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

描述（由申请人提供）：1型神经纤维瘤病（NF1）患者发展为周围神经良性肿瘤，称为神经纤维瘤和恶性周围神经鞘肿瘤（MPNSTs），这是一种起源于神经纤维瘤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肿瘤抑制基因如NF1和p53的突变合作，促进MPNST的肿瘤发生。我们假设来自神经调节蛋白-1 （NRG-1）生长和分化因子家族的蛋白质是促进MPNSTs中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同种异构体胶质生长因子-23 （GGF23）的转基因小鼠（P0-GGF23小鼠），发现这些动物发生了多发性神经纤维瘤和mpnst。我们还发现，人类神经纤维瘤和MPNST共表达多种NRG-1亚型及其erbB受体，并且用小分子erbB抑制剂PD158780和PD168393治疗后，人类MPNST细胞系的增殖受到严重抑制。基于这些初步研究，我们假设erbB受体的组成性激活对人MPNST细胞的增殖和/或存活至关重要，而PD168393和/或4D5 （Herceptin的衍生抗erbB2抗体）降低erbB活性将阻碍这些细胞的增殖和存活。我们将与人类MPNST细胞系、P0-GGF23小鼠和P0-GGF23小鼠模型中MPNST衍生的小鼠细胞系进行合作，以严格验证以下假设：1)抑制NRG-1受体（erbB2、erbB3和/或erbB4）会降低MPNST细胞在体内的增殖和/或存活；2)NRG-1通过激活特定的神经纤维蛋白调节的Ras蛋白及其下游效应物来促进MPNST细胞的增殖和/或存活。这些研究将严格评估利用有效的、现有的erbB抑制剂治疗MPNSTs的新疗法，并将为未来开发更有效的治疗方法奠定坚实的基础，这些治疗方法精确地针对NRG-1调节的关键细胞质信号分子，单独或与erbB抑制剂联合治疗nf1相关的MPNSTs。1型神经纤维瘤病（NF1）患者会发展为周围神经良性肿瘤，即神经纤维瘤，以及恶性周围神经鞘肿瘤（MPNSTs），这是一种起源于神经纤维瘤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肿瘤抑制基因如NF1和p53的突变合作，促进MPNST的肿瘤发生。

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.