Therapeutic Targeting of Receptor Tyrosine Kinase Hierarchies in Schwann Cell Neoplasms

恶性周围神经鞘瘤(MPNST)是源于雪旺细胞的侵袭性肿瘤。 在1型神经纤维瘤病(NF1)患者中常见的以及零星出现在 普通人口。MPNST患者的预后是严峻的，因为目前的放化疗- 治疗方案是无效的。RAS过度激活，由功能NF1的丧失引起，通常在 与其他抑癌基因突变(CDKN2A、TP53或SUZ12)结合是MPNSTs的特征。 这表明抑制RAS信号转导可能是治疗MPNSTs的有效手段。然而，RAS 已经被证明很难直接针对治疗，而针对RAS效应通路的药物还没有 对MPNSTs患者有效。这导致我们研究了治疗靶向的有效性。 RAS的关键上游激活物，如MPNSTs中的受体酪氨酸激酶(RTK)。我们研究了这个角色 对散发性和NF1相关的MPNST细胞系中的全部58个RTK进行药理学和基因组水平的研究 ShRNA筛选结合全面的基因组分析。我们基于RTK的药理筛查 证实了广谱ERBB抑制剂Canertinib和IGF1受体(IGF1R)抑制剂 鬼臼甲素能有效抑制MPNST生长和RAS激活。与这些结果保持一致，我们的 基因组规模的shRNA筛选证实ERBB3和IGF1R是MPNST细胞生长所必需的。 基于这些发现，我们假设MPNST在体内的生长依赖于 ErbB3和IGF1R以及同时针对这些关键RTK的治疗方案将 有效治疗MPNST。我们将在三个具体目标上严格检验这一假设。在具体目标1中，我们 将检验针对ERBB受体和IGF1R的联合疗法将有效抑制 MPNST异种移植瘤的体内生长。我们还将确定其他RTK是否可重复激活以推广 对ERBB和IGF1R抑制剂的耐药性与肿瘤复发。在特定的目标2中，我们将测试在体内的作用 ERBB3在异种移植瘤和基因工程小鼠模型肿瘤启动和药物敏感性中的作用 (GEMM)。在具体目标3中，我们将检验药物复发是由“继发性”RTK介导的假说。 补偿ERBB和IGF1R的抑制，以驱动关键的细胞质信号通路。这项实验 因此，该计划将使我们能够合理地为目前无法治疗的肉瘤类型开发有效的治疗方法。AS NF1突变和RAS过度激活在其他散发性肿瘤类型中越来越被认识到，我们的 这种方法在许多其他类型的人类癌症上都有更广泛的应用。

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive neoplasms derived from the Schwann cell lineage that occur commonly in patients with neurofibromatosis type 1 (NF1) as well as sporadically in the general population. The prognosis for patients with an MPNST is grim, as current radio- and chemo- therapeutic regimens are ineffective. Ras hyperactivation, which results from loss of functional NF1, typically in combination with other tumor suppressor mutations (CDKN2A, TP53, or SUZ12), is characteristic of MPNSTs. This suggests that inhibiting Ras signaling would be an effective means of treating MPNSTs. However, Ras has proven to be difficult to directly target therapeutically and drugs targeting Ras effector pathways have not been effective in patients with MPNSTs. This led us to investigate the effectiveness of therapeutically targeting key upstream activators of Ras, such as receptor tyrosine kinases (RTKs) in MPNSTs. We examined the role of all 58 RTKs in sporadic and NF1-associated MPNST cell lines using both pharmacologic and genome-scale shRNA screens coupled with comprehensive genomic analyses. Our RTK-based pharmacologic screens established that the broad-spectrum ERBB inhibitor canertinib and the IGF1 receptor (IGF1R) inhibitor picropodophyllin effectively inhibited MPNST growth and Ras activation. In keeping with these results, our genome-scale shRNA screens established ERBB3 and IGF1R as essential for the growth of MPNST cells. Based on these findings, we hypothesize that MPNST growth in vivo is dependent on the action of ERBB3 and IGF1R and that therapeutic regimens simultaneously targeting these key RTKs will effectively treat MPNSTs. We will rigorously test this hypothesis in three Specific Aims. In Specific Aim 1, we will test the hypothesis that combinatorial therapies targeting ERBB receptors and IGF1R will effectively inhibit MPNST xenograft growth in vivo. We will also determine if other RTKs are reproducibly activated to promote resistance to ERBB and IGF1R inhibitors and tumor recurrence. In Specific Aim 2, we will test the in vivo role of ERBB3 in tumor initiation and drug sensitivity using xenografts and a genetically engineered mouse model (GEMM). In Specific Aim 3, we will test the hypothesis that drug relapse is mediated by “secondary” RTKs that compensate for ERBB and IGF1R inhibition to drive key cytoplasmic signaling pathways. This experimental plan will thus allow us to logically develop effective therapies for a currently untreatable type of sarcoma. As NF1 mutations and Ras hyperactivation are increasingly recognized in other sporadic tumor types, our approach has broader application to many other types of human cancers.!