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.

项目概要/摘要 2 型神经纤维瘤病 (NF2) 是一种常染色体显性癌症易感综合征，其特征为 编码 Merlin 的 NF2 位点存在种系单倍体不足。 NF2 患者的特征是 由于 NF2 杂合性缺失导致双侧前庭神经鞘瘤 (VS) 和脊髓神经鞘瘤 施万细胞或施万细胞前体。尽管这些肿瘤大部分是良性的，但它们的生长可能会导致 严重的神经缺陷，包括但不限于耳聋、眩晕、面部肌肉无力、 慢性神经性疼痛，甚至死亡。由于与手术切除相关的广泛发病率 这些肿瘤，迫切需要开发药物方法来阻止或逆转进展 这些患者的肿瘤生长情况。迄今为止，尚无针对这些高度衰弱的长期有效疗法 肿瘤。 鉴于 NF2 等罕见肿瘤易感综合征的临床试验后勤工作具有挑战性， 建立连接临床前和临床研究的战略对于快速转化创新和 效率。我们开发了 NF2 基因工程小鼠模型 (GEMM)，可以准确地 概括了在 NF2 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 导致的进行性听力损失 形成。使用 Nf2 GEMM，我们确定 FDA 批准了多受体酪氨酸激酶 (RTK) 抑制剂布加替尼减少了神经鞘瘤肿瘤的大小和肿瘤数量。布加替尼被批准用于治疗 由另一种激酶、间变性淋巴瘤激酶 (ALK) 和两种 ALK 抑制剂克唑替尼和克唑替尼驱动的癌症 brigatinib 均已显示出针对 NF2 相关神经鞘瘤的临床前疗效，并且正在研究中 积极临床试验中的评估。虽然我们的研究结果表明 FAK1 在调节肿瘤进展中发挥着作用， 我们对 FAK1 作为 NF2 肿瘤单一靶点或与其他药物联合使用的作用的理解 目标不完整。我们建议通过 FAK1 (Ptk2) 基因消融来建立我们最近的临床前工作 在小鼠 (Nf2) 和人类 (NF2) 缺陷雪旺细胞中建立 FAK1 (Ptk2) 在促进 Nf2 缺陷型神经鞘瘤的起源及相关疾病（目标 1）。药物协同筛选 单独使用 IND 后 FAK 抑制剂以及与 RAF、MEK 和 BET 溴结构域抑制剂联合使用， 靶向 Merlin 调节的协同通路（目标 2），以及公正的 CRISPR-Cas9 激酶组敲除筛选 在小鼠和人类细胞中识别可利用的 FAK1 依赖性激酶漏洞 单独或联合治疗（目标 3）。我们在此应用中进行实验的总体目标是 确定可以方便地为患者进行 I/II 期临床试验的药物或药物组合 患有这种使人衰弱的神经系统疾病。