5, 95-96 (2002
71. Dasgupta, B., Dugan, L. L. & Gutmann, D. H. The neurofibromatosis 1 gene product neurofibromin regulates pituitary adenylate cyclase-activating polypeptide-mediated signaling in astrocytes. J. Neurosci. 23, 8949-8954 (2003
72. Brown, J. A., Gianino, S. M. & Gutmann, D. H. Defective cAMP generation underlies the sensitivity of CNS neurons to neurofibromatosis 1 heterozygosity. J. Neurosci. 30, 5579-5589 (2010
73. Rouleau, G. A. et al. Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature 363, 515-521 (1993
74. Trofatter, J. A. et al. A novel moesin, ezrin, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 72, 791-800 (1993
75. McClatchey, A. I. Merlin and ERM proteins: Unappreciated roles in cancer development? Nat. Rev. Cancer 3, 877-883 (2003
76. Shaw, R. J. et al. The Nf2 tumor suppressor, merlin, functions in Rac-dependent signaling. Dev. Cell 1, 63-72 (2001
77. Hamaratoglu, F. et al. The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nat. Cell Biol. 8, 27-36 (2006
78. Curto, M., Cole, B. K., Lallemand, D., Liu, C. H. & McClatchey, A. I. Contact-dependent inhibition of EGFR signaling by Nf2/Merlin. J. Cell Biol. 177, 893-903 (2007
79. James, M. F. et al. NF2/merlin is a novel negative regulator of mTOR complex 1, and activation of mTORC1 is associated with meningioma and schwannoma growth. Mol. Cell Biol. 29, 4250-4261 (2009
80. Levine, S. M., Levine, E., Taub, P. J. & Weinberg, H. Electrosurgical excision technique for the treatment of multiple cutaneous lesions in neurofibromatosis type I. J. Plast. Reconstr. Aesthet. Surg. 61, 958-962 (2008
81. Robertson, K. A. et al. Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: A phase 2 trial. Lancet Oncol. 13, 1218-1224 (2012
82. Mautner, V. F. et al. Clinical relevance of positron emission tomography and magnetic resonance imaging in the progression of internal plexiform neurofibroma in NF1. Anticancer Res. 27, 1819-1822 (2007
83. Ferner, R. E. et al.[18F]2 fluoro 2 deoxy d-glucose positron emission tomography (FDG PET) as a diagnostic tool for neurofibromatosis 1 (NF1) associated malignant peripheral nerve sheath tumours (MPNSTs): A long-term clinical study. Ann. Oncol. 19, 390-394 (2008
84. Tsai, L. L. et al.[18F]-Fluorodeoxyglucose positron emission tomography in children with neurofibromatosis type 1 and plexiform neurofibromas: Correlation with malignant transformation. J. Neurooncol. 108, 469-475 (2012
85. Karabatsou, K., Kiehl, T. R., Wilson, D. M., Hendler, A. & Guha, A. Potential role of 18fluorodeoxyglucose-positron emission tomography/computed tomography in differentiating benign neurofibroma from malignant peripheral nerve sheath tumor associated with neurofibromatosis 1. Neurosurgery 65 (Suppl4), A160-A170 (2009
86. Lakkaraju, A., Patel, C. N., Bradley, K. M. & Scarsbrook, A. F. PET/CT in primary musculoskeletal tumours: A step forward. Eur. Radiol. 20, 2959-2972 (2010
87. Moretti, V. M., Crawford, E. A., Staddon, A. P., Lackman, R. D. & Ogilvie, C. M. Early outcomes for malignant peripheral nerve sheath tumor treated with chemotherapy. Am. J. Clin. Oncol. 34, 417-421 (2011
88. Porter, D. E. et al. Survival in malignant peripheral nerve sheath tumours: A comparison between sporadic and neurofibromatosis type 1-associated tumours. Sarcoma 2009, 756395 (2009
89. Listernick, R., Louis, D. N., Packer, R. J. & Gutmann, D. H. Optic pathway gliomas in children with neurofibromatosis 1: Consensus statement from the NF1 Optic Pathway Glioma Task Force. Ann. Neurol. 41, 143-149 (1997
90. Evans, D. G. et al. Consensus recommendations to accelerate clinical trials for neurofibromatosis type 2. Clin. Cancer Res. 15, 5032-5039 (2009
91. Evans, D. G. et al. Management of the patient and family with neurofibromatosis 2: A consensus conference statement. Br. J. Neurosurg. 19, 5-12 (2005
92. Rowe, J., Radatz, M. & Kemeny, A. Radiosurgery for type II neurofibromatosis. Prog. Neurol. Surg. 21, 176-182 (2008
93. Flickinger, J. C., Kondziolka, D., Niranjan, A. & Lunsford, L. D. Results of acoustic neuroma radiosurgery: An analysis of 5 years' experience using current methods. J. Neurosurg. 94, 1-6 (2001
94. Plotkin, S. R. et al. Bevacizumab for progressive vestibular schwannoma in neurofibromatosis type 2: A retrospective review of 31 patients. Otol. Neurotol. 33, 1046-1052 (2012
95. US National Library of Medicine. ClinicalTrials.gov[online], http://clinicaltrials.gov/show/NCT01767792 (2013
96. Karajannis, M. A. et al. Phase II trial of lapatinib in adult and pediatric patients with neurofibromatosis type 2 and progressive vestibular schwannomas. Neuro Oncol. 14, 1163-1170 (2012
97. Mayes, D. A. et al. Perinatal or adult Nf1 inactivation using tamoxifen-inducible PlpCre each cause neurofibroma formation. Cancer Res. 71, 4675-4685 (2011
98. Wu, J. et al. Plexiform and dermal neurofibromas and pigmentation are caused by Nf1 loss in desert hedgehog-expressing cells. Cancer Cell 13, 105-116 (2008
99. Zhu, Y., Ghosh, P., Charnay, P., Burns, D. K. & Parada, L. F. Neurofibromas in NF1: Schwann cell origin and role of tumor environment. Science 296, 920-922 (2002
100. Bajenaru, M. L. et al. Optic nerve glioma in mice requires astrocyte Nf1 gene inactivation and Nf1 brain heterozygosity. Cancer Res. 63, 8573-8577 (2003
101. Zhu, Y. et al. Inactivation of NF1 in CNS causes increased glial progenitor proliferation and optic glioma formation. Development 132, 5577-5588 (2005
102. Dasgupta, B., Li, W., Perry, A. & Gutmann, D. H. Glioma formation in neurofibromatosis 1 reflects preferential activation of K RAS in astrocytes. Cancer Res. 65, 236-245 (2005
103. Cichowski, K. et al. Mouse models of tumor development in neurofibromatosis type 1. Science 286, 2172-2176 (1999
104. Vogel, K. S. et al. Mouse tumor model for neurofibromatosis type 1. Science 286, 2176-2179 (1999
105. Le, D. T. et al. Somatic inactivation of Nf1 in hematopoietic cells results in a progressive myeloproliferative disorder. Blood 103, 4243-4250 (2004
106. Giovannini, M. et al. Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2. Genes Dev. 14, 1617-1630 (2000
107. Giovannini, M. et al. Schwann cell hyperplasia and tumors in transgenic mice expressing a naturally occurring mutant NF2 protein. Genes Dev. 13, 978-986 (1999
108. Kalamarides, M. et al. Identification of a progenitor cell of origin capable of generating diverse meningioma histological subtypes. Oncogene 30, 2333-2344 (2011
109. Kalamarides, M. et al. Nf2 gene inactivation in arachnoidal cells is rate-limiting for meningioma development in the mouse. Genes Dev. 16, 1060-1065 (2002
110. Gutmann, D. H. & Giovannini, M. Mouse models of neurofibromatosis 1 and 2. Neoplasia 4, 279-290 (2002
111. Bajenaru, M. L. et al. Astrocyte-specific inactivation of the neurofibromatosis 1 gene (NF1) is insufficient for astrocytoma formation. Mol. Cell Biol. 22, 5100-5113 (2002
112. Riccardi, V. M. Cutaneous manifestation of neurofibromatosis: Cellular interaction, pigmentation, and mast cells. Birth Defects Orig. Artic. Ser. 17, 129-145 (1981
113. Wu, J. et al. Preclincial testing of sorafenib and RAD001 in the Nf(flox/flox);DhhCre mouse model of plexiform neurofibroma using magnetic resonance imaging. Pediatr. Blood Cancer 58, 173-180 (2012
114. Hegedus, B. et al. Preclinical cancer therapy in a mouse model of neurofibromatosis 1 optic glioma. Cancer Res. 68, 1520-1528 (2008
115. Mo, W. et al. CXCR4/CXCL12 mediate autocrine cell-cycle progression in NF1-associated malignant peripheral nerve sheath tumors. Cell 152, 1077-1090 (2013
116. Johannessen, C. M. et al. TORC1 is essential for NF1-associated malignancies. Curr. Biol. 18, 56-62 (2008
117. Warrington, N. M. et al. Cyclic AMP suppression is sufficient to induce gliomagenesis in a mouse model of neurofibromatosis 1. Cancer Res. 70, 5717-5727 (2010
118. Sabha, N. et al. Investigation of the in vitro therapeutic efficacy of nilotinib in immortalized human NF2-null vestibular schwannoma cells. PLoS ONE 7, e39412 (2012
119. Ammoun, S. et al. ErbB/HER receptor activation and preclinical efficacy of lapatinib in vestibular schwannoma. Neuro Oncol. 12, 834-843 (2010
120. Gutmann, D. H., Blakeley, J. O., Korf, B. R. & Packer, R. J. Optimizing biologically targeted clinical trials for neurofibromatosis. Expert Opin. Investig. Drugs 22, 443-462 (2013
121. US National Library of Medicine. ClinicalTrials.gov[online], http://clinicaltrials.gov/ct2/show/NCT00727233 (2013
122. US National Library of Medicine. ClinicalTrials.gov[online], http://clinicaltrials.gov/show/NCT01661283 (2013
123. US National Library of Medicine. ClinicalTrials.gov[online], http://clinicaltrials.gov/show/NCT01158651 (2013
124. Baser, M. E., Rai, H., Wallace, A. J. & Evans, D. G. Neurofibromatosis 2 (NF2) and malignant mesothelioma in a man with a constitutional NF2 missense mutation. Fam. Cancer 4, 321-322 (2005
125. Baser, M. E. et al. Neurofibromatosis 2 and malignant mesothelioma. Neurology 59, 290-291 (2002
126. Woodruff, J. M., Selig, A. M., Crowley, K. & Allen, P. W. Schwannoma (neurilemoma) with malignant transformation. A rare, distinctive peripheral nerve tumor. Am. J. Surg. Pathol. 18, 882-895 (1994
127. Gupta, A., Cohen, B. H., Ruggieri, P., Packer, R. J. & Phillips, P. C. Phase I study of thalidomide for the treatment of plexiform neurofibroma in neurofibromatosis 1. Neurology 60, 130-132 (2003
128. Packer, R. J. et al. Plexiform neurofibromas in NF1: Toward biologic-based therapy. Neurology 58, 1461-1470 (2002
129. Widemann, B. C. et al. 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. 24, 507-516 (2006
130. Babovic-Vuksanovic, D. et al. Phase II trial of pirfenidone in adults with neurofibromatosis type 1. Neurology 67, 1860-1862 (2006
131. Babovic-Vuksanovic, D. et al. Phase I trial of pirfenidone in children with neurofibromatosis 1 and plexiform neurofibromas. Pediatr. Neurol. 36, 293-300 (2007
132. Kissil, J. L. et al. What's new in neurofibromatosis? Proceedings from the 2009 NF Conference: New frontiers. Am. J. Med. Genet. A 152A, 269-283 (2010
133. Widemann, B. C. et al. Phase II study of the mTOR inhibitor sirolimus for nonprogressive NF1-associated plexiform neurofibromas: A Neurofibromatosis Consortium study[abstract e13601]. J. Clin. Oncol. 28 (Suppl.), e13601 (2010
134. Jakacki, R. I. et al. Phase I trial of pegylated interferon α 2b in young patients with plexiform neurofibromas. Neurology 76, 265-272 (2011
135. Kim, A. et al. Phase I trial and pharmacokinetic study of sorafenib in children with neurofibromatosis type I and plexiform neurofibromas. Pediatr. Blood Cancer 60, 396-401 (2013
136. Albritton, K. H. et al. Phase II study of erlotinib in metastatic or unresectable malignant peripheral nerve sheath tumors (MPNST)[abstract]. J. Clin. Oncol. 24 (Suppl.), a9518 (2006
137. Schuetze, S. et al. Results of a sarcoma alliance for research through collaboration (SARC) phase II trial of dasatinib in previously treated, high-grade, advanced sarcoma[abstract]. J. Clin. Oncol. 28 (Suppl.), a10009 (2009
138. Koenig, M. K. et al. Topical rapamycin therapy to alleviate the cutaneous manifestations of tuberous sclerosis complex: A double-blind, randomized, controlled trial to evaluate the safety and efficacy of topically applied rapamycin. Drugs R. D. 12, 121-126 (2012
139. Kwon, C. H. et al. Pten haploinsufficiency accelerates formation of high-grade astrocytomas. Cancer Res. 68, 3286-3294 (2008
140. Zhu, Y. et al. Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell 8, 119-130 (2005
141. Tischler, A. S., Shih, T. S., Williams, B. O. & Jacks, T. Characterization of pheochromocytomas in a mouse strain with a targeted disruptive mutation of the neurofibromatosis gene Nf1. Endocr. Pathol. 6, 323-335 (1995
142. Jongsma, J. et al. A conditional mouse model for malignant mesothelioma. Cancer Cell 13, 261-271 (2008