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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：
9897345
负责人：
Manjeet Kumar Rao
金额：
$ 42.93万
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/9897345
关键词：
Antidepressive Agents Antiestrogen Therapy BRCA1 gene Binding Biochemical Biological Assay Biology 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 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/antagonist innovation knock-down malignant breast neoplasm novel novel therapeutics overexpression pharmacokinetics and pharmacodynamics programs repaired response safety testing therapeutic evaluation therapeutic target therapy development therapy outcome therapy resistant 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易发癌的主要因素