FoXM1 inhibition: a novel therapeutic avenue to treat breast cancers

FoXM1 抑制：治疗乳腺癌的新途径

• 批准号: 10533572
• 负责人: Manjeet Kumar Rao
• 金额: $ 4.17万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10533572
• 关键词: Aromatase Inhibitors; Award; Binding; Biochemical; Biological Assay; Biophysics; Breast Cancer Cell; Cell model; Cessation of life; Confocal Microscopy; DNA Repair; DNA Repair Pathway; Drug resistance; Estrogen Antagonists; Estrogen receptor positive; FOXM1 gene; Feedback; Genes; Goals; Grant; Growth; Human; Imipramine; Immunofluorescence Immunologic; Ligand Binding; Malignant Neoplasms; Molecular Biology; Neoplasm Metastasis; Nonhomologous DNA End Joining; Proteins; Proto-Oncogenes; Radiolabeled; Relapse; Research; Research Methodology; Research Personnel; Resistance; Role; Signal Transduction; Structure; Testing; Therapeutic; Training; Translational Research; base; career development; chemotherapy; hormone therapy; humanized mouse; improved; inhibitor; knock-down; malignant breast neoplasm; novel; novel therapeutics; overexpression; parent grant; patient derived xenograft model; skills; standard of care; therapeutic evaluation; therapy resistant; treatment response; triple-negative invasive breast carcinoma; tumor growth; young woman

Abstract The training goal of this diversity supplement grant is for Daisy Medina to gain valuable skills in translational research methods and further her career development in such a way that will allow her to become a successful independent researcher. The research goal of this diversity supplement award will be to investigate the role of FOXM1-associated signaling in supporting rescue DNA repair pathways (e.g. alt-NHEJ) and consequently breast cancer growth, progression and drug resistance through the use of FOXM1 inhibitor that we have developed. A significant proportion of ER+ BCs, which account for ~70% of all BCs, initially respond to antiestrogens or aromatase inhibitors, but become therapy resistant and progress to incurable metastases. Furthermore, TNBC accounts for 10-20% of BC cases, commonly occur in younger women, have higher propensity to relapse and contribute to disproportionate number of deaths in BC. FOXM1 is a proto-oncogene that is highly expressed in ER+ and TNBCs and promotes tumor growth, progression as well as therapy resistance. As part of the parent grant, we propose that FOXM1 may promote ER+ and TNBC growth and therapy resistance by supporting alternative (backup) DNA repair pathways; and a novel FOXM1 inhibitor (Imipramine Blue; IB) that we recently developed, will block FOXM1’s DNA repair ability and sensitize breast cancer cells to standard of care therapies. To achieve these goals, the trainee will focus her efforts on the following aims as part of the contributions to this supplement. Aim 1. To characterize the IB-target protein interactions and determine the mechanism(s) by which IB regulates its target genes in TNBC and ER+BC. In this aim, we will establish whether IB treatment depletes FOXM1 by directly binding to the protein or whether it acts downstream and disrupts positive feedback activation of FOXM1 using biophysical, structure-based and molecular biology approaches. Mechanistic studies will also determine whether IB has FOXM1-independent effects. Aim 2. To elucidate the mechanism(s) by which IB inhibits TNBC and ER+BCs growth/metastasis and sensitizes chemotherapy and anti-endocrine therapy response. In this aim, we will test the hypothesis that IB inhibits TNBC and ER+BCs growth, metastasis, and enhances therapy response by inhibiting alternative/backup DNA repair pathways that these cancers employ to survive and progress. To accomplish these goals, we will use target gene overexpression, knockdown cell models, biochemical, immunofluorescence, radiolabeled ligand binding, confocal microscopy and DNA repair assays. Aim 3. To test the hypothesis that IB is a safe and viable therapeutic for treating TNBC and ER+BC. In this aim, we will rigorously test the therapeutic potential of IB in blocking the growth and progression of TNBC and ER+BC; by which improving the efficacy of chemotherapy using patient derived xenografts (PDX) in humanized mice and by using human breast cancer explant (PDEx) studies. Successful completion of this study will contribute significantly to a better understanding of the DNA repair mechanisms that TNBC and therapy resistant ER+ breast cancer cells employ to survive and progress. This study will also set the stage for a new way of treating TNBC and therapy resistant ER+BC using IB as a therapeutic.

抽象的 这项多样性补充赠款的培训目标是让黛西·梅迪纳获得转化方面的宝贵技能 研究方法并进一步促进她的职业发展，使她能够成为一名成功的人 该多样性补充奖的研究目标是调查独立研究人员的作用。 FOXM1 相关信号传导支持拯救 DNA 修复途径（例如 alt-NHEJ），从而促进乳腺修复 通过使用我们开发的 FOXM1 抑制剂，癌症的生长、进展和耐药性。 很大一部分 ER+ BC（约占所有 BC 的 70%）最初对抗雌激素或药物有反应 芳香酶抑制剂，但会产生治疗耐药性并进展为无法治愈的转移。 占 BC 病例的 10-20%，常见于年轻女性，复发倾向较高， FOXM1 是一种原癌基因，在 BC 中高表达。 ER+ 和 TNBC 会促进肿瘤生长、进展以及治疗耐药性。 授予，我们建议 FOXM1 可以通过支持来促进 ER+ 和 TNBC 的生长和治疗耐药性 替代（备用）DNA 修复途径；以及我们最近发现的一种新型 FOXM1 抑制剂（Imipramine Blue；IB） 开发的，将阻断 FOXM1 的 DNA 修复能力并使乳腺癌细胞对标准护理疗法敏感。 为了实现这些目标，学员将集中精力实现以下目标，作为对此做出贡献的一部分 。 目标 1. 表征 IB-靶蛋白相互作用并确定 IB 发生作用的机制 在 TNBC 和 ER+BC 中调节其靶基因。在此目标中，我们将确定 IB 治疗是否会耗尽。 FOXM1 通过直接与蛋白质结合或它是否作用于下游并破坏正反馈激活 还将使用生物物理、基于结构和分子生物学方法对 FOXM1 进行研究。 确定 IB 是否具有 FOXM1 独立效应。 目标 2. 阐明 IB 抑制 TNBC 和 ER+BC 生长/转移的机制 使化疗和抗内分泌治疗反应敏感。为此，我们将检验以下假设： IB 抑制 TNBC 和 ER+BC 生长、转移，并通过抑制来增强治疗反应 这些癌症用来生存和发展的替代/备用 DNA 修复途径。 这些目标，我们将使用靶基因过表达、敲低细胞模型、生物化学、免疫荧光、 放射性标记配体结合、共聚焦显微镜和 DNA 修复测定。 目标 3. 检验 IB 是治疗 TNBC 和 ER+BC 的安全且可行的疗法的假设。 我们将严格测试 IB 在阻止 TNBC 生长和进展方面的治疗潜力，以及 ER+BC；通过人源化异种移植物（PDX）提高化疗效果 小鼠和使用人类乳腺癌外植体（PDEx）的研究。 成功完成这项研究将极大地有助于更好地了解 DNA 修复 TNBC 和治疗耐药的 ER+ 乳腺癌细胞生存和进展的机制。 研究还将为使用 IB 作为治疗 TNBC 和治疗耐药 ER+BC 的新方法奠定基础 治疗性的。