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：
10304196
负责人：
Manjeet Kumar Rao
金额：
$ 39.04万
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/10304196
关键词：
Antidepressive Agents Antiestrogen Therapy BRCA1 gene Binding Biochemical Biological Assay Biophysics Breast Cancer Patient Breast Cancer therapy Cancer Center Cancer Patient Cell model Cells Clinic Clinical Confocal Microscopy DNA DNA Damage DNA Repair DNA Repair Gene DNA Repair Pathway DNA biosynthesis Defect Distant Metastasis Drug Targeting 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 Radiation Regimen Relapse Reporting Resistance Role Signal Transduction Structure Tamoxifen Testing Therapeutic Toxic effect Translating Xenograft Model Xenograft procedure aggressive breast cancer analog base breast cancer progression breast cancer survival cancer addiction cancer cell cancer subtypes chemotherapy clinical development 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 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）的缺陷是易感正常细胞获得致癌的主要因素突变。但是，肿瘤发生后，癌细胞通过修复DNA损伤来管理其生存由未检查的DNA复制产生。癌细胞可以使用替代或备用DNA修复程序克服其DDR缺陷。例如，具有同源重组（HR）缺乏缺乏的癌细胞蛋白质（例如BRCA1）可以通过依靠其他高度表达的HR相关蛋白来修复其DNA （例如RAD51或PARP1）或使用其他DNA修复机制，例如替代性非同源端加入（ALT NHEJ）和基础切除修复（BER）。癌细胞成瘾这些救助DNA修复途径有助于治疗耐药；因此，成功靶向在多个DNA修复途径将具有有希望的临床结果。 DNA修复途径的改变通常在乳腺癌（BC）进展过程中发生。例如，三重阴性乳腺癌（TNBC）积极的BC亚型经常复发为远的转移，具有功能失调的BRCA1，但表达 RAD51的高水平。此外，占所有BC的70％的雌激素受体阳性BC（ER+BC），使用Alt Nhej，人力资源或BER来修复其DNA。值得注意的是，ER+BCS获得了对内分泌治疗的耐药性通过诱导DNA修复基因的表达来对DNA的化疗药物受损。一个关键因素是参与调节多个DNA修复途径的是FOXM1，它在TNBC和治疗中高度表达抗性ER+BC。已知FOXM1促进对化疗药物和抗雌激素疗法的抗性。在此提案中，我们提供了令人信服的证据表明，丙咪胺蓝（IB）是一种新型抗抑郁药的类似物丙氨酸最近合成抑制了FOXM1相关的信号传导阻碍DNA修复能力 TNBC和ER+BC。使用卑诗省患者和肿瘤异种移植模型的肿瘤外植体，我们证明了 IB抑制TNBC和ER+BC的生长，而不会诱导任何毒性。此外，我们的研究表明 IB可能会使内分泌ER+BC敏感到他莫昔芬（TAM）并提高DNA损害的功效 TNBC中的化学疗法药物。基于这些观察结果，我们假设FOXM1是关键的组成部分 BC沉迷于生存的救援DNA修复途径； IB抑制ER+BC和TNBC增长通过靶向FOXM1及其相关信号传导，进展并增强治疗反应； IB是治疗ER+BC和TNBC的安全有效药物。在AIM 1中，我们将描述IB-Target 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AIM 2中，我们将测试IB抑制TNBC和ER+BCS生长，转移并增强治疗的假设通过抑制这些癌症生存的备用DNA修复途径的反应。在AIM 3中，我们将测试通过在人源化小鼠中使用患者衍生的异种移植并使用人类乳房，IB的安全性和生存能力癌症外植体研究。我们还将建立IB未来临床开发所需的PK/PD参数。