Novel Treatment of NF-1 Associated Malignant Peripheral Nerve Sheath Tumors

NF-1 相关恶性周围神经鞘瘤的新疗法

• 批准号: 7751842
• 负责人: STEVEN L. CARROLL
• 金额: $ 30.09万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-07 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7751842
• 关键词: 1-Phosphatidylinositol 3-Kinase; Animals; Antibodies; Benign; Cell Proliferation; Cell Survival; Cells; Clinical Research; DNA Synthesis Inhibition; Development; Differentiation and Growth; ERBB2 gene; ErbB4 gene; Family; Figs - dietary; Future; Glial Growth Factor; Goals; Growth Factor; Human; Immunoblotting; Inhibitory Concentration 50; Investigation; Knowledge; Malignant Peripheral Nerve Sheath Tumor; Mediating; Molecular; Mus; Mutation; Neoplasms; Neoplastic Schwann Cell; Neuregulin 1; Neurofibromatoses; Neurofibromatosis 1; Neurofibromatosis Type 1 Protein; Paper; Pathway interactions; Patients; Peripheral Nervous System Neoplasms; Protein Isoforms; Proteins; Publishing; Reporting; Roche brand of trastuzumab; Role; Schwann Cells; Signal Pathway; Signal Transduction; Signaling Molecule; Sirolimus; Stimulation of Cell Proliferation; Suggestion; TP53 gene; Testing; Transgenic Mice; Tumor Cell Line; Tumor Suppressor Genes; Twin Multiple Birth; Wild Type Mouse; base; cell growth; effective therapy; human FRAP1 protein; improved; in vivo; inhibitor/antagonist; interest; mind control; mouse model; neoplastic cell; neurofibroma; novel; preclinical study; ras Proteins; receptor; research study; sciatic nerve; tumor; tumorigenesis

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：神经纤维瘤病1型（NF1）患者形成了被称为神经纤维瘤和恶性周围神经鞘瘤肿瘤（MPNST）的良性肿瘤，这是一种高度积极的schwann细胞Neoplasm，来自神经纤维瘤。人们认为，生长因子的不当刺激与肿瘤抑制基因（如NF1和p53）的突变合作，以促进MPNST肿瘤发生。我们假设来自Neuregulin-1（NRG-1）生长和分化因子家族的蛋白质是促进MPNST中肿瘤schwann细胞的增殖和/或存活的分子之一。为了检验这一假设，我们在Schwann细胞（P0-GGF23小鼠）中产生了表达NRG-1同工胶质胶质生长因子23（GGF23）的转基因小鼠，发现这些动物会形成多种神经纤维纤维瘤和MPNST。我们还发现，人神经纤维瘤和MPNSTS共表达多种NRG-1同工型及其ERBB受体，并且通过用小分子ERBB抑制剂PD158780和PD168393的小分子ERBB抑制剂处理，人类MPNST细胞系的增殖受到了极大的抑制。基于这些初步研究，我们假设ERBB受体的构型激活对于人MPNST细胞的增殖和/或存活至关重要，并且可以降低ERBB活性，而ERBB活性则使用PD168393和/或4D5（抗赫普蛋白的抗体抗体，赫斯特蛋白是衍生的，将衍生出这些细胞和这些细胞，这些抗体都会使这些细胞衍生和幸存。我们将与人类MPNST细胞系合作，这是源自P0-GGF23小鼠的MPNST和P0-GGF23小鼠模型的小鼠系，以严格检验：1）抑制NRG-1受体（ERBB2，ERBB3和/或ERBB4）的抑制作用，降低了NRG-1受体（ERBB2和/或ERBB4）的细胞和/或降低了2个细胞，并在MPN中降低了2）。通过激活特定神经纤维蛋白调节的RAS蛋白及其下游效应子来促进MPNST细胞的增殖和/或存活。这些研究将对使用有效的现有ERBB抑制剂的MPNST进行批判性评估，并将为未来更有效的疗法的未来开发建立强有力的基础，即精确靶向关键的NRG-1调节的细胞质信号分子，单独或与ERBB抑制剂组合，在NF1与NF1-MPNSTS中相结合。神经纤维瘤病1型（NF1）患者形成了被称为神经纤维瘤的周围神经的良性肿瘤和恶性周围神经鞘瘤（MPNSTS），这是一种高度侵略性的Schwann细胞肿瘤，由神经纤维瘤产生。人们认为，生长因子的不当刺激与肿瘤抑制基因（如NF1和p53）的突变合作，以促进MPNST肿瘤发生。