The Aryl Hydrocarbon Receptor as a New Therapeutic Target for Cancer

芳基烃受体作为癌症新治疗靶点

• 批准号: 8080200
• 负责人: Daniel F Liefwalker
• 金额: $ 3.19万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-14 至 2013-05-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8080200
• 关键词: AHR gene; ARNT protein; Androgen Antagonists; Androgen Receptor; Antineoplastic Agents; Antisense Oligonucleotides; Aromatic Polycyclic Hydrocarbons; Aryl Hydrocarbon Receptor; Award; Binding; Biological; Biological Assay; Cancer cell line; Cell Nucleus; Cell Proliferation; Clinic; Complex; Data; Dependency; Development; Dioxins; Drug usage; Endocrine; Family; Flutamide; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Growth; Helix-Turn-Helix Motifs; Hormonal; Human; Inhibition of Cell Proliferation; Ligand Binding; Ligands; Malignant Neoplasms; Mediating; Molecular Target; Monitor; Pathway interactions; Pharmaceutical Preparations; Play; Receptor Activation; Reporter Genes; Research; Resistance; Response Elements; Role; Signal Transduction; Structure-Activity Relationship; Testing; Tetrachlorodibenzodioxin; Xenobiotic Metabolism; Xenobiotics; activating transcription factor; analog; aryl hydrocarbon receptor ligand; base; cancer cell; cancer prevention; cancer therapy; clinically relevant; drug metabolism; member; new therapeutic target; pre-doctoral; receptor; receptor expression; response; small hairpin RNA; tumor

DESCRIPTION (provided by applicant): The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and member of the bHLH/PAS (basic Helix-Loop-Helix/Per-ARNT-SiM) family of chemosensors and developmental regulators. The AhR modulates a variety of cellular responses including drug metabolism, cell proliferation, differentiation, and endocrine signaling. There is a large amount of untended findings that strongly indicate that AhR can be modulated to yield biological responses that can be exploited for the treatment of cancer. Specifically, it is hypothesized that AhR ligands are capable of initiating discrete biological responses and that specific AhR-dependent effects can be utilized for the development of new cancer treatments. During a screen for AhR ligands in our lab, a clinically used drug was identified to enhance AhR-dependent transcription. I have carefully characterized this drug as an AhR ligand, and probed its biological effects. The goal of this research is to demonstrate that this drug functions as an anti-cancer agent via the AhR. The proposed research encompasses three specific aims: Aim 1: Determine the AhR dependency for AhR ligand-induced anti-proliferative effects in human cancer cell lines. AhR expression will be suppressed by AhR antisense oligonucleotides and/or shRNA to determine the requirement of AhR for growth inhibition in cancer cells Aim 2: Determine the structure activity relationship for ligand in activating AhR-dependent transcription and inhibition of cancer cell proliferation. I will use 14 structural analogs of the AhR ligand to determine the structural requirements necessary for induction of AhR-mediated transcription and AhR-dependent inhibition of proliferation Aim 3: Discover how the AhR mediates the anti-proliferative effects of the AhR ligand. I will determine the critical downstream target genes of AhR that mediate the anti-proliferative effects. I propose to identify AhR regulated genes to discover the biological pathways that are perturbed through AhR ligand induced activation. Relevance: Clinical use of this drug in the treatment of cancers has been based primarily on the expression of another hormonal receptor, not the AhR. This research will demonstrate the utility of AhR as a new therapeutic target in the treatment of cancer, and provide immediate impacts in the clinic by broadening this drug's usage to tumors expressing the AhR.

描述（由申请人提供）：芳基烃受体（AHR）是配体激活的转录因子，也是化学传感器和发育调节剂的BHLH/PAS（基本的Helix-loop-helix/per-arnt-SIM）的成员。 AHR调节各种细胞反应，包括药物代谢，细胞增殖，分化和内分泌信号传导。有大量的未定义的发现强烈表明AHR可以调节以产生可以利用用于治疗癌症的生物学反应。 具体而言，假设AHR配体能够启动离散的生物学反应，并且可以将特定的AHR依赖性作用用于开发新的癌症治疗方法。在我们实验室中AHR配体的屏幕上，确定了一种临床使用的药物以增强AHR依赖性转录。我已经仔细地将这种药物描述为AHR配体，并探测了其生物学作用。这项研究的目的是证明该药物通过AHR充当抗癌剂。拟议的研究涵盖了三个特定目的：目标1：确定人类癌细胞系中AHR配体诱导的抗增殖作用的AHR依赖性。 AHR反义寡核苷酸和/或SHRNA将抑制AHR表达，以确定AHR对癌细胞生长抑制的需求目标2：确定配体在激活AHR依赖性转录和抑制癌细胞增殖的结构活性关系。我将使用AHR配体的14种结构类似物来确定诱导AHR介导的转录和AHR依赖性抑制增殖目标所需的结构要求3：发现AHR如何介导AHR配体的抗增殖作用。我将确定介导抗增殖作用的AHR的关键下游靶基因。我建议鉴定AHR调节的基因，以发现通过AHR配体诱导的激活扰动的生物学途径。 相关性：该药物在癌症治疗中的临床用途主要基于另一种激素受体的表达，而不是AHR。这项研究将证明AHR作为癌症治疗的新治疗靶标的实用性，并通过扩大该药物对表达AHR的肿瘤的使用来立即对诊所产生影响。