FoXM1 inhibition: a novel therapeutic avenue to treat breast cancers

FoXM1 抑制：治疗乳腺癌的新途径

基本信息

批准号：
10533268
负责人：
Manjeet Kumar Rao
金额：
$ 39.01万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
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/10533268
关键词：
Antidepressive Agents Antiestrogen Therapy BRCA1 gene Binding Biochemical Biological Assay Biophysics Breast Cancer Patient Cancer Center Cancer Patient Cell model Cells Chemotherapy and/or radiation Clinic Clinical Confocal Microscopy DNA DNA Damage DNA Repair DNA Repair Gene DNA Repair Pathway DNA biosynthesis Defect Distant Metastasis Endocrine Estrogen receptor positive Excision Repair FDA approved FOXM1 gene Feedback Funding Future Genes Goals Growth Human Imipramine Immune Immunofluorescence Immunologic Legal patent Lesion Malignant Neoplasms Modeling Molecular Biology Mutation Neoplasm Metastasis Nodal Nonhomologous DNA End Joining Normal Cell Oncogenic Outcome Pathway interactions Patients Pharmaceutical Preparations Phase I Clinical Trials Play Positioning Attribute Predisposing Factor Privatization Proliferating Proteins Regimen Reporting Resistance Role Signal Transduction Structure Tamoxifen Testing Therapeutic Toxic effect Translating Xenograft Model Xenograft procedure aggressive breast cancer analog breast cancer progression breast cancer survival cancer addiction cancer cell cancer subtypes chemotherapy clinical development coping drug development genotoxicity homologous recombination hormone therapy humanized mouse improved inhibitor innovation knock-down malignant breast neoplasm novel novel therapeutics overexpression patient derived xenograft model pharmacokinetics and pharmacodynamics programs repaired response safety testing targeted treatment therapeutic evaluation therapeutic target therapy development therapy outcome therapy resistant translational potential treatment response triple-negative invasive breast carcinoma tumor tumor xenograft

项目摘要

Defects in DNA damage response (DDR) is major factor that predispose normal cells to acquire oncogenic mutations. However, after a tumor develops, cancer cells manage their survival by repairing DNA damage resulting from unchecked DNA replication. Cancer cells can use the alternative or backup DNA repair programs to overcome their DDR defects. For example, cancer cells with deficiency in homologous recombination (HR) proteins (such as BRCA1) can repair their DNA by either relying on other highly expressed HR-related proteins (such as RAD51 or PARP1) or by using other DNA repair mechanisms such as alternative non-homologous end joining (ALT NHEJ) and basal excision repair (BER). The addiction of cancer cells to these rescue DNA repair pathways contributes to therapy-resistance; therefore, successful targeting of factor(s) that play critical role in multiple DNA repair pathways will have promising clinical outcomes. Alterations in DNA repair pathways commonly occur during breast cancer (BC) progression. For example, triple negative breast cancer (TNBC) an aggressive BC subtype that frequently relapses as distant metastases, have dysfunctional BRCA1 but expresses high levels of RAD51. Further, estrogen receptor positive BC (ER+BC), which accounts for ~70% of all BCs, employs ALT NHEJ, HR or BER to repair their DNA. Notably, ER+BCs acquire resistance to endocrine therapy and DNA-damaging chemotherapy drugs by inducing expression of DNA repair genes. A key factor that is involved in regulating multiple DNA repair pathways is FOXM1, which is highly expressed in TNBC and therapy resistant ER+BCs. FOXM1 is known to promote resistance to chemotherapy drugs and anti-estrogen therapies. In this proposal, we provide compelling evidence that imipramine blue (IB), a novel analogue of anti-depressant imipramine that we recently synthesized inhibits FOXM1-associated signaling impeding DNA repair ability of TNBCs and ER+BC. Using tumor explants from BC patients and tumor xenograft models, we have demonstrated that IB inhibits the growth of TNBC and ER+BC without inducing any toxicity. Further, our studies have shown that IB may sensitize endocrine resistant ER+BCs to tamoxifen (TAM) and improve the efficacy of DNA damaging chemotherapy drugs in TNBC. Based on these observations, we hypothesize that FOXM1 is a critical component of rescue DNA repair pathways that BCs get addicted to survive; that IB suppresses ER+BC and TNBC growth and progression as well as enhances the therapy response by targeting FOXM1 and its associated signaling; and that IB is a safe and effective drug for treating ER+BC and TNBC. In Aim 1, we will characterize the IB-target protein interaction and determine the mechanism(s) by which IB regulates its target genes in TNBC and ER+BC. In Aim 2, we will test the hypothesis that IB inhibits TNBC and ER+BCs growth, metastasis, and enhances therapy response by inhibiting backup DNA repair pathways that these cancers employ to survive. In Aim 3, we will test the safety and viability of IB by using patient derived xenografts in humanized mice and by using human breast cancer explant studies. We will also establish PK/PD parameters required for future clinical development of IB.

DNA损伤反应（DDR）缺陷是导致正常细胞获得致癌性的主要因素突变。然而，肿瘤发生后，癌细胞通过修复 DNA 损伤来维持生存由不受控制的 DNA 复制造成的。癌细胞可以使用替代或备份 DNA 修复程序克服其DDR缺陷。例如，同源重组（HR）缺陷的癌细胞蛋白质（例如 BRCA1）可以通过依赖其他高表达的 HR 相关蛋白质来修复其 DNA （例如 RAD51 或 PARP1）或使用其他 DNA 修复机制，例如替代非同源末端连接（ALT NHEJ）和基底切除修复（BER）。癌细胞对这些拯救DNA修复的成瘾途径导致治疗抵抗；因此，成功地瞄准在其中发挥关键作用的因素多种DNA修复途径将产生有希望的临床结果。 DNA修复途径的改变通常发生在乳腺癌 (BC) 进展过程中。例如，三阴性乳腺癌 (TNBC) 侵袭性 BC 亚型，经常因远处转移而复发，具有功能失调的 BRCA1，但表达高水平的 RAD51。此外，雌激素受体阳性 BC (ER+BC) 约占所有 BC 的 70%，使用 ALT NHEJ、HR 或 BER 来修复其 DNA。值得注意的是，ER+BC 对内分泌治疗产生耐药性以及通过诱导 DNA 修复基因表达来破坏 DNA 的化疗药物。一个关键因素是 FOXM1 参与调节多种 DNA 修复途径，在 TNBC 和治疗中高表达耐药 ER+BC。众所周知，FOXM1 会促进化疗药物和抗雌激素疗法的耐药性。在这项提案中，我们提供了令人信服的证据，证明丙咪嗪蓝（IB）是一种新型抗抑郁药类似物我们最近合成的丙咪嗪可抑制 FOXM1 相关信号传导，从而阻碍 DNA 修复能力 TNBC 和 ER+BC。使用 BC 患者的肿瘤外植体和肿瘤异种移植模型，我们证明了 IB 抑制 TNBC 和 ER+BC 的生长而不诱导任何毒性。此外，我们的研究表明 IB 可能会使内分泌耐药 ER+BC 对他莫昔芬 (TAM) 敏感并提高 DNA 损伤的功效 TNBC 中的化疗药物。基于这些观察，我们假设 FOXM1 是一个关键组件 BC 为生存而上瘾的救援 DNA 修复途径； IB 抑制 ER+BC 和 TNBC 生长通过靶向 FOXM1 及其相关信号传导，促进疾病进展并增强治疗反应； IB是治疗ER+BC和TNBC的安全有效的药物。在目标 1 中，我们将描述 IB 目标的特征蛋白质相互作用并确定 IB 在 TNBC 和 ER+BC 中调节其靶基因的机制。在目标 2 中，我们将检验 IB 抑制 TNBC 和 ER+BC 生长、转移并增强治疗的假设通过抑制这些癌症赖以生存的备用 DNA 修复途径来做出反应。在目标 3 中，我们将测试通过在人源化小鼠中使用患者来源的异种移植物以及使用人类乳房来研究 IB 的安全性和可行性癌症外植体研究。我们还将建立 IB 未来临床开发所需的 PK/PD 参数。