Targeting oncogenic pathways for chemoprevention of head and neck cancer by FLLL12
通过 FLLL12 靶向致癌途径对头颈癌进行化学预防
基本信息
- 批准号:10497514
- 负责人:
- 金额:$ 44.4万
- 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:2023-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AKT1 geneAffectAnimal ModelAwardBindingBinding SitesBiological AssayBiological MarkersCancer BiologyCancer ModelCancer cell lineCarcinogensCell Culture TechniquesCell DeathCell LineCell SurvivalCell-Free SystemCellsChemopreventionChemopreventive AgentCurcuminDataDeletion MutationDiseaseDrug KineticsDrug TargetingEGFR inhibitionEffectivenessEpidermal Growth Factor ReceptorFRAP1 geneFacultyFutureGenesGenetic TranscriptionGoalsGrantGrowthHead and Neck Squamous Cell CarcinomaHistologicHumanIn VitroIncidenceJAK2 geneJanus kinaseLesionMalignant NeoplasmsMalignant Squamous Cell NeoplasmMeasuresMediatingMethodsModelingMolecularMorbidity - disease rateMouth NeoplasmsMusNatural CompoundNormal CellOncogenicOralOutcomePathway interactionsPhosphorylation InhibitionPhosphotransferasesPlasmidsPremalignant CellPreventionProcessPromoter RegionsProto-Oncogene Proteins c-aktRegulationReporterResearchResistanceRisk ReductionRoleSTAT3 geneSignal PathwaySignal TransductionSignal Transduction PathwayTestingTissuesTobaccoTranscriptTreatment ProtocolsWritingXenograft Modelanalogcancer cellcancer chemopreventioncancer invasivenesscarcinogenesiscell growthchemical carcinogenchemotherapeutic agentchromatin immunoprecipitationclinical developmentconstitutive expressiondifferential expressioneffective therapyexperimental studygraduate studenthead and neck cancer preventionimprovedin vivointerdisciplinary collaborationmRNA Expressionmalignant mouth neoplasmmembermetermortalitymouse modelnoveloral carcinogenesisoverexpressionpharmacologicpreclinical developmentpremalignantpreventpromotertraining opportunitytranscription factortranscriptome sequencingtumor growthundergraduate student
项目摘要
PROJECT SUMMARY
The delay or prevent the progression of premalignant lesions to invasive cancer by chemoprevention of
squamous cell carcinoma of head and neck (SCCHN) is a devastating disease with significant morbidity and
mortality. This research will investigate the use of FLLL12, a compound structurally related to the natural
compound curcumin, as a novel compound for chemoprevention of this deadly cancer; FLLL12 demonstrates a
cell signaling profile of binding to Janus kinase (JAK)2 and inhibition of the phosphorylation of STAT3. In addition,
FLLL12 inhibits EGFR and AKT transcripts resulting in inhibition of EGFR/AKT-mTOR signaling. These signaling
pathways confer cells with the ability to acquire the advantage of unlimited growth and resistance to cell death -
two hallmarks of carcinogenesis. An effective chemoprevention method implemented before an invasive cancer
develops is needed to reduce the incidence of SCCHN; however, currently no such treatment regimen is
available. Thus, the identification of new compounds effective in preventing SCCHN carcinogenesis is warranted.
In this proposal, we will develop FLLL12 as a therapeutic agent for the chemoprevention of SCCHN. Our
preliminary data demonstrate that FLLL12 has IC50 values in a highly selective range (<1 µM against most
SCCHN cell lines and 0.35 µM against a premalignant oral cancer cell line). Pharmacokinetic studies reveal that
a pharmacologically relevant concentration is achievable in mice. FLLL12 also effectively inhibits tumor growth
in a xenograft model of SCCHN. This proposal will test the ability of FLLL12 to prevent or delay the progression
of premalignant lesions to SCCHN in a carcinogen-induced oral cancer model in a mouse model and uncover
the cell signaling mechanism(s) of action for this agent. We hypothesize that FLLL12 regulates JAK-STAT3 and
EGFR/AKT-mTOR survival pathways to reverse and/or slow the progression of premalignant lesions to a
squamous cell cancer. Three specific aims are proposed. Aim 1: Evaluate the JAK-STAT3 pathway as a direct
target of FLLL12. We will test the prediction that FLLL12 interacts with JAK2 and inhibits JAK-STAT3 pathway
to mediate the chemoprevention effects of this compound. A cell free system, in vitro kinase assays, reporter
assays and a constitutively active STAT3 plasmid will be used. Aim 2: Define the mechanism of regulation of the
EGFR-AKT pathway by FLLL12. By employing promoter deletion-mutation, we will identify transcription factor(s)
that inhibit EGFR and AKT transcripts. Aim 3: Analyze the in vivo efficacy of FLLL12 as a chemoprevention agent
in a carcinogen-induced oral carcinogenesis model. A 4NQO-induced oral cancer mouse model will evaluate the
prevention or delay in oral carcinogenesis with administration of FLLL12. The outcome of the in vivo studies will
confirm the chemoprevention effects of FLLL12 in SCCHN. Importantly, this R15 award will provide a stimulating
training opportunity for undergraduate and graduate students to participate actively in the research and discovery
process to improve our understanding of the signal transduction pathways involved in cancer biology.
项目概要
通过化学预防来延缓或预防癌前病变进展为浸润性癌症
头颈鳞状细胞癌 (SCCHN) 是一种具有显着发病率和死亡率的毁灭性疾病
死亡。本研究将调查 FLLL12 的用途,FLLL12 是一种结构与天然产物相关的化合物。
复合姜黄素,作为一种化学预防这种致命癌症的新型化合物; FLLL12 演示了
结合 Janus 激酶 (JAK)2 和抑制 STAT3 磷酸化的细胞信号传导谱。此外,
FLLL12 抑制 EGFR 和 AKT 转录物,从而抑制 EGFR/AKT-mTOR 信号传导。这些信号
途径赋予细胞获得无限生长和抵抗细胞死亡的优势的能力 -
致癌的两个标志。在侵袭性癌症发生前实施的有效化学预防方法
需要开发以减少 SCCHN 的发生率;但目前还没有这样的治疗方案
可用的。因此,有必要鉴定出有效预防 SCCHN 致癌的新化合物。
在本提案中,我们将开发 FLLL12 作为 SCCHN 化学预防的治疗剂。我们的
初步数据表明,FLLL12 的 IC50 值处于高度选择性范围内(相对于大多数药物,<1 µM)
SCCHN 细胞系和针对癌前口腔癌细胞系的 0.35 µM)。药代动力学研究表明
在小鼠中可以达到药理学相关的浓度。 FLLL12还有效抑制肿瘤生长
SCCHN 异种移植模型中。该提案将测试 FLLL12 预防或延迟进展的能力
小鼠模型中致癌物诱导的口腔癌模型中 SCCHN 癌前病变的变化并揭示
该药物的细胞信号传导机制。我们假设 FLLL12 调节 JAK-STAT3 和
EGFR/AKT-mTOR 生存途径逆转和/或减缓癌前病变进展
鳞状细胞癌。提出了三个具体目标。目标 1:评估 JAK-STAT3 通路作为直接通路
FLLL12 的目标。我们将测试FLLL12与JAK2相互作用并抑制JAK-STAT3通路的预测
介导该化合物的化学预防作用。无细胞系统,体外激酶测定,报告器
将使用组成型活性 STAT3 质粒进行测定。目标 2:明确监管机制
FLLL12 的 EGFR-AKT 通路。通过采用启动子缺失突变,我们将鉴定转录因子
抑制 EGFR 和 AKT 转录。目标 3:分析 FLLL12 作为化学预防剂的体内功效
在致癌物诱导的口腔致癌模型中。 4NQO 诱导的口腔癌小鼠模型将评估
通过给予 FLLL12 预防或延迟口腔癌发生。体内研究的结果将
证实 FLLL12 对 SCCHN 的化学预防作用。重要的是,这个 R15 奖项将提供一个令人兴奋的
为本科生和研究生提供积极参与研究和发现的培训机会
提高我们对癌症生物学中涉及的信号转导途径的理解的过程。
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 }}
A.R.M. Ruhul Amin其他文献
A.R.M. Ruhul Amin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('A.R.M. Ruhul Amin', 18)}}的其他基金
Targeting both intrinsic and extrinsic apoptosis by FLLL-12 in lung cancer
FLLL-12 靶向肺癌中的内在和外在细胞凋亡
- 批准号:
8512434 - 财政年份:2013
- 资助金额:
$ 44.4万 - 项目类别:
Targeting both intrinsic and extrinsic apoptosis by FLLL-12 in lung cancer
FLLL-12 靶向肺癌中的内在和外在细胞凋亡
- 批准号:
8627594 - 财政年份:2013
- 资助金额:
$ 44.4万 - 项目类别:
Mechanism of chemopreventive synergism from the combination of EGCG and Erlotinib
EGCG与厄洛替尼联用的化学预防协同作用机制
- 批准号:
8435344 - 财政年份:2012
- 资助金额:
$ 44.4万 - 项目类别:
Mechanism of chemopreventive synergism from the combination of EGCG and Erlotinib
EGCG与厄洛替尼联用的化学预防协同作用机制
- 批准号:
8244871 - 财政年份:2012
- 资助金额:
$ 44.4万 - 项目类别:
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 44.4万 - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 44.4万 - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 44.4万 - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 44.4万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 44.4万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 44.4万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 44.4万 - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 44.4万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 44.4万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 44.4万 - 项目类别:
Studentship














{{item.name}}会员




