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.

项目摘要通过化学预防的延迟或防止预防性病变导致侵袭性癌症的发展头颈部鳞状细胞癌（SCCHN）是一种毁灭性疾病，发病率明显，死亡。这项研究将调查使用FLLL12的使用，FLLL12是一种与自然相关的化合物复合姜黄素，作为这种致命癌症化学预防的新颖化合物； flll12证明a 与Janus激酶（JAK）2结合的细胞信号传导谱图和STAT3磷酸化的抑制。此外， FLLL12抑制EGFR和AKT转录物，从而抑制EGFR/AKT-MTOR信号传导。这些信号传导途径会议细胞具有获得无限生长和对细胞死亡抗性的优势的能力 - 癌变的两个标志。在侵入性癌症之前实施的有效的化学预防方法需要发展以减少SCCHN的事件；但是，目前尚无这种治疗方案可用的。这是有效防止SCCHN致癌作用的新化合物的鉴定。在此提案中，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在高度选择范围内具有IC50值（相对于大多数 SCCHN细胞系和0.35 µM针对口腔癌细胞系）。药代动力学研究表明在小鼠中实现了与药物相关的浓度。 FLLL12也有效抑制肿瘤的生长在SCCHN的异种移植模型中。该建议将测试FLLL12预防或延迟进展的能力在癌变诱导的口腔癌模型中，在小鼠模型中对SCCHN的预先病变的病变，并发现该药物的作用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，以逆转和/或减慢预立剂病变的进展鳞状细胞癌。提出了三个具体目标。 AIM 1：将JAK-STAT3途径评估为直接 FLLL12的目标。我们将测试FLLL12与JAK2相互作用并抑制JAK-STAT3途径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，记者将使用测定和组成性活性STAT3质粒。目标2：定义调节机制 FLLL12的EGFR-AKT途径。通过使用启动子删除声名，我们将确定转录因子抑制EGFR和AKT转录本。目标3：分析FLLL12作为化学预防剂的体内效率在致癌的口服癌变模型中。 4NQO诱导的口腔癌小鼠模型将评估通过施用FLLL12预防或延迟口服癌变。体内研究的结果将确认FLLL12在SCCHN中的化学预防作用。重要的是，该R15奖将提供刺激性培训本科生和研究生积极参与研究和发现的机会提高我们对癌症生物学涉及的信号转导途径的理解的过程。