Understanding and Overcoming Resistance to BRAF/MEK Kinase Inhibitors in Melanoma
了解并克服黑色素瘤对 BRAF/MEK 激酶抑制剂的耐药性
基本信息
- 批准号:10381269
- 负责人:
- 金额:$ 4.62万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:Administrative SupplementAutomobile DrivingBRAF geneBar CodesBiologyCellsComputational BiologyDevelopmentDiseaseDoseDrug resistanceEventExperimental DesignsGoalsGrantImmunotherapyMAP3K1 geneMalignant NeoplasmsMethodsMolecularParentsPathway interactionsPatientsPharmaceutical PreparationsPopulationPropertyRNARNA ComputationsRecurrent diseaseRegimenRelapseResistanceStatistical Data InterpretationTechniquesWorkcellular imagingkinase inhibitormelanomanew therapeutic targetresponsetargeted treatmenttheoriestherapy resistanttranscriptome sequencing
项目摘要
PROJECT SUMMARY/ABSTRACT
Targeted immunotherapies against BRAFV600E/K-positive melanoma cancers have been
efficacious at eradicating disease in >80% of patients. Nevertheless, the existence of populations
of pre-resistant rare cells has posed a challenge to the efficacy of melanoma-targeted therapies,
often leading to a disease relapse in the majority of patients. In the parent R01 grant, we proposed
a multi-faceted approach combining new experimental techniques, statistical analysis, and theory
to understand the origin of these rare, transient drug-resistant cell states and devise strategies to
control them. In the current administrative supplement, our goal is to dissect the primordial cellular
pathways governing cellular reprogramming that convert the transient state of resistance in the
rare single cells into the permanent state of drug resistance that drive relapse. This work is related
to the parent R01, but explores new concepts and experimental designs. By using a low dose
exposure regimen, followed by high dose exposures, we seek to investigate whether a selective
or an adaptive cellular response underlies the mechanism resulting in the conversion to
permanent drug resistance. In a selection response, the permanently resistant cells share the
same final resistant properties as the transient initial population. In an adaptive response,
however, the final resistant properties of the permanently resistant cells could be different, most
likely greater, than that of the initial transient cells. We will employ a multi-pronged approach
consisting of single cell imaging, single cell barcoding, single cell RNA FISH, RNA sequencing
and computational biology techniques to elucidate the primordial cellular/molecular regulators
driving cellular reprogramming that results in permanently resistant cells. The mechanisms
revealed by these studies will be important for the development of new targeted therapies that
will be able to eradicate the relapse caused by therapy resistant cells.
项目总结/文摘
项目成果
期刊论文数量(0)
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Meenhard F Herlyn其他文献
Meenhard F Herlyn的其他文献
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{{ truncateString('Meenhard F Herlyn', 18)}}的其他基金
Gamma delta T cell based melanoma therapies
基于 Gamma Delta T 细胞的黑色素瘤疗法
- 批准号:
10365762 - 财政年份:2021
- 资助金额:
$ 4.62万 - 项目类别:
Neoadjuvant immunotherapy approaches to early stage melanoma
早期黑色素瘤的新辅助免疫治疗方法
- 批准号:
10480856 - 财政年份:2021
- 资助金额:
$ 4.62万 - 项目类别:
Gamma delta T cell based melanoma therapies
基于 Gamma Delta T 细胞的黑色素瘤疗法
- 批准号:
10540374 - 财政年份:2021
- 资助金额:
$ 4.62万 - 项目类别:
Explore Gamma delta T cell-based glioblastoma therapies
探索基于 Gamma delta T 细胞的胶质母细胞瘤疗法
- 批准号:
10829731 - 财政年份:2021
- 资助金额:
$ 4.62万 - 项目类别:
Neoadjuvant immunotherapy approaches to early stage melanoma
早期黑色素瘤的新辅助免疫治疗方法
- 批准号:
10268746 - 财政年份:2021
- 资助金额:
$ 4.62万 - 项目类别:
Understanding and Overcoming Resistance to BRAF/MEK Kinase Inhibitors in Melanoma
了解并克服黑色素瘤对 BRAF/MEK 激酶抑制剂的耐药性
- 批准号:
10307107 - 财政年份:2019
- 资助金额:
$ 4.62万 - 项目类别:
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