Prevention of post-therapy breast cancer metastasis

预防乳腺癌治疗后转移

基本信息

批准号：
10380153
负责人：
Xinhui Wang
金额：
$ 36.49万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2019-04-12 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10380153
关键词：
4T1 Abscopal effect Address Adjuvant Adjuvant Therapy Alcoholism Aldehydes Apoptosis Applications Grants Binding Blood Breast Breast Cancer Cell Breast Cancer Prevention Breast Cancer therapy Breast cancer metastasis CD44 gene Cancer Etiology Cell Death Cell Proliferation Cells Ceruloplasmin Cessation of life Chelating Agents Chemotherapy and/or radiation Chronic Clinical Research Clinical Trials Combination Drug Therapy Complex Copper Copper Gluconate DNA Diagnosis Disease Disseminated Malignant Neoplasm Distant Disulfiram Dose Down-Regulation Drug Metabolic Detoxication Epidemiology FDA approved Foundations Genes Human Immune response Immunodeficient Mouse Immunologics In Vitro Inbred BALB C Mice Incidence Innovative Therapy Lead Legal patent Link Lipids Malignant Neoplasms Mammary Neoplasms Metastatic Neoplasm to the Liver Metastatic Neoplasm to the Lung Metastatic breast cancer Modeling Monitor Mouse Mammary Tumor Virus Mus Nature Neoadjuvant Therapy Neoplasm Metastasis Normal tissue morphology Operative Surgical Procedures Pathway interactions Patient risk Patient-derived xenograft models of breast cancer Patients Pharmaceutical Preparations Postoperative Period Prevention Primary Neoplasm Proteasome Inhibitor Proteins Radiation Radiation induced damage Radiation therapy Radio Reactive Oxygen Species Refractory Reporting Resistance Schedule Serum Site Solid Neoplasm Source Testing Time Toxic effect Trace Elements Transgenic Organisms Treatment Efficacy Xenograft procedure alcoholism therapy aldehyde dehydrogenases base cancer cell cancer clinical trial cancer stem cell cancer therapy chemoradiation chemotherapy design endoplasmic reticulum stress epidemiology study immunogenic cell death in vivo inhibitor interest malignant breast neoplasm metastasis prevention mortality mortality risk mouse model neoplastic cell novel novel therapeutics patient derived xenograft model pre-clinical prevent programs response biomarker standard care stemness targeted agent therapy resistant transcription factor treatment response tumor

项目摘要

Despite advances in standard therapies,30-40% of patients with early-stage breast cancer will develop post- therapy metastases. Breast cancer stem cells (BCSC) give rise to metastases and are resistant to standard chemotherapy and radiation therapy. Moreover, radiation (IR) or chemotherapy (chemo) can reprogram nonstem breast cancer cells into BCSC, namely iBCSC. Thus, effective cancer treatment must eliminate therapy-resistant BCSC and block formation of therapy-induced BCSC. Both BCSC/iBCSC express elevated levels of aldehyde dehydrogenase (ALDH). Disulfiram (DSF) is an FDA-approved inhibitor of ALDH for treatment of alcoholism. Its toxicity to breast cancer cells is enhanced by the binding of the essential trace element copper (Cu) to form DSF/Cu complexes. DSF/Cu is an effective proteasome inhibitor resulting in inhibition of the key transcriptional factor NF-κB, which is linked to cancer and radio-, chemo-resistance and Consistent with the most recent epidemiological report indicating that DSF significantly reduced patient risk of death from cancer, we found that DSF and IR effectively targets BSCS/iBCSC and significantly prevented lung metastasis in the aggressive mouse mammary tumor 4T1 model, while IR alone was ineffective. We also found that DSF/Cu can block in vitro and in vivo IR- or chemo-induced BCSC via down- regulation of the NF-κB-stemness gene pathway and target BCSC by reduction of pro-survival ALDH activity and induction of endoplasmic reticulum (ER) stress- immunological cell death (ICD). Moreover, DSF and IR induced a robust immune response against primary tumor and lung metastasis in 4T1 mouse models. ICD cell stemness. These findings provide the rationale for our hypothesis that DSF/Cu, which induces of therapy-resistant BCSC and blocks formation of IR- or chemo- induced BCSC, is effective in preventing breast cancer metastasis when combined with the most frequently used standard treatment, i.e., surgery, IR and chemo. Since Cu is tumor promoting and found at elevated levels in tumors and sera of breast cancer patents, tailored use of exogenous Cu with DSF in vivo will be based on tumor Cu level in all Aims. In Aim1, we will assess the therapeutic efficacy of IR and/or chemo combined with DSF/Cu on preventing metastasis of patient breast cancer-derived xenograft (PDX) and MMTV-PyMT transgenic mammary tumors in an adjuvant setting. In Aim2, we will assess the therapeutic efficacy of chemo combined with DSF/Cu on preventing metastasis of PDX and MMTV-PyMT tumors in a neoadjuvant setting. In Aim3, we will analyze the mechanisms by which DSF/Cu systemically targets BCSC via induction of ICD and modulation of IR-induced immune response . At the conclusion of this study, we will have: i) evaluated DSF/Cu as a novel agent targeting BCSC/ iBCSC in the context of surgery, chemo-and/or IR treatment; ii) elucidated mechanisms by which DSF/Cu and IR induce a robust immune response against breast cancer metastasis; and iii) formed the preclinical foundation for designing a clinical research program to test this novel therapy to prevent post-therapy breast cancer metastasis.

尽管标准疗法取得了进步，但30-40％的早期乳腺癌患者将在治疗转移。乳腺癌干细胞（BCSC）会引起转移，并且对标准有抵抗力化学疗法和放射疗法。此外，辐射（IR）或化学疗法（化学疗法）可以重新编程非茎乳腺癌细胞进入BCSC，即IBCSC。那，有效的癌症治疗必须消除耐药的BCSC和治疗诱导的BCSC的嵌段形成。 BCSC/IBCSC Express均高架醛脱氢酶（ALDH）的水平。二硫仑（DSF）是ALDH的FDA批准抑制剂酒精中毒的治疗。基本痕迹的结合增强了对乳腺癌细胞的毒性元素铜（CU）形成DSF/CU复合物。 DSF/CU是有效的蛋白酶体抑制剂导致抑制关键转录因子NF-κB，该因子与癌症和无线电，化学抗性以及与最近的流行病学报告一致，表明DSF显着降低患者患癌症死亡的风险，我们发现DSF和IR有效地针对BSC/IBCSC，并且显着地靶向防止侵略性小鼠乳腺肿瘤4T1模型中的肺转移，而仅IR为无效。我们还发现，DSF/CU可以通过下部阻断体外和体内IR-或化学诱导的BCSC 通过降低生存ALDH活性来调节NF-κB-STEMNENS基因途径和靶BCSC 并诱导内质网（ER）应激 - 免疫细胞死亡（ICD）。而且，DSF和IR 在4T1小鼠模型中，诱导了针对原发性肿瘤和肺转移的强劲免疫反应。 ICD 细胞干。这些调查结果为我们的假设提供了理由，即DSF/CU，它诱导了抗治疗的BCSC和 IR-或化学诱导的BCSC的块形成可有效预防乳腺癌转移结合最常用的标准治疗方法，即手术，IR和化学疗法。因为铜是肿瘤促进并在乳腺癌专利的肿瘤和血清中升高并发现外源性的使用带有DSF体内DSF的CU将基于所有目的的肿瘤CU水平。在AIM1中，我们将评估疗法 IR和/或化学疗法与DSF/CU的功效对预防患者乳腺癌衍生的转移异种移植（PDX）和MMTV-PYMT转基因乳腺肿瘤在调节环境中。在AIM2中，我们将评估化疗的治疗效率与DSF/CU结合在预防PDX和MMTV-PYMT转移方面在新辅助环境中的肿瘤。在AIM3中，我们将分析DSF/CU的机制通过诱导ICD和IR诱导的免疫反应的调节来靶向BCSC 。在此结束时研究，我们将有：i）在手术背景下，将DSF/ CU评估为针对BCSC/ IBCSC的新药物，化学和/或IR治疗； ii） DSF/CU和IR诱导强大的免疫的阐明机制对乳腺癌转移的反应； iii）构成了设计临床的临床前基础测试这种新型疗法的研究计划，以防止疗法后乳腺癌转移。