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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

基本信息

批准号：
7537237
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
项目类别：
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/7537237
关键词：
Animals Antibodies Benign Breast Adenocarcinoma Cell Line Cell Proliferation Cell Survival Clinical Trials Development Differentiation and Growth Dominant-Negative Mutation Drug Kinetics ERBB2 gene Effectiveness ErbB4 gene Family Foundations Future Gene Mutation Glial Growth Factor Growth Growth Factor HRAS gene Human Image In Vitro Individual Knowledge Light Luciferases Malignant Peripheral Nerve Sheath Tumor Mediating Mitogens Molecular Monoclonal Antibodies Mus Mutation NIH-III Mouse Neoplasms Neoplastic Schwann Cell Neuregulin 1 Neurofibromatoses Neurofibromatosis 1 Neurofibromatosis Type 1 Protein Pathogenesis Pathway interactions Patients Peripheral Nerve Sheath Neoplasm Peripheral Nervous System Neoplasms Pharmacodynamics Phosphotransferases Protein Isoforms Proteins RNA Interference Roche brand of trastuzumab Schwann Cells Signal Pathway Signaling Molecule Stimulation of Cell Proliferation Suppressor Mutations TP53 gene Testing Therapeutic Therapeutic Agents Toxic effect Transgenes Transgenic Mice Trastuzumab Tumor Cell Line Tumor Suppressor Genes Tumor Suppressor Proteins base effective therapy in vivo inhibitor/antagonist malignant breast neoplasm mouse model neoplastic cell neurofibroma neutralizing antibody novel overexpression preclinical study ras Proteins receptor research study response sciatic nerve small hairpin RNA therapeutic target tumor tumor growth tumorigenesis

项目摘要

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(申请人提供)：1型神经纤维瘤病(NF1)患者发展为称为神经纤维瘤的周围神经良性肿瘤和恶性周围神经鞘瘤(MPNSTs)，这是一种由神经纤维瘤引起的高度侵袭性的雪旺细胞肿瘤。生长因子的不适当刺激被认为与NF1和P53等肿瘤抑制基因的突变协同促进MPNST肿瘤的发生。我们推测，在MPNSTs中，神经调节蛋白-1(NRG-1)家族的生长和分化因子是促进肿瘤雪旺细胞增殖和/或存活的分子之一。为了验证这一假设，我们在雪旺细胞中产生了表达NRG-1异构体胶质生长因子-23(GGF23)的转基因小鼠(P0-GGF23小鼠)，并发现这些动物发展为多发性神经纤维瘤和MPNSTs。我们还发现，人神经纤维瘤和MPNST共表达多种NRG-1亚型及其erb B受体，小分子erb B抑制剂PD158780和PD168393可显著抑制人MPNST细胞系的增殖。在这些初步研究的基础上，我们假设erB受体的结构性激活对人MPNST细胞的增殖和/或生存是必不可少的，而用产生Herceptin的抗erbB2抗体PD168393和/或4D5降低erbB的活性将延缓这些细胞的增殖和生存。我们将与人MPNST细胞株、来源于P0-GGF23小鼠的MPNST小鼠细胞系和P0-GGF23小鼠模型合作，关键检验以下假设：1)抑制NRG-1受体(erbB2、erbB3和/或ERBB4)可降低体内MPNST细胞的增殖和/或存活；2)NRG-1通过激活特定的神经纤维蛋白调节的RAS蛋白及其下游效应分子促进MPNST细胞的增殖和/或存活。这些研究将对利用有效的、现有的erbB抑制剂治疗MPNSTs的新疗法进行关键评估，并将为未来开发更有效的疗法奠定坚实的基础，这些疗法精确地针对NF1相关MPNSTs中NRG-1调节的关键细胞质信号分子，或与erbB抑制剂联合使用。1型神经纤维瘤病(NF1)的患者会发展为周围神经良性肿瘤，称为神经纤维瘤，以及恶性周围神经鞘瘤(MPNSTs)，这是一种由神经纤维瘤引起的高度侵袭性的雪旺细胞肿瘤。生长因子的不适当刺激被认为与NF1和P53等肿瘤抑制基因的突变协同促进MPNST肿瘤的发生。