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 这种多样性补充赠款的培训目标是黛西·麦地那（Daisy Medina）获得转化的宝贵技能 研究方法并进一步发展她的职业发展，使她成为成功 独立研究员。这种多样性补充奖的研究目标是调查 支持救援DNA修复途径（例如Alt-Nhej）的FOXM1相关信号，因此乳房 通过使用我们开发的FOXM1抑制剂，癌症的生长，进展和耐药性。 占所有BC的70％的ER+ BC的很大一部分，最初对抗雌激素做出反应或 芳香酶抑制剂，但会抗治疗，并发展为无法治愈的转移。此外，TNBC 占BC病例的10-20％，通常发生在年轻妇女中，具有更高的复发倾向和 卑诗省的死亡人数不成比例。 FOXM1是一种原始癌基因，在 ER+和TNBC并促进肿瘤的生长，进展以及耐药性。作为父母的一部分 Grant，我们建议FOXM1通过支持来促进ER+和TNBC的增长和耐药性 替代（备份）DNA修复途径；以及我们最近的一种新颖的FOXM1抑制剂（丙氨酸蓝色； IB） 开发的，将阻止FOXM1的DNA修复能力，并使乳腺癌细胞对护理疗法的标准敏感。 为了实现这些目标，学员将把她的努力集中在以下目标上，作为对此贡献的一部分 补充。 目的1。表征IB目标蛋白相互作用并确定IB的机制 调节其在TNBC和ER+BC中的靶基因。在此目标中，我们将确定IB治疗是否耗尽 FOXM1直接与蛋白质结合，或者它是否作用于下游并破坏正反馈激活 使用生物物理，基于结构和分子生物学方法的FOXM1。机械研究也将 确定IB是否具有与FOXM1无关的效应。 目标2。阐明Ib抑制TNBC和ER+BCS生长/转移的机制 敏感化疗和抗分泌疗法反应。在此目标中，我们将检验以下假设 IB抑制TNBC和ER+BCS生长，转移，并通过抑制来增强治疗反应 这些癌症用于生存和进步的替代/备用DNA修复途径。完成 这些目标，我们将使用靶基因过表达，敲低细胞模型，生化，免疫荧光， 放射标记的配体结合，共聚焦显微镜和DNA修复测定法。 目的3。测试IB是治疗TNBC和ER+BC的安全可行的假设。在这个 目的，我们将严格测试IB在阻止TNBC和进展的IB的治疗潜力 ER+BC;通过其中，使用患者衍生异种移植物（PDX）在人源化中提高化学疗法的疗效 小鼠和使用人类乳腺癌外植体（PDEX）研究。 这项研究的成功完成将有助于更好地理解DNA修复 TNBC和耐药ER+乳腺癌细胞的生存和进步的机制。这 研究还将为使用IB作为一种新方法治疗TNBC和抗治疗ER+BC奠定阶段 治疗性。