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.

项目摘要 /摘要 神经纤维瘤病2型（NF2）是一种常染色体显性癌易感综合征，其特征是 编码Merlin的NF2基因座的生殖线单倍不足。 NF2患者特征性发展 双侧前庭schwannomas（VS）和脊柱schwannomas由于NF2的杂合性丧失而导致 Schwann细胞或Schwann细胞前体。尽管这些肿瘤基本上是良性的，但它们的生长可能导致 明显的神经系统缺陷，包括但不限于死亡，眩晕，面部肌肉无力， 慢性神经性疼痛和死亡。由于与手术去除有关的广泛发病率 这些肿瘤迫切需要开发制药方法来停止或扭转进展 这些患者的肿瘤生长。迄今为止，这些高度衰弱的人尚无长期有效疗法 肿瘤。 鉴于在罕见肿瘤易感综合征（例如NF2）中挑战临床试验物流，它是 建立将临床前和临床研究联系起来的策略至关重要的，以快速翻译创新和 效率。我们已经开发了NF2的一般设计的鼠标模型（GEMM） 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 脊柱式schwannomas伴有100％事件，以及与VS发生的进行性听力损失相结合 形成。使用NF2 GEMM，我们确定FDA批准的多受体酪氨酸激酶（RTK） 抑制剂Brigatinib降低了切旺纳马瘤肿瘤的大小和肿瘤数。 Brigatinib被批准用于治疗 癌症由另一个激酶，变性淋巴瘤激酶（ALK）和两个ALK抑制剂，Crizotinib和Crizotinib和 Brigatinib均显示针对NF2相关的schwannomas的临床前效率，并且在 在主动临床试验中评估。尽管我们的发现表明FAK1在调节肿瘤进展中的作用，但 我们对FAK1作为NF2肿瘤的单个靶标的作用或与其他药物结合的理解 目标是不完整的。我们建议通过FAK1的遗传消融（PTK2）来建立我们最近的临床前工作。 在鼠（NF2）和人（NF2）中缺乏schwann细胞，以确定FAK1（PTK2）在促进中的作用 NF2缺乏的造型瘤和相关的病因的起源（AIM 1）。毒品协同筛查与 单独并与RAF，MEK和BET BET BOTOMODOMAIN抑制剂结合使用后FAK抑制剂 目标合作梅林调节的途径（AIM 2）和无偏的CRISPR-CAS9 Kinome敲除筛选 在鼠和人类细胞中，可以识别可以探索的FAK1依赖性激酶漏洞 治疗，单独或组合（目标3）。我们在此应用程序中实验的总体目标是 识别可能非常可能对患者进行I/II期临床试验的药物或药物组合 这种使神经系统疾病令人衰弱。