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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：
A.R.M. Ruhul Amin
金额：
$ 44.4万
依托单位：
MARSHALL UNIVERSITY
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：
https://reporter.nih.gov/project-details/10497514
关键词：
AKT1 gene Affect Animal Model Award Binding Binding Sites Biological Assay Biological Markers Cancer Biology Cancer Model Cancer cell line Carcinogens Cell Culture Techniques Cell Death Cell Line Cell Survival Cell-Free System Cells Chemoprevention Chemopreventive Agent Curcumin Data Deletion Mutation Disease Drug Kinetics Drug Targeting EGFR inhibition Effectiveness Epidermal Growth Factor Receptor FRAP1 gene Faculty Future Genes Genetic Transcription Goals Grant Growth Head and Neck Squamous Cell Carcinoma Histologic Human In Vitro Incidence JAK2 gene Janus kinase Lesion Malignant Neoplasms Malignant Squamous Cell Neoplasm Measures Mediating Methods Modeling Molecular Morbidity - disease rate Mouth Neoplasms Mus Natural Compound Normal Cell Oncogenic Oral Outcome Pathway interactions Phosphorylation Inhibition Phosphotransferases Plasmids Premalignant Cell Prevention Process Promoter Regions Proto-Oncogene Proteins c-akt Regulation Reporter Research Resistance Risk Reduction Role STAT3 gene Signal Pathway Signal Transduction Signal Transduction Pathway Testing Tissues Tobacco Transcript Treatment Protocols Writing Xenograft Model analog cancer cell cancer chemoprevention cancer invasiveness carcinogenesis cell growth chemical carcinogen chemotherapeutic agent chromatin immunoprecipitation clinical development constitutive expression differential expression effective therapy experimental study graduate student head and neck cancer prevention improved in vivo interdisciplinary collaboration mRNA Expression malignant mouth neoplasm member meter mortality mouse model novel oral carcinogenesis overexpression pharmacologic preclinical development premalignant prevent promoter training opportunity transcription factor transcriptome sequencing tumor growth undergraduate 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。