Identification of novel therapeutic combinations for NF2 schwannomas
鉴定 NF2 神经鞘瘤的新型治疗组合
基本信息
- 批准号:10564452
- 负责人:
- 金额:$ 46.33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AblationAcoustic NeuromaAffectAffinity ChromatographyAllelesBenignBilateralBiochemicalBrain StemBromodomains and extra-terminal domain inhibitorCRISPR screenCRISPR/Cas technologyCell Culture TechniquesCellsCessation of lifeCharacteristicsClinicClinical ResearchClinical TrialsDataDependenceDevelopmentDrug CombinationsDrug SynergismDrug TargetingEvaluationExcisionExhibitsFDA approvedFacial MusclesFocal Adhesion Kinase 1GenerationsGeneticGenetically Engineered MouseGenomic approachGoalsGrowthHistologyHumanIn VitroIncidenceIndividualInvestigational TherapiesKineticsKnock-outLaboratoriesLinkLogisticsLoss of HeterozygosityLoxP-flanked alleleMAP Kinase GeneMEKsMalignant NeoplasmsMass Spectrum AnalysisMediatingModelingMolecularMorbidity - disease rateMotorMusMuscle WeaknessMutationNeurilemmomaNeurofibromatosis 2Neurofibromin 2NeurologicOperative Surgical ProceduresPTK2 genePathologicPathway interactionsPatientsPersonsPharmaceutical PreparationsPharmacologic SubstancePhasePhase I/II Clinical TrialPhosphotransferasesPredispositionProteinsRare DiseasesReceptor Protein-Tyrosine KinasesResearch PersonnelResistanceRoleSchwann CellsSignal TransductionSpinalSyndromeTestingTherapeuticToxic effectTranslationsTumor Suppressor GenesTumor TissueTyrosine Kinase InhibitorVertebral columnVertigoWorkanaplastic lymphoma kinaseautosomebilateral vestibular Schwannomacancer predispositionchemotherapychronic neuropathic painchronic paincombinatorialcrizotinibdeafnessearly phase clinical trialeffective therapyexperimental studyhearing impairmentimprovedin vivoinhibitorinnovationinsightkinase inhibitornervous system disordernext generationnovel strategiesnovel therapeuticspharmacologicpre-clinicalpreclinical efficacypreclinical studyprecursor cellprogressive hearing lossrare cancerresponsescreeningsingle-cell RNA sequencingsmall moleculesuccesssynergismtargeted treatmenttranscriptometranslational potentialtumortumor growthtumor progressiontumorigenesistumorigenic
项目摘要
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遗传的癌症易感综合征,其特征是
在编码Merlin的NF2基因座上,生殖系单倍体不足。NF2患者的特征是
NF2杂合性缺失导致的双侧前庭神经鞘瘤和脊髓神经鞘瘤
雪旺细胞或雪旺细胞前体。尽管这些肿瘤大部分是良性的,但它们的生长可以导致
严重的神经缺陷,包括但不限于耳聋、眩晕、面部肌肉无力、
慢性神经病理性疼痛和死亡。因为与外科手术切除相关的广泛的发病率
对于这些肿瘤,迫切需要开发药物方法来阻止或逆转其进展
这些患者的肿瘤生长情况。到目前为止,对于这些高度虚弱的人还没有长期有效的治疗方法。
肿瘤。
考虑到像NF2这样一种罕见的肿瘤易感综合征的临床试验后勤具有挑战性,它是
至关重要的是制定一项战略,将临床前和临床研究联系起来,以实现快速的转化创新和
效率。我们已经开发出NF2的基因工程小鼠模型(GEMM),
概述NF2患者的肿瘤生长动力学和组织病理学特征-VS和
脊柱旁神经鞘瘤100%发生率,合并进行性听力损失,发生在VS
队形。使用NF2 GEMM,我们确定FDA批准的多受体酪氨酸激酶(RTK)
Brigatinib抑制剂减少了神经鞘瘤肿瘤的大小和肿瘤数量。布里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Crizotinib和
Brigatinib都显示出对NF2相关神经鞘瘤的临床前疗效,并正在
在积极的临床试验中进行评估。虽然我们的发现表明FAK1在调节肿瘤进展中发挥了作用,
我们对FAK1作为NF2肿瘤单一靶点或与其他药物联合作用的理解
目标是不完整的。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FAK1(Ptk2)
在小鼠(NF2)和人(NF2)缺陷雪旺细胞中建立FAK1(Ptk2)的促进作用
Nf2缺陷性神经鞘瘤及其相关疾病的发生(目标1)。药物协同筛选
IND后FAK抑制剂单独以及与RAF、MEK和BET溴域抑制剂联合使用
靶向协同Merlin调节通路(Aim 2)和无偏CRISPR-Caskinome基因敲除筛查
在小鼠和人类细胞中识别可以利用的FAK1依赖的激酶漏洞
在治疗上,单独或联合使用(目标3)。我们在此应用程序中进行实验的首要目标是
确定可方便地为患者进行I/II期临床试验的药物或药物组合
这种令人衰弱的神经疾病。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Steven P Angus其他文献
Steven P Angus的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
相似海外基金
Structural and connectivity analysis in acoustic neuroma patients
听神经瘤患者的结构和连接分析
- 批准号:
566109-2021 - 财政年份:2021
- 资助金额:
$ 46.33万 - 项目类别:
Alexander Graham Bell Canada Graduate Scholarships - Master's
The molecular mechanism of hearing loss in acoustic neuroma patients.
听神经瘤患者听力损失的分子机制。
- 批准号:
17K16949 - 财政年份:2017
- 资助金额:
$ 46.33万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Safe, Rapid Access to the Internal Auditory Canal for Acoustic Neuroma
安全、快速地进入内耳道治疗听神经瘤
- 批准号:
8500735 - 财政年份:2013
- 资助金额:
$ 46.33万 - 项目类别:
Safe, Rapid Access to the Internal Auditory Canal for Acoustic Neuroma
安全、快速地进入内耳道治疗听神经瘤
- 批准号:
8610913 - 财政年份:2013
- 资助金额:
$ 46.33万 - 项目类别:














{{item.name}}会员




