Identification of novel therapeutic combinations for NF2 schwannomas

鉴定 NF2 神经鞘瘤的新型治疗组合

• 批准号: 10564452
• 负责人: Steven P Angus
• 金额: $ 46.33万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10564452
• 关键词: Ablation; Acoustic Neuroma; Affect; Affinity Chromatography; Alleles; Benign; Bilateral; Biochemical; Brain Stem; Bromodomains and extra-terminal domain inhibitor; CRISPR screen; CRISPR/Cas technology; Cell Culture Techniques; Cells; Cessation of life; Characteristics; Clinic; Clinical Research; Clinical Trials; Data; Dependence; Development; Drug Combinations; Drug Synergism; Drug Targeting; Evaluation; Excision; Exhibits; FDA approved; Facial Muscles; Focal Adhesion Kinase 1; Generations; Genetic; Genetically Engineered Mouse; Genomic approach; Goals; Growth; Histology; Human; In Vitro; Incidence; Individual; Investigational Therapies; Kinetics; Knock-out; Laboratories; Link; Logistics; Loss of Heterozygosity; LoxP-flanked allele; MAP Kinase Gene; MEKs; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Modeling; Molecular; Morbidity - disease rate; Motor; Mus; Muscle Weakness; Mutation; Neurilemmoma; Neurofibromatosis 2; Neurofibromin 2; Neurologic; Operative Surgical Procedures; PTK2 gene; Pathologic; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I/II Clinical Trial; Phosphotransferases; Predisposition; Proteins; Rare Diseases; Receptor Protein-Tyrosine Kinases; Research Personnel; Resistance; Role; Schwann Cells; Signal Transduction; Spinal; Syndrome; Testing; Therapeutic; Toxic effect; Translations; Tumor Suppressor Genes; Tumor Tissue; Tyrosine Kinase Inhibitor; Vertebral column; Vertigo; Work; anaplastic lymphoma kinase; autosome; bilateral vestibular Schwannoma; cancer predisposition; chemotherapy; chronic neuropathic pain; chronic pain; combinatorial; crizotinib; deafness; early phase clinical trial; effective therapy; experimental study; hearing impairment; improved; in vivo; inhibitor; innovation; insight; kinase inhibitor; nervous system disorder; next generation; novel strategies; novel therapeutics; pharmacologic; pre-clinical; preclinical efficacy; preclinical study; precursor cell; progressive hearing loss; rare cancer; response; screening; single-cell RNA sequencing; small molecule; success; synergism; targeted treatment; transcriptome; translational potential; tumor; tumor growth; tumor progression; tumorigenesis; tumorigenic

PROJECT SUMMARY / ABSTRACT Neurofibromatosis type 2 (NF2) is an autosomal dominant cancer predisposition syndrome characterized by germline haploinsufficiency at the NF2 locus, which encodes Merlin. NF2 patients characteristically develop bilateral vestibular schwannomas (VS) and spinal schwannomas as a result of loss of heterozygosity of NF2 in Schwann cells or Schwann cell precursors. Although these tumors are largely benign, their growth can result in significant neurological deficiencies including, but not limited to, deafness, vertigo, facial muscle weakness, chronic neuropathic pain, and death. Because of the extensive morbidity associated with surgical removal of these tumors, there is an urgent need to develop pharmaceutical approaches to halt or reverse the progression of tumor growth in these patients. To date, no long-term effective therapies exist for these highly debilitating tumors. Given the challenging clinical trial logistics in a rare tumor predisposition syndrome such as NF2, it is critical to establish a strategy linking preclinical and clinical studies for rapid translational innovation and efficiency. We have developed genetically engineered mouse models (GEMMs) of NF2 that accurately recapitulate tumor growth kinetics and histopathologic characteristics observed in NF2 patients—VS and paraspinal schwannomas with 100% incidence, combined with progressive hearing loss that occurs with VS formation. Using the Nf2 GEMM, we determined that the FDA approved multi-receptor tyrosine kinase (RTK) inhibitor brigatinib reduced schwannoma tumor size and tumor number. Brigatinib is approved to treat cancer driven by another kinase, anaplastic lymphoma kinase (ALK) and two ALK inhibitors, crizotinib and brigatinib, have both shown preclinical efficacy against NF2-associated schwannomas and are under evaluation in active clinical trials. While our findings suggest a role for FAK1 in modulating tumor progression, our understanding of the role of FAK1 as a single target for NF2 tumors or in combination with other drug targets is incomplete. We propose to build on our recent preclinical work by genetic ablation of FAK1 (Ptk2) in murine (Nf2) and human (NF2) deficient Schwann cells to establish the role of FAK1 (Ptk2) in promoting the genesis of Nf2 deficient schwannomas and associated morbidities (Aim 1). Drug synergy screening with post-IND FAK inhibitors alone and in combination with RAF, MEK, and BET bromodomain inhibitors to target cooperating Merlin-regulated pathways (Aim 2), and unbiased CRISPR-Cas9 kinome knockout screening in murine and human cells to identify FAK1-dependent kinase vulnerabilities that can be exploited therapeutically, alone or in combination (Aim 3). Our overarching goal with experiments in this application is to identify drugs or drug combinations that could expediently proceed to phase I/II clinical trials for patients with this debilitating neurological disease.

项目总结/摘要 2型神经纤维瘤病（NF 2）是一种常染色体显性遗传的癌症易感综合征，其特征在于： 在NF 2基因座，编码梅林的种系单倍不足。NF 2患者特征性地发展为 双侧前庭神经鞘瘤（VS）和脊髓神经鞘瘤由于NF 2杂合性丢失， 许旺细胞或许旺细胞前体。虽然这些肿瘤大部分是良性的，但它们的生长可导致 严重的神经系统缺陷，包括但不限于耳聋、眩晕、面部肌肉无力， 慢性神经性疼痛和死亡。由于与手术切除相关的广泛发病率， 因此，迫切需要开发药物方法来阻止或逆转这些肿瘤的进展。 肿瘤的生长。迄今为止，对于这些高度衰弱的患者，还没有长期有效的治疗方法。 肿瘤的 鉴于在罕见的肿瘤易感综合征（如NF 2）中具有挑战性的临床试验物流， 关键是建立一个战略，将临床前和临床研究联系起来，以实现快速转化创新， 效率我们已经开发了NF 2的基因工程小鼠模型（GEMM）， 概括了在NF 2患者中观察到的肿瘤生长动力学和组织病理学特征-VS和 发生率为100%的椎旁神经鞘瘤，伴有VS发生的进行性听力损失 阵使用Nf 2 GEMM，我们确定FDA批准的多受体酪氨酸激酶（RTK） 抑制剂Brigatinib可降低神经鞘瘤肿瘤大小和肿瘤数量。Brigatinib获批用于治疗 由另一种激酶，间变性淋巴瘤激酶（ALK）和两种ALK抑制剂，克唑替尼和 brigatinib均显示出对NF 2相关神经鞘瘤的临床前疗效， 在活跃的临床试验中进行评价。虽然我们的研究结果表明FAK 1在调节肿瘤进展中的作用， 我们对FAK 1作为NF 2肿瘤的单一靶点或与其他药物联合作用的理解 目标不完整。我们建议在我们最近的临床前工作的基础上，通过基因消融FAK 1（Ptk 2） 在鼠（Nf 2）和人（Nf 2）缺陷型雪旺细胞中，以确定FAK 1（Ptk 2）在促进 Nf 2缺陷型神经鞘瘤的发生和相关发病率（目的1）。药物协同作用筛选， IND后FAK抑制剂单独和与RAF、MEK和BET布罗莫结构域抑制剂组合， 靶向协作Merlin调节通路（Aim 2），以及无偏CRISPR-Cas9激酶组敲除筛选 在小鼠和人类细胞中鉴定FAK 1依赖性激酶的脆弱性， 治疗上，单独或组合（目的3）。我们在这个应用程序中进行实验的首要目标是 确定可以方便地进行I/II期临床试验的药物或药物组合， 这种神经系统疾病