Hostname: page-component-745bb68f8f-b6zl4 Total loading time: 0 Render date: 2025-01-25T17:20:23.063Z Has data issue: false hasContentIssue false
  • English
  • Français

Malignant peripheral nerve sheath tumour (MPNST): the clinical implications of cellular signalling pathways

Published online by Cambridge University Press:  19 October 2009

Daniela Katz ,
Alexander Lazar  and
Dina Lev
Daniela Katz
Affiliation:
Department of Surgical Oncology and Sarcoma Research Center, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Alexander Lazar
Affiliation:
Department of Pathology and Sarcoma Research Center, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Dina Lev*
Affiliation:
Department of Cancer Biology and Sarcoma Research Center, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
*
*Corresponding author: Dina Lev, Department of Cancer Biology and Sarcoma Research Center, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1104, Houston, TX 77030, USA. Tel: +1 713 792 1637; Fax: +1 713 563 1185; E-mail: dlev@mdanderson.org
Get access Rights & Permissions [Opens in a new window]

Abstract

Malignant peripheral nerve sheath tumour (MPNST) is a rare malignancy accounting for 3–10% of all soft tissue sarcomas. Most MPNSTs arise in association with peripheral nerves or deep neurofibromas and may originate from neural crest cells, although the specific cell of origin is uncertain. Approximately half of MPNSTs occur in the setting of neurofibromatosis type 1 (NF1), an autosomal dominant disorder with an incidence of approximately one in 3500 persons; the remainder of MPNSTs develop sporadically. In addition to a variety of clinical manifestations, approximately 8–13% of NF1 patients develop MPNSTs, which are the leading cause of NF1-related mortality. Surgical resection is the mainstay of MPNST clinical management. However, because of invasive growth, propensity to metastasise, and limited sensitivity to chemotherapy and radiation, MPNST has a guarded to poor prognosis. Five-year survival rates of only 20–50% indicate an urgent need for improved therapeutic approaches. Recent work in this field has identified several altered intracellular signal transduction cascades and deregulated tyrosine kinase receptors, posing the possibility of personalised, targeted therapeutics. However, expanded knowledge of MPNST molecular pathobiology will be needed to meaningfully apply such approaches for the benefit of afflicted patients.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 11 , July 2009 , e30
Copyright
Copyright © Cambridge University Press 2009

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

References

1Grobmyer, S.R. et al. (2008) Malignant peripheral nerve sheath tumor: molecular pathogenesis and current management considerations. Journal of Surgical Oncology 97, 340-349CrossRefGoogle ScholarPubMed
2Cashen, D.V. et al. (2004) Survival data for patients with malignant schwannoma. Clinical Orthopaedics and Related Research 426, 69-73CrossRefGoogle Scholar
3Anghileri, M. et al. (2006) Malignant peripheral nerve sheath tumors: prognostic factors and survival in a series of patients treated at a single institution. Cancer 107, 1065-1074Google Scholar
4Angelov, L. et al. (1998) Neurogenic sarcomas: experience at the University of Toronto. Neurosurgery 43, 56-64; discussion 64-55Google Scholar
5Evans, D.G. et al. (2002) Malignant peripheral nerve sheath tumours in neurofibromatosis 1. Journal of Medical Genetics 39, 311-314CrossRefGoogle ScholarPubMed
6Ducatman, B.S. et al. (1986) Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases. Cancer 57, 2006-2021Google Scholar
7Ferner, R.E. and Gutmann, D.H. (2002) International consensus statement on malignant peripheral nerve sheath tumors in neurofibromatosis. Cancer Research 62, 1573-1577Google ScholarPubMed
8Tucker, T. et al. (2005) Association between benign and malignant peripheral nerve sheath tumors in NF1. Neurology 65, 205-211CrossRefGoogle ScholarPubMed
9Friedman, J.M. (1999) Epidemiology of neurofibromatosis type 1. American Journal of Medical Genetics 89, 1-63.0.CO;2-8>CrossRefGoogle ScholarPubMed
10Gutmann, D.H. et al. (1997) The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. Journal of the American Medical Association 278, 51-57CrossRefGoogle ScholarPubMed
11Zadeh, G. et al. (2007) Radiation induced peripheral nerve tumors: case series and review of the literature. Journal of Neuro-Oncology 83, 205-212CrossRefGoogle ScholarPubMed
12Adamson, D.C., Cummings, T.J. and Friedman, A.H. (2004) Malignant peripheral nerve sheath tumor of the spine after radiation therapy for Hodgkin's lymphoma. Clinical Neuropathology 23, 245-255Google ScholarPubMed
13Gupta, G., Mammis, A. and Maniker, A. (2008) Malignant peripheral nerve sheath tumors. Neurosurgery Clinics of North America 19, 533-543CrossRefGoogle ScholarPubMed
14Vauthey, J.N., Woodruff, J.M. and Brennan, M.F. (1995) Extremity malignant peripheral nerve sheath tumors (neurogenic sarcomas): a 10-year experience. Annals of Surgical Oncology 2, 126-131Google Scholar
15Van Herendael, B.H. et al. (2006) The value of magnetic resonance imaging in the differentiation between malignant peripheral nerve-sheath tumors and non-neurogenic malignant soft-tissue tumors. Skeletal Radiology 35, 745-753Google Scholar
16Cardona, S. et al. (2003) Evaluation of F18-deoxyglucose positron emission tomography (FDG-PET) to assess the nature of neurogenic tumours. European Journal of Surgical Oncology 29, 536-541Google Scholar
17Woodruff, J.M. (1996) Pathology of the major peripheral nerve sheath neoplasms. Monographs in Pathology 38, 129-161Google ScholarPubMed
18Lin, B.T., Weiss, L.M. and Medeiros, L.J. (1997) Neurofibroma and cellular neurofibroma with atypia: a report of 14 tumors. American Journal of Surgical Pathology 21, 1443-1449CrossRefGoogle ScholarPubMed
19Zou, C. et al. (2009) Clinical, pathological, and molecular variables predictive of malignant peripheral nerve sheath tumor outcome. Annals of Surgery 249, 1014-1022Google Scholar
20De Raedt, T. et al. (2003) Elevated risk for MPNST in NF1 microdeletion patients. American Journal of Human Genetics 72, 1288-1292CrossRefGoogle ScholarPubMed
21Warbey, V.S. et al. (2009) [18F]FDG PET/CT in the diagnosis of malignant peripheral nerve sheath tumours in neurofibromatosis type-1. European Journal of Nuclear Medicine and Molecular Imaging 36, 751-757CrossRefGoogle ScholarPubMed
22Furniss, D. et al. (2008) A 10-year review of benign and malignant peripheral nerve sheath tumors in a single center: clinical and radiographic features can help to differentiate benign from malignant lesions. Plastic and Reconstructive Surgery 121, 529-533Google Scholar
23Hruban, R.H. et al. (1990) Malignant peripheral nerve sheath tumors of the buttock and lower extremity. A study of 43 cases. Cancer 66, 1253-1265Google Scholar
24Kourea, H.P. et al. (1998) Subdiaphragmatic and intrathoracic paraspinal malignant peripheral nerve sheath tumors: a clinicopathologic study of 25 patients and 26 tumors. Cancer 82, 2191-2203Google Scholar
25Wong, W.W. et al. (1998) Malignant peripheral nerve sheath tumor: analysis of treatment outcome. International Journal of Radiation Oncology Biology Physics 42, 351-360Google Scholar
26Sharif, S. et al. (2006) Second primary tumors in neurofibromatosis 1 patients treated for optic glioma: substantial risks after radiotherapy. Journal of Clinical Oncology 24, 2570-2575Google Scholar
27Sordillo, P.P. et al. (1981) Malignant schwannoma–clinical characteristics, survival, and response to therapy. Cancer 47, 2503-25093.0.CO;2-3>CrossRefGoogle ScholarPubMed
28Carli, M. et al. (2005) Pediatric malignant peripheral nerve sheath tumor: the Italian and German soft tissue sarcoma cooperative group. Journal of Clinical Oncology 23, 8422-8430Google Scholar
29D'Agostino, A.N., Soule, E.H. and Miller, R.H. (1963) Sarcomas of the Peripheral Nerves and Somatic Soft Tissues Associated with Multiple Neurofibromatosis (Von Recklinghausen's Disease). Cancer 16, 1015-1027Google Scholar
30Poyhonen, M., Niemela, S. and Herva, R. (1997) Risk of malignancy and death in neurofibromatosis. Archives of Pathology and Laboratory Medicine 121, 139-143Google ScholarPubMed
31Perry, A. et al. (2001) NF1 deletions in S-100 protein-positive and negative cells of sporadic and neurofibromatosis 1 (NF1)-associated plexiform neurofibromas and malignant peripheral nerve sheath tumors. American Journal of Pathology 159, 57-61CrossRefGoogle ScholarPubMed
32Bottillo, I. et al. (2009) Germline and somatic NF1 mutations in sporadic and NF1-associated malignant peripheral nerve sheath tumours. Journal of Pathology 217, 693-701Google Scholar
33Holtkamp, N. et al. (2007) MMP-13 and p53 in the progression of malignant peripheral nerve sheath tumors. Neoplasia 9, 671-677Google Scholar
34Menon, A.G. et al. (1990) Chromosome 17p deletions and p53 gene mutations associated with the formation of malignant neurofibrosarcomas in von Recklinghausen neurofibromatosis. Proceedings of the National Academy of Sciences of the United States of America 87, 5435-5439Google Scholar
35Birindelli, S. et al. (2001) Rb and TP53 pathway alterations in sporadic and NF1-related malignant peripheral nerve sheath tumors. Laboratory Investigation 81, 833-844Google Scholar
36Legius, E. et al. (1994) TP53 mutations are frequent in malignant NF1 tumors. Genes Chromosomes and Cancer 10, 250-255Google Scholar
37Johannessen, C.M. et al. (2005) The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proceedings of the National Academy of Sciences of the United States of America 102, 8573-8578CrossRefGoogle ScholarPubMed
38Ambrosini, G. et al. (2008) Sorafenib inhibits growth and mitogen-activated protein kinase signaling in malignant peripheral nerve sheath cells. Molecular Cancer Therapeutics 7, 890-896Google Scholar
39Perrone, F. et al. (2009) PDGFRA, PDGFRB, EGFR, and downstream signalling activation in malignant peripheral nerve sheath tumor. Neuro-Oncology Feb 26; [Epub ahead of print]CrossRefGoogle ScholarPubMed
40Watson, M.A. et al. (2004) Gene expression profiling reveals unique molecular subtypes of Neurofibromatosis Type I-associated and sporadic malignant peripheral nerve sheath tumors. Brain Pathology 14, 297-303Google Scholar
41Mahller, Y.Y. et al. (2006) Malignant peripheral nerve sheath tumors with high and low Ras-GTP are permissive for oncolytic herpes simplex virus mutants. Pediatric Blood and Cancer 46, 745-754Google Scholar
42Mattingly, R.R. et al. (2006) The mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor PD184352 (CI-1040) selectively induces apoptosis in malignant schwannoma cell lines. Journal of Pharmacology and Experimental Therapeutics 316, 456-465Google Scholar
43Tang, Y. et al. (1998) A role for Pak protein kinases in Schwann cell transformation. Proceedings of the National Academy of Sciences of the United States of America 95, 5139-5144CrossRefGoogle ScholarPubMed
44Ingram, D.A. et al. (2001) Hyperactivation of p21(ras) and the hematopoietic-specific Rho GTPase, Rac2, cooperate to alter the proliferation of neurofibromin-deficient mast cells in vivo and in vitro. Journal of Experimental Medicine 194, 57-69Google Scholar
45Yang, F.C. et al. (2003) Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for Nf1 + /− mast cells. Journal of Clinical Investigation 112, 1851-1861Google ScholarPubMed
46Donovan, S. et al. (2002) Hyperactivation of protein kinase B and ERK have discrete effects on survival, proliferation, and cytokine expression in Nf1-deficient myeloid cells. Cancer Cell 2, 507-514Google Scholar
47Lau, N. et al. (2000) Loss of neurofibromin is associated with activation of RAS/MAPK and PI3-K/AKT signaling in a neurofibromatosis 1 astrocytoma. Journal of Neuropathology and Experimental Neurology 59, 759-767Google Scholar
48Zhang, Y.Y. et al. (1998) Nf1 regulates hematopoietic progenitor cell growth and ras signaling in response to multiple cytokines. Journal of Experimental Medicine 187, 1893-1902CrossRefGoogle ScholarPubMed
49Holtkamp, N. et al. (2008) EGFR and erbB2 in malignant peripheral nerve sheath tumors and implications for targeted therapy. Neuro-Oncology 10, 946-957CrossRefGoogle ScholarPubMed
50Mawrin, C. et al. (2002) Immunohistochemical and molecular analysis of p53, RB, and PTEN in malignant peripheral nerve sheath tumors. Virchows Archiv 440, 610-615Google Scholar
51Schneider-Stock, R. et al. (1997) p53 gene mutations in soft-tissue sarcomas–correlations with p53 immunohistochemistry and DNA ploidy. Journal of Cancer Research and Clinical Oncology 123, 211-218Google Scholar
52Kindblom, L.G. et al. (1995) Immunohistochemical and molecular analysis of p53, MDM2, proliferating cell nuclear antigen and Ki67 in benign and malignant peripheral nerve sheath tumours. Virchows Archiv 427, 19-26Google Scholar
53Kourea, H.P. et al. (1999) Deletions of the INK4A gene occur in malignant peripheral nerve sheath tumors but not in neurofibromas. American Journal of Pathology 155, 1855-1860Google Scholar
54Nielsen, G.P. et al. (1999) Malignant transformation of neurofibromas in neurofibromatosis 1 is associated with CDKN2A/p16 inactivation. American Journal of Pathology 155, 1879-1884Google Scholar
55Kourea, H.P. et al. (1999) Expression of p27(kip) and other cell cycle regulators in malignant peripheral nerve sheath tumors and neurofibromas: the emerging role of p27(kip) in malignant transformation of neurofibromas. American Journal of Pathology 155, 1885-1891CrossRefGoogle ScholarPubMed
56Perry, A. et al. (2002) Differential NF1, p16, and EGFR patterns by interphase cytogenetics (FISH) in malignant peripheral nerve sheath tumor (MPNST) and morphologically similar spindle cell neoplasms. Journal of Neuropathology and Experimental Neurology 61, 702-709Google Scholar
57Mantripragada, K.K. et al. (2008) High-resolution DNA copy number profiling of malignant peripheral nerve sheath tumors using targeted microarray-based comparative genomic hybridization. Clinical Cancer Research 14, 1015-1024Google Scholar
58Theos, A. and Korf, B.R. (2006) Pathophysiology of neurofibromatosis type 1. Annals of Internal Medicine 144, 842-849Google Scholar
59Ballester, R. et al. (1990) The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 63, 851-859Google Scholar
60Xu, G.F. et al. (1990) The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. Cell 63, 835-841Google Scholar
61Daum, G. et al. (1994) The ins and outs of Raf kinases. Trends in Biochemical Sciences 19, 474-480CrossRefGoogle ScholarPubMed
62Fu, H.W. and Casey, P.J. (1999) Enzymology and biology of CaaX protein prenylation. Recent Progress in Hormone Research 54, 315-342; discussion 342–313Google Scholar
63Rubio, I. et al. (1999) Farnesylation of Ras is important for the interaction with phosphoinositide 3-kinase gamma. European Journal of Biochemistry 266, 70-82CrossRefGoogle ScholarPubMed
64Basso, A.D., Kirschmeier, P. and Bishop, W.R. (2006) Lipid posttranslational modifications. Farnesyl transferase inhibitors. Journal of Lipid Research 47, 15-31Google Scholar
65Roy, S. et al. (2005) Individual palmitoyl residues serve distinct roles in H-ras trafficking, microlocalization, and signaling. Molecular and Cellular Biology 25, 6722-6733CrossRefGoogle ScholarPubMed
66Wong, W.W. et al. (2002) HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis. Leukemia 16, 508-519Google Scholar
67Morgan, M.A., Ganser, A. and Reuter, C.W. (2003) Therapeutic efficacy of prenylation inhibitors in the treatment of myeloid leukemia. Leukemia 17, 1482-1498Google Scholar
68Mendola, C.E. and Backer, J.M. (1990) Lovastatin blocks N-ras oncogene-induced neuronal differentiation. Cell Growth and Differentiation 1, 499-502Google Scholar
69Sebti, S.M., Tkalcevic, G.T. and Jani, J.P. (1991) Lovastatin, a cholesterol biosynthesis inhibitor, inhibits the growth of human H-ras oncogene transformed cells in nude mice. Cancer Communications 3, 141-147Google Scholar
70Wojtkowiak, J.W. et al. (2008) Induction of apoptosis in neurofibromatosis type 1 malignant peripheral nerve sheath tumor cell lines by a combination of novel farnesyl transferase inhibitors and lovastatin. Journal of Pharmacology and Experimental Therapeutics 326, 1-11Google Scholar
71Krab, L.C. et al. (2008) Effect of simvastatin on cognitive functioning in children with neurofibromatosis type 1: a randomized controlled trial. Journal of the American Medical Association 300, 287-294Google Scholar
72Sun, J. et al. (1998) Both farnesyltransferase and geranylgeranyltransferase I inhibitors are required for inhibition of oncogenic K-Ras prenylation but each alone is sufficient to suppress human tumor growth in nude mouse xenografts. Oncogene 16, 1467-1473Google Scholar
73Rowell, C.A. et al. (1997) Direct demonstration of geranylgeranylation and farnesylation of Ki-Ras in vivo. Journal of Biological Chemistry 272, 14093-14097Google Scholar
74Yan, N. et al. (1995) Farnesyltransferase inhibitors block the neurofibromatosis type I (NF1) malignant phenotype. Cancer Research 55, 3569-3575Google ScholarPubMed
75Widemann, B.C. et al. (2006) Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitor tipifarnib in children with refractory solid tumors or neurofibromatosis type I and plexiform neurofibromas. Journal of Clinical Oncology 24, 507-516Google Scholar
76Chang, F. et al. (2003) Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention. Leukemia 17, 1263-1293Google Scholar
77Lavoie, J.N. et al. (1996) Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. Journal of Biological Chemistry 271, 20608-20616Google Scholar
78Katz, M.E. and McCormick, F. (1997) Signal transduction from multiple Ras effectors. Current Opinion in Genetics and Development 7, 75-79CrossRefGoogle ScholarPubMed
79Rini, B.I. (2007) Sunitinib. Expert Opinion on Pharmacotherapy 8, 2359-2369Google Scholar
80Maki, R.G. et al. (2008) Sorafenib Sarcoma Study Group Updated results of a phase II study of oral multi-kinase inhibitor sorafenib in sarcomas, CTEP study #7060. Journal of Clinical Oncology 26 (May 20 Suppl: ASCO Annual Meeting Proceedings), Abstract 10531Google Scholar
81Diwakar, G. et al. (2008) Neurofibromin as a regulator of melanocyte development and differentiation. Journal of Cell Science 121, 167-177Google Scholar
82Dilworth, J.T. et al. (2006) Molecular targets for emerging anti-tumor therapies for neurofibromatosis type 1. Biochemical Pharmacology 72, 1485-1492Google Scholar
83Johansson, G. et al. (2008) Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors. Molecular Cancer Therapeutics 7, 1237-1245Google Scholar
84Guertin, D.A. and Sabatini, D.M. (2005) An expanding role for mTOR in cancer. Trends in Molecular Medicine 11, 353-361Google Scholar
85LoPiccolo, J. et al. (2008) Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resistance Updates 11, 32-50Google Scholar
86Zou, C.Y. et al. (2009) Dual targeting of AKT and mammalian target of rapamycin: A potential therapeutic approach for malignant peripheral nerve sheath tumor. Molecular Cancer Therapeutics May 5; [Epub ahead of print]Google Scholar
87Vezina, C., Kudelski, A. and Sehgal, S.N. (1975) Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. Journal of Antibiotics 28, 721-726Google Scholar
88Sabatini, D.M. (2006) mTOR and cancer: insights into a complex relationship. Nature Reviews Cancer 6, 729-734Google Scholar
89Wan, X. and Helman, L.J. (2007) The biology behind mTOR inhibition in sarcoma. Oncologist 12, 1007-1018Google Scholar
90Guba, M. et al. (2002) Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nature Medicine 8, 128-135Google Scholar
91Sun, S.Y. et al. (2005) Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Research 65, 7052-7058Google Scholar
92Wang, X. et al. (2007) Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and Mnk-mediated eukaryotic translation initiation factor 4E phosphorylation. Molecular and Cellular Biology 27, 7405-7413Google Scholar
93Mita, M.M. et al. (2008) Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. Journal of Clinical Oncology 26, 361-367CrossRefGoogle ScholarPubMed
94Chawla, S.P. et al. (2007) Survival results of AP23573, a novel mTOR inhibitor, in patients with advanced soft tissue or bone sarcomas: update of a phase II trial. Journal of Clinical Oncology 25 (June 20 Suppl: ASCO Annual Meeting Proceedings), Abstract 10076Google Scholar
95Fetterly, G.J. et al. (2008) Pharmacokinetics of oral deforolimus (AP23573, MK-8669). Journal of Clinical Oncology 26 (May 20 Suppl: ASCO Annual Meetings Proceedings), Abstract 14555Google Scholar
96 [No authors listed] ClinicalTrials.gov. A pivotal trial to determine the efficacy and safety of AP23573 when administered as maintenance therapy to patients with metastatic soft-tissue or bone sarcomas. http://clinicaltrials.gov/ct2/show/NCT00538239Google Scholar
97Raynaud, F.I. et al. (2007) Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases. Cancer Research 67, 5840-5850Google Scholar
98Gschwind, A., Fischer, O.M. and Ullrich, A. (2004) The discovery of receptor tyrosine kinases: targets for cancer therapy. Nature Reviews Cancer 4, 361-370Google Scholar
99Yarden, Y. (2001) The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. European Journal of Cancer 37 (Suppl 4), S3-8Google Scholar
100DeClue, J.E. et al. (2000) Epidermal growth factor receptor expression in neurofibromatosis type 1-related tumors and NF1 animal models. Journal of Clinical Investigation 105, 1233-1241Google Scholar
101Tawbi, H. et al. (2008) Epidermal growth factor receptor expression and mutational analysis in synovial sarcomas and malignant peripheral nerve sheath tumors. Oncologist 13, 459-466Google Scholar
102Albritton, K.H. et al. (2008) Phase II study of erlotinib in metastatic or unresectable malignant peripheral nerve sheath tumors (MPNST). Journal of Clinical Oncology 24 (June 20 Suppl: ASCO Annual Meeting Proceedings), Abstract 9518Google Scholar
103Li, H. et al. (2002) Epidermal growth factor receptor signaling pathways are associated with tumorigenesis in the Nf1:p53 mouse tumor model. Cancer Research 62, 4507-4513Google ScholarPubMed
104Ling, B.C. et al. (2005) Role for the epidermal growth factor receptor in neurofibromatosis-related peripheral nerve tumorigenesis. Cancer Cell 7, 65-75Google Scholar
105Holtkamp, N. et al. (2004) Subclassification of nerve sheath tumors by gene expression profiling. Brain Pathology 14, 258-264Google Scholar
106Keizman, D. et al. (2009) Expression and significance of EGFR in malignant peripheral nerve sheath tumor. Journal of Neuro-Oncology 94, 383-388Google Scholar
107Raymond, E., Faivre, S. and Armand, J.P. (2000) Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy. Drugs 60 (Suppl 1), 15-23; discussion 41-12Google Scholar
108Su, W. et al. (2003) Malignant peripheral nerve sheath tumor cell invasion is facilitated by Src and aberrant CD44 expression. Glia 42, 350-358Google Scholar
109Mahller, Y.Y. et al. (2007) Oncolytic HSV and erlotinib inhibit tumor growth and angiogenesis in a novel malignant peripheral nerve sheath tumor xenograft model. Molecular Therapy 15, 279-286Google Scholar
110Herbst, R.S. et al. (2002) Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase I trial. Journal of Clinical Oncology 20, 3815-3825Google Scholar
111Benvenuti, S. et al. (2007) Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Research 67, 2643-2648Google Scholar
112van Zandwijk, N. et al. (2007) EGFR and KRAS mutations as criteria for treatment with tyrosine kinase inhibitors: retro- and prospective observations in non-small-cell lung cancer. Annals of Oncology 18, 99-103Google Scholar
113Perrone, F. et al. (2009) PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Annals of Oncology 20, 84-90Google Scholar
114Frattini, M. et al. (2007) PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. British Journal of Cancer 97, 1139-1145Google Scholar
115Geyer, C.E. et al. (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. New England Journal of Medicine 355, 2733-2743Google Scholar
116Heldin, C.H. and Westermark, B. (1984) Growth factors: mechanism of action and relation to oncogenes. Cell 37, 9-20Google Scholar
117Betsholtz, C., Karlsson, L. and Lindahl, P. (2001) Developmental roles of platelet-derived growth factors. Bioessays 23, 494-507Google Scholar
118Badache, A. and De Vries, G.H. (1998) Neurofibrosarcoma-derived Schwann cells overexpress platelet-derived growth factor (PDGF) receptors and are induced to proliferate by PDGF BB. Journal of Cellular Physiology 177, 334-342Google Scholar
119Holtkamp, N. et al. (2004) Differentially expressed genes in neurofibromatosis 1-associated neurofibromas and malignant peripheral nerve sheath tumors. Acta Neuropathologica 107, 159-168Google Scholar
120Holtkamp, N. et al. (2006) Mutation and expression of PDGFRA and KIT in malignant peripheral nerve sheath tumors, and its implications for imatinib sensitivity. Carcinogenesis 27, 664-671Google Scholar
121Dang, I. and DeVries, G.H. (2005) Schwann cell lines derived from malignant peripheral nerve sheath tumors respond abnormally to platelet-derived growth factor-BB. Journal of Neuroscience Research 79, 318-328Google Scholar
122Jones, S.M. and Kazlauskas, A. (2000) Connecting signaling and cell cycle progression in growth factor-stimulated cells. Oncogene 19, 5558-5567Google Scholar
123Aoki, M. et al. (2007) Imatinib mesylate inhibits cell invasion of malignant peripheral nerve sheath tumor induced by platelet-derived growth factor-BB. Laboratory Investigation 87, 767-779Google Scholar
124Buchdunger, E. et al. (2000) Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. Journal of Pharmacology and Experimental Therapeutics 295, 139-145Google Scholar
125Badache, A., Muja, N. and De Vries, G.H. (1998) Expression of Kit in neurofibromin-deficient human Schwann cells: role in Schwann cell hyperplasia associated with type 1 neurofibromatosis. Oncogene 17, 795-800Google Scholar
126Reilly, K.M. and Van Dyke, T. (2008) It takes a (dysfunctional) village to raise a tumor. Cell 135, 408-410Google Scholar
127Zhu, Y. et al. (2002) Neurofibromas in NF1: Schwann cell origin and role of tumor environment. Science 296, 920-922Google Scholar
128DuBois, S. and Demetri, G. (2007) Markers of angiogenesis and clinical features in patients with sarcoma. Cancer 109, 813-819Google Scholar
129Hicklin, D.J. and Ellis, L.M. (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. Journal of Clinical Oncology 23, 1011-1027Google Scholar
130Harper, S.J. and Bates, D.O. (2008) VEGF-A splicing: the key to anti-angiogenic therapeutics? Nature Reviews Cancer 8, 880-887Google Scholar
131Wasa, J. et al. (2008) Differential expression of angiogenic factors in peripheral nerve sheath tumors. Clinical and Experimental Metastasis 25, 819-825CrossRefGoogle ScholarPubMed
132Angelov, L. et al. (1999) Inhibition of angiogenesis by blocking activation of the vascular endothelial growth factor receptor 2 leads to decreased growth of neurogenic sarcomas. Cancer Research 59, 5536-5541Google ScholarPubMed
133D'Adamo, D.R. et al. (2005) Phase II study of doxorubicin and bevacizumab for patients with metastatic soft-tissue sarcomas. Journal of Clinical Oncology 23, 7135-7142Google Scholar
134Verschraegen, C.F. et al. (2008) Phase I/II study of docetaxel, gemcitabine, and bevacizumab in patients with advanced or recurrent soft tissue sarcoma. Journal of Clinical Oncology 25 (June 20 Suppl: ASCO Annual Meeting Proceedings), Abstract 10056Google Scholar
135Hensley, M.L. et al. (2002) Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. Journal of Clinical Oncology 20, 2824-2831Google Scholar

Further reading, resources and contacts

Ongoing studies available for MPNST patients are provided as a service of the US National Institutes of Health:

Grobmyer, S.R. et al. (2008) Malignant peripheral nerve sheath tumor: molecular pathogenesis and current management considerations. Journal of Surgical Oncology 97, 340-349Google Scholar
Gupta, G., Mammis, A. and Maniker, A. (2008) Malignant peripheral nerve sheath tumors. Neurosurgery Clinics of North America 19, 533-543Google Scholar
Rubin, J.B. and Gutmann, D.H. (2005) Neurofibromatosis type 1 – a model for nervous system tumour formation? Nature Reviews Cancer 5, 557-564Google Scholar
Gschwind, A., Fischer, O.M. and Ullrich, A. (2004) The discovery of receptor tyrosine kinases: targets for cancer therapy. Nature Reviews Cancer 4, 361-370Google Scholar
Sebolt-Leopold, J.S. and Herrera, R. (2004) Targeting the mitogen-activated protein kinase cascade to treat cancer. Nature Reviews Cancer 4, 937-947Google Scholar
Sabatini, D.M. (2006) mTOR and cancer: insights into a complex relationship. Nature Reviews Cancer 6, 729-734Google Scholar
http://clinicaltrials.gov/ct2/results?cond=%22Nerve+Sheath+Neoplasms%22Google Scholar
http://sarcomahelp.org/learning_center/mpnst.htmlGoogle Scholar
http://www.sarctrials.org/homeGoogle Scholar
Grobmyer, S.R. et al. (2008) Malignant peripheral nerve sheath tumor: molecular pathogenesis and current management considerations. Journal of Surgical Oncology 97, 340-349Google Scholar
Gupta, G., Mammis, A. and Maniker, A. (2008) Malignant peripheral nerve sheath tumors. Neurosurgery Clinics of North America 19, 533-543Google Scholar
Rubin, J.B. and Gutmann, D.H. (2005) Neurofibromatosis type 1 – a model for nervous system tumour formation? Nature Reviews Cancer 5, 557-564Google Scholar
Gschwind, A., Fischer, O.M. and Ullrich, A. (2004) The discovery of receptor tyrosine kinases: targets for cancer therapy. Nature Reviews Cancer 4, 361-370Google Scholar
Sebolt-Leopold, J.S. and Herrera, R. (2004) Targeting the mitogen-activated protein kinase cascade to treat cancer. Nature Reviews Cancer 4, 937-947Google Scholar
Sabatini, D.M. (2006) mTOR and cancer: insights into a complex relationship. Nature Reviews Cancer 6, 729-734Google Scholar
http://clinicaltrials.gov/ct2/results?cond=%22Nerve+Sheath+Neoplasms%22Google Scholar
http://sarcomahelp.org/learning_center/mpnst.htmlGoogle Scholar
http://www.sarctrials.org/homeGoogle Scholar