Novel microtubule-targeting agents for the treatment of glioblastoma multiform
用于治疗多形性胶质母细胞瘤的新型微管靶向药物
基本信息
- 批准号:9755531
- 负责人:
- 金额:$ 22.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-15 至 2020-12-31
- 项目状态:已结题
- 来源:
- 关键词:ApoptosisApplications GrantsBindingBiological ModelsBlood - brain barrier anatomyBrainCell membraneCellsChromosomal InstabilityColchicineDataDevelopmentDiagnosisDoseDrug KineticsExhibitsFoundationsGlioblastomaGoalsGrantIn VitroLaboratoriesMalignant NeoplasmsMalignant neoplasm of brainMeasuresMicrotubulesMolecular Mechanisms of ActionMusPatientsPenetrationPeripheralPharmaceutical ChemistryPharmacodynamicsPre-Clinical ModelPropertyRegimenResearchSafetySeriesSiteSolidSurvival RateTestingTherapeuticTherapeutic StudiesTimeTreatment EfficacyTubulinUniversitiesWashingtonWorkXenograft Modelbrain endothelial cellcancer typedesignexperimental studyfluorescence imagingimaging approachin vivomouse modelnanomolarnovelnovel therapeuticsoutcome forecastpre-clinicalstandard of caretargeted agenttumoruptake
项目摘要
Microtubule targeting agents (MTAs) are commonly prescribed to successfully treat many types of cancers; yet
their use for the treatment of brain cancers, such as GBM, has been hindered by their inability to penetrate the
brain in therapeutically-relevant doses. Recent evidence shows that GBMs are particularly sensitive to
disruptions of microtubule (MT) functions and die by apoptosis, providing a rational to develop brain-penetrant
MTAs.
The laboratory of Dr. Nephi Stella at the University of Washington developed a new series of MTAs (ST
compounds) and showed that these compounds destabilize MT through a different MOA from currently known
MTAs. These MTAs kill GBM cells by triggering apoptosis both in vitro and in vivo. The work outline in this R21
grant proposal will provide foundational results on the novel MOA of ST compounds, as well as proof-of-
concept in vivo efficacy results in preclinical model systems of PD-PGM, both of which will help develop this
therapeutic approach for the treatment of GBM. Our aims are
Aim 1: Determine the MOA of ST compounds on tubulin and MT dynamics, as well as their ability to
cross cell membranes
Aim 2: Determine the therapeutic efficacy and mechanism of ST compounds in PD-GBM xenograft
model
Our long-term goal is to help better understand and develop novel therapeutics to treat devastating cancers
such as GBM.
微管靶向剂(MTA)通常用于成功治疗许多类型的癌症;然而,
它们用于治疗脑癌如GBM的用途受到了阻碍,因为它们不能穿透肿瘤细胞。
治疗相关剂量的大脑。最近的证据表明,GBM对
微管(MT)功能的破坏并通过凋亡而死亡,为开发脑渗透剂提供了理论依据。
MTA。
华盛顿大学的Nephi Stella博士的实验室开发了一系列新的MTA(ST
化合物),并表明这些化合物通过与目前已知的不同的MOA使MT不稳定
MTA。这些MTA通过在体外和体内触发细胞凋亡来杀死GBM细胞。本R21中的工作大纲
赠款提案将提供ST化合物的新型MOA的基础性结果,以及
概念体内功效导致PD-PGM的临床前模型系统,这两者都将有助于开发这一
治疗GBM的方法。我们的目标是
目的1:确定ST化合物对微管蛋白和MT动力学的MOA,以及它们对微管蛋白和MT动力学的影响的能力。
穿过细胞膜
目的2:确定ST化合物在PD-GBM异种移植物中的治疗效果和机制
模型
我们的长期目标是帮助更好地理解和开发新的疗法来治疗毁灭性的癌症
例如GBM。
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)
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Nephi Stella其他文献
Nephi Stella的其他文献
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{{ truncateString('Nephi Stella', 18)}}的其他基金
Role of CB1R expressed in the prefrontal cortex in the control of locomotion
前额皮质表达的 CB1R 在运动控制中的作用
- 批准号:
10590320 - 财政年份:2023
- 资助金额:
$ 22.46万 - 项目类别:
Differential control of 2-AG’s activity at CB1R by ABHD6 and MAGL
ABHD6 和 MAGL 对 CB1R 上 2-AG 活性的差异控制
- 批准号:
10664172 - 财政年份:2023
- 资助金额:
$ 22.46万 - 项目类别:
Differential response of glioblastomas to microtubule targeting agents
胶质母细胞瘤对微管靶向剂的差异反应
- 批准号:
10650168 - 财政年份:2020
- 资助金额:
$ 22.46万 - 项目类别:
Differential response of glioblastomas to microtubule targeting agents
胶质母细胞瘤对微管靶向剂的差异反应
- 批准号:
10208829 - 财政年份:2020
- 资助金额:
$ 22.46万 - 项目类别:
Impact on adult mouse brain of oral THC and CBD consumption during adolescence
青春期口服 THC 和 CBD 对成年小鼠大脑的影响
- 批准号:
10206087 - 财政年份:2020
- 资助金额:
$ 22.46万 - 项目类别:
Molecular mechanism of ABHD6 enzymatic activity in neurons
神经元ABHD6酶活性的分子机制
- 批准号:
10040363 - 财政年份:2020
- 资助金额:
$ 22.46万 - 项目类别:
Differential response of glioblastomas to microtubule targeting agents
胶质母细胞瘤对微管靶向剂的差异反应
- 批准号:
10434745 - 财政年份:2020
- 资助金额:
$ 22.46万 - 项目类别:
Impact on adult mouse brain of oral THC and CBD consumption during adolescence
青春期口服 THC 和 CBD 对成年小鼠大脑的影响
- 批准号:
10039866 - 财政年份:2020
- 资助金额:
$ 22.46万 - 项目类别:
Anti-Epileptic Action of ABHD6 Inhibitors as Treatment for Dravet Syndrome
ABHD6 抑制剂治疗 Dravet 综合征的抗癫痫作用
- 批准号:
9331065 - 财政年份:2017
- 资助金额:
$ 22.46万 - 项目类别: