Development and Testing of ERE-Targeting Molecules for Breast Cancer Therapy

用于乳腺癌治疗的 ERE 靶向分子的开发和测试

• 批准号: 7466837
• 负责人: NEIL SIDELL
• 金额: $ 33.14万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7466837
• 关键词: Affect; Animal Model; Antiestrogen Therapy; Aromatase; Aromatase Inhibitors; Arts; Binding; Binding Sites; Biological; Biological Testing; Breast Cancer Cell; Breast Cancer Treatment; Cells; Chromatin; Class; Clinical; Competitive Binding; Complex; Computer Simulation; Condition; Consensus; DNA; DNA Binding; DNA Sequence; DNA Structure; Data; Development; Elements; Engineering; Estrogen Antagonists; Estrogen Receptor Modulators; Estrogen Receptor Status; Estrogen Receptors; Estrogen receptor positive; Estrogens; Exhibits; Gene Targeting; Genes; Genetic; Genetic Transcription; Genome; Goals; Hormonal; Hormone Responsive; Inherited; Intercalating Agents; Length; Letrozole; Life; Ligands; Major Groove; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Measures; Mediating; Methodology; Modality; Molecular; Molecular Computers; Molecular Target; Nature; Nuclear Magnetic Resonance; Oligonucleotides; Pathway interactions; Pharmaceutical Preparations; Phenazines; Predisposition; Property; Protein Overexpression; Public Health; Receptor Inhibition; Regulatory Element; Resistance; Response Elements; Signal Pathway; Signal Transduction; Site; Specificity; Staging; Standards of Weights and Measures; Structure; Tamoxifen; Techniques; Technology; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transgenic Model; Transgenic Organisms; Treatment Protocols; Variant; Woman; Work; XR5944; base; cancer cell; cancer therapy; carcinogenesis; chemotherapy; concept; design; hormone therapy; in vivo; inhibitor/antagonist; malignant breast neoplasm; molecular modeling; mouse model; non-genomic; novel; piperidinedione; promoter; prototype; receptor binding; response; small molecule; transcription factor; treatment effect; tumor

DESCRIPTION (provided by applicant): Estrogen receptor (ER)-targeting endocrine therapies that interfere with estrogen signaling have become a standard treatment for breast cancer. These treatments involve either direct ER binders (e.g. tamoxifen) or aromatase inhibitors that reduce mammary tissue estrogen levels (e.g. letrozole). Despite being an effective treatment for ER-expressing breast cancer, current therapies have significant limitations related to inherent or acquired resistance. Our recent work has characterized a DNA-intercalating agent (designated XR5944) which possess anticancer properties through a novel mechanism of action; inhibition of gene transcription via direct binding at critical DNA regulatory sites. We have demonstrated potent antiestrogenic activity of XR5944 through specific inhibition of the binding of ER with estrogen response elements (ERE). As a result of these studies, we hypothesis that small molecules which specifically target ERE can be promising drug candidates for the treatment of breast cancer and would be effective in overcoming the resistance to current antiestrogen therapies. Using XR5944 as a prototype, it is our overall goal to develop such compounds using state-of-the- art molecular and in silico techniques. Aim 1 will characterize the nature and specificity of ERE as the molecular target of XR5944 action in breast cancer cells. As part of this aim, we will perform a genome-wide identification of the DNA-binding sites for ER which are affected by XR5944 and, in so doing, determine the target genes and downstream molecular pathways that are affected by XR5944-DNA interactions. Using nuclear magnetic resonance (NMR) technology, aim 2 will determine the detailed structure of the XR5944-ERE complex, and use this information, along with computer molecular modeling studies, as a basis for designing better ERE inhibitors. Upon identification of promising new compounds, they will be synthesized and promising candidates further tested for biological activity and mechanisms of action. Structural features that promote ERE binding and subsequent ER inhibition will be utilized to guide further drug improvement. Finally, aim 3 will evaluate the specificity and therapeutic consequences of blocking estrogen signaling by the ERE- intercalating compounds in two in vivo mouse models; an aromatase transgenic model which gives rise to estrogen-dependent breast tumors, and a wild-type Sencar (SENsitivity to CARcinogenesis) mouse model with which to determine the specificity and effects of the compounds on estrogen-independent cancers. PUBLIC HEALTH RELEVANCE: Breast cancer is a major public health issue that will affect approximately one of nine women sometime during her life. Since current endocrine therapies for ER-positive tumors have limitations, new treatment modalities are desperately needed. In addition to providing a basic framework for the development of new antiestrogen compounds, these studies will establish a new concept of inhibiting DNA/transcription factor interactions with small molecule DNA binders.

描述（由申请人提供）：干扰雌激素信号传导的雌激素受体（ER）靶向内分泌疗法已成为乳腺癌的标准治疗方法。这些治疗涉及直接ER结合剂（例如他莫昔芬）或降低乳腺组织雌激素水平的芳香酶抑制剂（例如来曲唑）。尽管是表达ER的乳腺癌的有效治疗，但目前的疗法具有与固有或获得性抗性相关的显著局限性。我们最近的工作已经表征了一种DNA嵌入剂（指定为XR 5944），其通过一种新的作用机制具有抗癌特性;通过直接结合关键的DNA调控位点来抑制基因转录。我们已经证明XR 5944通过特异性抑制ER与雌激素反应元件（ERE）的结合而具有强效抗雌激素活性。作为这些研究的结果，我们假设特异性靶向ERE的小分子可以成为治疗乳腺癌的有希望的候选药物，并且可以有效克服对当前抗雌激素治疗的耐药性。使用XR 5944作为原型，我们的总体目标是使用最先进的分子和计算机技术开发此类化合物。目的1将表征ERE作为乳腺癌细胞中XR 5944作用的分子靶点的性质和特异性。作为这一目标的一部分，我们将在全基因组范围内鉴定受XR 5944影响的ER DNA结合位点，并在此过程中确定受XR 5944-DNA相互作用影响的靶基因和下游分子途径。利用核磁共振（NMR）技术，目标2将确定XR 5944-ERE复合物的详细结构，并利用这些信息，沿着计算机分子建模研究，作为设计更好的ERE抑制剂的基础。在确定有前途的新化合物后，将合成它们，并进一步测试有前途的候选物的生物活性和作用机制。促进ERE结合和随后的ER抑制的结构特征将用于指导进一步的药物改进。最后，目的3将在两种体内小鼠模型中评估通过ERE嵌入化合物阻断雌激素信号传导的特异性和治疗结果;芳香酶转基因模型，其产生雌激素依赖性乳腺肿瘤，和野生型Sencar（对癌发生的敏感性）小鼠模型，用其确定化合物对雌激素非依赖性癌症的特异性和作用。 乳腺癌是一个重大的公共卫生问题，大约九分之一的妇女在其一生中的某个时候会受到影响。由于目前ER阳性肿瘤的内分泌治疗存在局限性，因此迫切需要新的治疗方式。除了为开发新的抗雌激素化合物提供基本框架外，这些研究还将建立用小分子DNA结合剂抑制DNA/转录因子相互作用的新概念。