Copper-depleting nanotheranostics for treating triple negative breast cancer

用于治疗三阴性乳腺癌的铜消耗纳米治疗剂

基本信息

批准号：
10413265
负责人：
Jianghong Rao
金额：
$ 20.07万
依托单位：
STANFORD UNIVERSITY
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：
2019-09-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10413265
关键词：
Apoptosis Biochemical Reaction Biological Assay Biological Markers Biology Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment California Cancer Biology Cancerous Cause of Death Cell physiology Cells Cessation of life Collaborations Communities Copper Copper Chelation Development Disease Distant Electrodes Electron Transport Environment Funding Growth Heterogeneity Home In Vitro Ions Life Malignant Neoplasms Measures Membrane Potentials Metabolic Metabolism Metalloproteins Metals Methods Microfluidics Microscopic Mitochondria Modeling Molecular Chaperones Morphology Nanostructures Nanotechnology Neoplasm Metastasis Oncogenes Outcome Outer Mitochondrial Membrane Parents Pathway interactions Patient Self-Report Pharmaceutical Preparations Pharmacology Play Polymers Porifera Primary Neoplasm Proteins Research Resistance Risk Role Serum Site Techniques Technology Therapeutic Time Tissues Toxic effect Treatment Efficacy Tumor Tissue Universities Validation Warburg Effect Woman angiogenesis anti-cancer base cancer cell cancer therapy cancer type cytotoxicity design graphene heteroplasmy in vivo insight malignant breast neoplasm mitochondrial membrane nanoparticle nanotechnology platform nanotheranostics new technology novel professor response side effect systemic toxicity theranostics therapy outcome tool treatment effect treatment response triple-negative invasive breast carcinoma tumor tumor heterogeneity tumor metabolism tumor progression

项目摘要

ABSTRACT Breast cancer is the number two cause of death among all types of cancers in women. The deadliest subtype of breast cancer, triple-negative, carries the highest metastatic risk and poorest outcome due to the resistance to current therapeutic methods. Triple-negative breast cancer (TNBC) is an intrinsically heterogeneous disease. Targeting single biomarker or oncogene often yields unsatisfactory therapeutic outcome in TNBC treatment. To achieve a broader therapeutic benefit, our starting point is copper ion, one critical metal ion that plays irreplaceable roles in a broad range of biochemical reactions. Copper excess in serum and cancerous tissues has been long recognized in breast cancer patients. Dysregulation of copper metalloproteins is found to be involved in uncontrolled growth, invasion, dissemination of cancer cells, angiogenesis and secondary tumor formation at distant sites. Despite the well-recognized importance, successful attempts to treat cancer with copper chelation are rather limited. Our parent R01 project aims to establish a self-reporting copper depletion nanoplatform to effectively deplete copper in TNBC and ultimately inhibit primary tumor progression and metastasis formation through designing copper-depleting nanocomplex with high depleting efficiency, low toxicity and self-reporting function as TNBC theranostics (Aim 1), determining the treatment effect of copper-depleting nanocomplex and identify the therapeutic mechanism in vitro (Aim 2), and defining the therapeutic efficacy of copper-depleting nanocomplex for primary and metastatic TNBC tumor models (Aim 3). In response to the RFA-CA-21-007, this revision application will introduce the cutting-edge technology on mitochondria isolation and characterization to scrutinize the mitochondria-related cellular function alterations after the CDN treatment (e.g. apoptosis and metabolism) and reveal basic mechanistic insights into how mitochondrial heterogeneity may contribute to the resistance to copper depletion treatment (new Aim 4). The research will be a collaborative effort between the PI of the parent R01 and Professor Peter J Burke from University of California-Irvine, the developer of the mitochondrial analysis techniques through the IMAT funding to apply the IMAT technology for the analysis of function of single mitochondrion upon copper depletion. This R01-IMAT unity will largely extend current understanding of the biology associated with copper depletion and help expand the scope of parent R01 to other cancer types beyond TNBC.

抽象的乳腺癌是女性所有癌症中排名第二的癌症。最致命的亚型三阴性乳腺癌由于耐药性而具有最高的转移风险和最差的结果到目前的治疗方法。三阴性乳腺癌（TNBC）是一种本质上异质的疾病。在 TNBC 治疗中，针对单一生物标志物或癌基因通常会产生不令人满意的治疗结果。到为了实现更广泛的治疗效果，我们的出发点是铜离子，一种发挥作用的关键金属离子在广泛的生化反应中发挥着不可替代的作用。血清和癌组织中铜过量早已在乳腺癌患者中得到认可。发现铜金属蛋白的失调参与癌细胞不受控制的生长、侵袭、扩散、血管生成和继发性肿瘤在远处形成。尽管癌症的重要性已得到广泛认可，但治疗癌症的成功尝试铜螯合相当有限。我们的母公司 R01 项目旨在建立一个自我报告的铜消耗纳米平台，以有效地消耗铜 TNBC 中的铜，并通过设计最终抑制原发性肿瘤进展和转移形成具有高消耗效率、低毒性和TNBC自我报告功能的消耗铜纳米复合物治疗诊断学（目标 1），确定铜消耗纳米复合物的治疗效果并确定体外治疗机制（目标 2），并确定铜消耗纳米复合物的治疗功效用于原发性和转移性 TNBC 肿瘤模型（目标 3）。响应RFA-CA-21-007，本次修订申请将引入尖端技术线粒体分离和表征，以检查线粒体相关的细胞功能改变 CDN 处理后（例如细胞凋亡和代谢）并揭示了如何进行的基本机制见解线粒体异质性可能导致对铜消耗治疗的抵抗（新目标 4）。这该研究将是母体 R01 的 PI 和来自英国的 Peter J Burke 教授的合作成果。加州大学欧文分校，通过 IMAT 资助开发线粒体分析技术应用IMAT技术分析单个线粒体在铜耗尽后的功能。这 R01-IMAT 统一将在很大程度上扩展当前对与铜消耗和相关生物学相关的理解帮助将母体 R01 的范围扩大到 TNBC 以外的其他癌症类型。