Patients with neurofibromatosis type 1 (NF1) develop benign tumors of peripheral nerve known as neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs), a highly aggressive form of Schwann cell neoplasm that arises from neurofibromas. Inappropriate stimulation by growth factors is thought to cooperate with mutations of tumor suppressor genes such as NF1 and p53 to promote MPNST tumorigenesis. We hypothesized that proteins from the neuregulin-1 (NRG-1) family of growth and differentiation factors are among the molecules promoting the proliferation and/or survival of neoplastic Schwann cells in MPNSTs. To test this hypothesis, we generated transgenic mice expressing the NRG-1 isoform glial growth factor-23 (GGF23) in Schwann cells (P0-GGF23 mice) and found that these animals develop multiple neurofibromas and MPNSTs. We have also found that human neurofibromas and MPNSTs coexpress multiple NRG-1 isoforms and their erbB receptors and that the proliferation of human MPNST cell lines is profoundly inhibited by treatment with the small molecular erbB inhibitors PD158780 and PD168393. Based on these preliminary studies, we hypothesize that constitutive activation of erbB receptors is essential for the proliferation and/or survival of human MPNST cells and that decreasing erbB activity with PD168393 and/or 4D5, the anti-erbB2 antibody from which Herceptin was derived, will retard the proliferation and survival of these cells. We will partner human MPNST cell lines, mouse lines derived from MPNSTs arising in P0-GGF23 mice and the P0- GGF23 mouse model to critically test the hypotheses that: 1) inhibition of the NRG-1 receptors (erbB2, erbB3 and/or erbB4) decreases the proliferation and/or survival of MPNST cells in vivo and 2) NRG-1 promotes the proliferation and/or survival of MPNST cells by activating specific neurofibromin-regulated Ras proteins and their downstream effectors. These studies will critically evaluate novel therapies for MPNSTs that utilize effective, existing erbB inhibitors and will establish a strong basis for the future development of even more effective therapies precisely targeting critical NRG-1 regulated cytoplasmic signaling molecules, alone or in combination with erbB inhibitors, in NF1-associated MPNSTs. Patients with neurofibromatosis type 1 (NF1) develop benign tumors of peripheral nerve known as neurofibromas, and malignant peripheral nerve sheath tumors (MPNSTs), a highly aggressive form of Schwann cell neoplasm that arises from neurofibromas. Inappropriate stimulation by growth factors is thought to cooperate with mutations of tumor suppressor genes such as NF1 and p53 to promote MPNST tumorigenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA122804-05
Application #
8196983
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Jhappan, Chamelli
Project Start
2007-12-07
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2013-11-30
Support Year
5
Fiscal Year
2012
Total Cost
$291,849
Indirect Cost
$90,574
Name
University of Alabama Birmingham
Department
Pathology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Brosius, Stephanie N; Turk, Amy N; Byer, Stephanie J et al. (2014) Combinatorial therapy with tamoxifen and trifluoperazine effectively inhibits malignant peripheral nerve sheath tumor growth by targeting complementary signaling cascades. J Neuropathol Exp Neurol 73:1078-90
Brosius, Stephanie N; Turk, Amy N; Byer, Stephanie J et al. (2014) Neuregulin-1 overexpression and Trp53 haploinsufficiency cooperatively promote de novo malignant peripheral nerve sheath tumor pathogenesis. Acta Neuropathol 127:573-91
Kaza, Niroop; Kohli, Latika; Graham, Christopher D et al. (2014) BNIP3 regulates AT101 [(-)-gossypol] induced death in malignant peripheral nerve sheath tumor cells. PLoS One 9:e96733
Byer, Stephanie J; Brossier, Nicole M; Peavler, Lafe T et al. (2013) Malignant peripheral nerve sheath tumor invasion requires aberrantly expressed EGF receptors and is variably enhanced by multiple EGF family ligands. J Neuropathol Exp Neurol 72:219-33
Kazmi, Syed J; Byer, Stephanie J; Eckert, Jenell M et al. (2013) Transgenic mice overexpressing neuregulin-1 model neurofibroma-malignant peripheral nerve sheath tumor progression and implicate specific chromosomal copy number variations in tumorigenesis. Am J Pathol 182:646-67
Kohli, Latika; Kaza, Niroop; Coric, Tatjana et al. (2013) 4-Hydroxytamoxifen induces autophagic death through K-Ras degradation. Cancer Res 73:4395-405
Kohli, Latika; Kaza, Niroop; Carroll, Steven L et al. (2013) Protector turns predator: Autophagic death via selective degradation of KRAS. Autophagy 9:1438-9
Carroll, Steven L (2012) Molecular mechanisms promoting the pathogenesis of Schwann cell neoplasms. Acta Neuropathol 123:321-48
Liu, R-M; van Groen, T; Katre, A et al. (2011) Knockout of plasminogen activator inhibitor 1 gene reduces amyloid beta peptide burden in a mouse model of Alzheimer's disease. Neurobiol Aging 32:1079-89
Byer, Stephanie J; Eckert, Jenell M; Brossier, Nicole M et al. (2011) Tamoxifen inhibits malignant peripheral nerve sheath tumor growth in an estrogen receptor-independent manner. Neuro Oncol 13:28-41

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