Therapeutic Targeting of Receptor Tyrosine Kinase Hierarchies in Schwann Cell Neoplasms
雪旺细胞肿瘤中受体酪氨酸激酶层次结构的治疗靶向
基本信息
- 批准号:10629381
- 负责人:
- 金额:$ 37.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AblationAntibodiesApoptosisAutomobile DrivingBiological AssayBreast CarcinomaCDKN2A geneCanertinibCause of DeathCell DeathCell LineCell LineageCell ProliferationCharacteristicsClinicalCompensationCoupledCytoplasmDoseDrug TargetingDrug resistanceEGFR geneERBB3 geneEffectivenessGeneral PopulationGenetic DiseasesGenetically Engineered MouseGenomicsGlioblastomaGrowthHumanIGF1 geneImmunocompetentIn VitroIndividualMAP Kinase GeneMalignant NeoplasmsMediatingMethodsMutationNeoplasmsNeurofibromatosis 1NeurofibrosarcomaOutcomePI3K/AKTPIK3CG genePathogenesisPathway interactionsPatientsPharmaceutical PreparationsPhenotypeProliferatingRAS inhibitionRadiationRadiation therapyRadioReceptor InhibitionReceptor Protein-Tyrosine KinasesReceptor SignalingRecurrent tumorRegimenRelapseReproducibilityResistanceRoleSchwann CellsSignal PathwaySignal TransductionSiteSuppressor MutationsTP53 geneTestingTherapeuticTumor Cell LineTumor PromotionTumor SubtypeTumor Suppressor GenesTumor Suppressor ProteinsTumor TissueXenograft procedurecombinatorialdesigndrug candidatedrug relapsedrug sensitivityeffective therapyeffectiveness evaluationfunctional lossgenome-widehyperactive Rasin vivoin vivo evaluationinhibitorlung Carcinomamelanomaneoplastic celloverexpressionpatient prognosispharmacologicreceptorrecruitresponsesarcomasmall hairpin RNAsmall moleculetargeted agenttargeted treatmenttherapeutic effectivenesstherapeutic targettumortumor growthtumor initiationtumor xenografttumorigenesis
项目摘要
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.!
恶性周围神经鞘肿瘤(MPNSTs)是源自雪旺细胞的侵袭性肿瘤
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 L. CARROLL其他文献
STEVEN L. CARROLL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 }}
{{ truncateString('STEVEN L. CARROLL', 18)}}的其他基金
Core: Biorepository and Clinical Trial Office Shared Resource
核心:生物样本库和临床试验办公室共享资源
- 批准号:
10911643 - 财政年份:2023
- 资助金额:
$ 37.77万 - 项目类别:
Therapeutic Targeting of Receptor Tyrosine Kinase Hierarchies in Schwann Cell Neoplasms
雪旺细胞肿瘤中受体酪氨酸激酶层次结构的治疗靶向
- 批准号:
10832284 - 财政年份:2020
- 资助金额:
$ 37.77万 - 项目类别:
Therapeutic Targeting of Receptor Tyrosine Kinase Hierarchies in Schwann Cell Neoplasms
雪旺细胞肿瘤中受体酪氨酸激酶层次结构的治疗靶向
- 批准号:
10249969 - 财政年份:2020
- 资助金额:
$ 37.77万 - 项目类别:
Therapeutic Targeting of Receptor Tyrosine Kinase Hierarchies in Schwann Cell Neoplasms
雪旺细胞肿瘤中受体酪氨酸激酶层次结构的治疗靶向
- 批准号:
10436971 - 财政年份:2020
- 资助金额:
$ 37.77万 - 项目类别:
Therapeutic Targeting of Receptor Tyrosine Kinase Hierarchies in Schwann Cell Neoplasms - Supplement for Diversity
雪旺细胞肿瘤中受体酪氨酸激酶层次结构的治疗靶向 - 多样性补充
- 批准号:
10527086 - 财政年份:2020
- 资助金额:
$ 37.77万 - 项目类别:
Core: Biorepository and Clinical Trial Office Shared Resource
核心:生物样本库和临床试验办公室共享资源
- 批准号:
10246909 - 财政年份:2017
- 资助金额:
$ 37.77万 - 项目类别:
Novel Treatment of NF-1 Associated Malignant Peripheral Nerve Sheath Tumors
NF-1 相关恶性周围神经鞘瘤的新疗法
- 批准号:
7537237 - 财政年份:2007
- 资助金额:
$ 37.77万 - 项目类别:
Novel Treatment of NF-1 Associated Malignant Peripheral Nerve Sheath Tumors
NF-1 相关恶性周围神经鞘瘤的新疗法
- 批准号:
7751842 - 财政年份:2007
- 资助金额:
$ 37.77万 - 项目类别:
相似海外基金
University of Aberdeen and Vertebrate Antibodies Limited KTP 23_24 R1
阿伯丁大学和脊椎动物抗体有限公司 KTP 23_24 R1
- 批准号:
10073243 - 财政年份:2024
- 资助金额:
$ 37.77万 - 项目类别:
Knowledge Transfer Partnership
Role of Natural Antibodies and B1 cells in Fibroproliferative Lung Disease
天然抗体和 B1 细胞在纤维增生性肺病中的作用
- 批准号:
10752129 - 财政年份:2024
- 资助金额:
$ 37.77万 - 项目类别:
CAREER: Next-generation protease inhibitor discovery with chemically diversified antibodies
职业:利用化学多样化的抗体发现下一代蛋白酶抑制剂
- 批准号:
2339201 - 财政年份:2024
- 资助金额:
$ 37.77万 - 项目类别:
Continuing Grant
Isolation and characterisation of monoclonal antibodies for the treatment or prevention of antibiotic resistant Acinetobacter baumannii infections
用于治疗或预防抗生素耐药鲍曼不动杆菌感染的单克隆抗体的分离和表征
- 批准号:
MR/Y008693/1 - 财政年份:2024
- 资助金额:
$ 37.77万 - 项目类别:
Research Grant
Discovery of novel nodal antibodies in the central nervous system demyelinating diseases and elucidation of the mechanisms through an optic nerve demyelination model
发现中枢神经系统脱髓鞘疾病中的新型节点抗体并通过视神经脱髓鞘模型阐明其机制
- 批准号:
23K14783 - 财政年份:2023
- 资助金额:
$ 37.77万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Elucidation of the mechanisms controlling the physicochemical properties and functions of supercharged antibodies and development of their applications
阐明控制超电荷抗体的理化性质和功能的机制及其应用开发
- 批准号:
23KJ0394 - 财政年份:2023
- 资助金额:
$ 37.77万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Developing first-in-class aggregation-specific antibodies for a severe genetic neurological disease
开发针对严重遗传神经系统疾病的一流聚集特异性抗体
- 批准号:
10076445 - 财政年份:2023
- 资助金额:
$ 37.77万 - 项目类别:
Grant for R&D
PLA2G2D Antibodies for Cancer Immunotherapy
用于癌症免疫治疗的 PLA2G2D 抗体
- 批准号:
10699504 - 财政年份:2023
- 资助金额:
$ 37.77万 - 项目类别:
Genetic adjuvants to elicit neutralizing antibodies against HIV
基因佐剂可引发抗艾滋病毒中和抗体
- 批准号:
10491642 - 财政年份:2023
- 资助金额:
$ 37.77万 - 项目类别:
Novel Immunogens to Elicit Broadly Cross-reactive Antibodies That Target the Hemagglutinin Head Trimer Interface
新型免疫原可引发针对血凝素头三聚体界面的广泛交叉反应抗体
- 批准号:
10782567 - 财政年份:2023
- 资助金额:
$ 37.77万 - 项目类别: