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.
项目摘要
通过化学预防来延迟或防止癌前病变向浸润性癌的进展,
头颈部鳞状细胞癌(SCCHN)是一种具有显著发病率的毁灭性疾病,
mortality.这项研究将调查FLLL 12的使用,FLLL 12是一种结构上与天然药物相关的化合物。
化合物姜黄素,作为一种新的化合物,用于化学预防这种致命的癌症; FLLL 12表明,
结合Janus激酶(JAK)2的细胞信号传导谱和抑制STAT 3的磷酸化。此外,本发明还提供了一种方法,
FLLL 12抑制EGFR和AKT转录物,导致EGFR/AKT-mTOR信号传导的抑制。这些信令
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,
致癌的两个标志一种有效的化学预防方法在浸润性癌症之前实施
降低SCCHN的发病率是必要的;然而,目前还没有这样的治疗方案,
available.因此,鉴定新的化合物有效地防止SCCHN致癌是必要的。
在这个提议中,我们将开发FLLL 12作为SCCHN化学预防的治疗剂。我们
初步数据表明,FLLL 12的IC 50值在高度选择性范围内(对大多数药物<1 µM)
SCCHN细胞系和0.35 µM针对癌前口腔癌细胞系)。药代动力学研究表明,
在小鼠中可达到与药物浓度相关的浓度。FLLL 12还有效抑制肿瘤生长
在SCCHN异种移植模型中。该提案将测试FLLL 12预防或延迟进展的能力
在致癌物诱导的小鼠口腔癌模型中,
该试剂的细胞信号传导机制。我们假设FLLL 12调节JAK-STAT 3,
EGFR/AKT-mTOR生存通路逆转和/或减缓癌前病变进展至癌前病变
鳞状细胞癌提出了三个具体目标。目的1:评估JAK-STAT 3通路作为直接的
FLLL 12的目标。我们将验证FLLL 12与JAK 2相互作用并抑制JAK-STAT 3通路的预测
介导这种化合物的化学预防作用。无细胞系统,体外激酶测定,报告基因
将使用组成型活性STAT 3质粒。目标2:确定监管机制,
FLLL 12的EGFR-AKT通路。通过启动子缺失-突变,我们将鉴定转录因子,
抑制EGFR和AKT转录物。目的3:分析FLLL 12作为化学预防剂的体内功效
在致癌物诱导的口腔癌发生模型中。4 NQO诱导的口腔癌小鼠模型将评估
通过施用FLLL 12预防或延迟口腔癌发生。体内研究的结果将
证实了FLLL 12在SCCHN中的化学预防作用。重要的是,这个R15奖项将提供一个刺激的
为本科生和研究生提供积极参与研究和发现的培训机会
这一过程有助于提高我们对癌症生物学中信号转导途径的理解。
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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A.R.M. Ruhul Amin其他文献
A.R.M. Ruhul Amin的其他文献
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{{ 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:
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