Prevention of post-therapy breast cancer metastasis

预防乳腺癌治疗后转移

基本信息

批准号：
9914094
负责人：
Xinhui Wang
金额：
$ 37.23万
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/9914094
关键词：
4T1 Abscopal effect Address Adjuvant Adjuvant Therapy Alcoholism Aldehydes Apoptosis Applications Grants Binding Blood Breast Breast Cancer Cell Breast Cancer Patient 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 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/antagonist interest malignant breast neoplasm metastasis prevention mortality mortality risk mouse model neoplastic cell novel novel therapeutics pre-clinical prevent programs response biomarker standard care stemness targeted agent therapy resistant transcription factor 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% 的早期乳腺癌患者仍会在治疗后发展为乳腺癌。乳腺癌干细胞（BCSC）会产生转移并且对标准具有抵抗力。此外，放疗（IR）或化疗（chemo）可以重新编程。因此，有效的癌症治疗必须消除非干乳腺癌细胞转化为BCSC，即iBCSC。 BCSC/iBCSC 表达升高。双硫仑 (DSF) 是 FDA 批准的 ALDH 抑制剂。酒精中毒的治疗通过与必需微量物质的结合而增强其对乳腺癌细胞的毒性。元素铜(Cu)形成DSF/Cu络合物是一种有效的方法。蛋白酶体抑制剂导致抑制关键转录因子 NF-κB，该因子与癌症以及放射、化学抗性和与最新流行病学报告一致，表明 DSF 显着减少患者因癌症死亡的风险，我们发现 DSF 和 IR 有效地针对 BSCS/iBCSC，并且显着在侵袭性小鼠乳腺肿瘤 4T1 模型中预防肺转移，而单独 IR 则有效我们还发现 DSF/Cu 可以通过下调阻断体外和体内 IR 或化疗诱导的 BCSC。通过降低促生存 ALDH 活性来调节 NF-κB 干基因通路和靶标 BCSC 和诱导内质网（ER）应激-免疫细胞死亡（ICD）此外，DSF和IR。在 4T1 小鼠模型中诱导针对原发肿瘤和肺转移的强大免疫反应。 ICD 细胞干性。这些研究结果为我们的假设提供了理论依据：DSF/Cu 可诱导治疗耐药的 BCSC 和阻断 IR 或化疗诱导的 BCSC 的形成，可有效预防乳腺癌转移与最常用的标准治疗相结合，即手术、IR 和化疗。由于铜是肿瘤促进并发现在乳腺癌专利的肿瘤和血清中水平升高，定制使用外源性体内 DSF 的 Cu 将基于所有目标中的肿瘤 Cu 水平。在目标 1 中，我们将评估治疗效果 IR和/或化疗联合DSF/Cu预防乳腺癌患者转移的功效在 Aim2 中，我们将评估辅助环境中的异种移植 (PDX) 和 MMTV-PyMT 转基因乳腺肿瘤。化疗联合DSF/Cu预防PDX和MMTV-PyMT转移的疗效在 Aim3 中，我们将进行新辅助治疗中的肿瘤。分析 DSF/Cu 系统性作用的机制通过诱导 ICD 和调节 IR 诱导的免疫反应来靶向 BCSC 在此结论中研究中，我们将： i) 评估 DSF/Cu 作为手术中针对 BCSC/ iBCSC 的新型药物，化疗和/或红外线治疗；阐明了 DSF/Cu 和 IR 诱导强大免疫系统的机制针对乳腺癌转移的反应；以及 iii) 为设计临床方案奠定了临床前基础研究计划旨在测试这种新疗法预防治疗后乳腺癌转移的效果。