Therapeutic Targeting of Receptor Tyrosine Kinase Hierarchies in Schwann Cell Neoplasms

恶性周围神经鞘瘤是来源于雪旺细胞的侵袭性肿瘤 通常发生在1型神经纤维瘤病（NF 1）患者中，也偶尔发生在 一般人口。MPNST患者的预后是严峻的，因为目前的放疗和化疗- 治疗方案无效。Ras过度活化，其由功能性NF 1的丧失引起，通常在 与其他肿瘤抑制基因突变（CDKN 2A、TP 53或SUZ 12）的组合是MPNST的特征。 这表明抑制Ras信号传导将是治疗MPNST的有效手段。然而，Ras 已经证明很难直接靶向治疗，靶向Ras效应通路的药物还没有 对MPNST患者有效。这促使我们研究治疗靶向的有效性， Ras的关键上游激活剂，如MPNST中的受体酪氨酸激酶（RTK）。我们研究了 使用药理学和基因组规模，在散发性和NF 1相关MPNST细胞系中的所有58种RTK中， shRNA筛选结合全面的基因组分析。我们基于RTK的药理学筛选 确定了广谱ERBB抑制剂canertinib和IGF 1受体（IGF 1 R）抑制剂 苦鬼臼脂素能有效抑制MPNST的生长和Ras的激活。根据这些结果，我们 基因组规模的shRNA筛选确定ERBB 3和IGF 1 R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 ERBB 3和IGF 1 R，同时靶向这些关键RTK的治疗方案将 有效治疗MPNST。我们将在三个具体目标中严格检验这一假设。在具体目标1中， 将检验靶向ERBB受体和IGF 1 R的组合疗法将有效抑制 体内MPNST异种移植物生长。我们还将确定其他RTK是否可重复激活，以促进 ERBB和IGF 1 R抑制剂的耐药性和肿瘤复发。在具体目标2中，我们将测试体内作用 使用异种移植物和基因工程小鼠模型研究ERBB 3在肿瘤发生和药物敏感性中的作用 （GEMM）.在具体目标3中，我们将检验药物复吸由“继发性”RTK介导的假设， 补偿ERBB和IGF 1 R抑制，以驱动关键的细胞质信号传导途径。该实验 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。作为 NF 1突变和Ras过度激活在其他散发性肿瘤类型中越来越多地被认识到，我们 这种方法对许多其他类型的人类癌症有更广泛的应用。

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.!