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

• 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
• 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

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 乳腺癌是女性所有类型的癌症中死亡的第二名。最致命的亚型 三重阴性的乳腺癌具有最高的转移风险和最差的结果 目前的治疗方法。三阴性乳腺癌（TNBC）是一种本质上异质性疾病。 靶向单个生物标志物或癌基通常在TNBC治疗中会产生不令人满意的治疗结果。到 获得更广泛的治疗益处，我们的起点是铜离子，一种临界金属离子 在广泛的生化反应中不可替代的作用。血清和癌组织中的铜过量 长期以来在乳腺癌患者中得到认可。发现铜金属蛋白的失调是 参与不受控制的生长，侵袭，癌细胞的传播，血管生成和继发性肿瘤 在遥远的地点形成。尽管认识到很重要，但成功地试图治疗癌症 铜螯合是相当有限的。 我们的父级R01项目旨在建立自我报告的铜耗尽纳米板，以有效耗尽 TNBC中的铜，最终通过设计抑制原发性肿瘤的进展和转移形成 具有高耗尽效率，低毒性和自我报告功能的铜纳米复合物作为TNBC 疗法学（AIM 1），确定消耗铜的纳米复合物的治疗效果，并确定 体外的治疗机制（AIM 2），并定义缺乏铜纳米复合物的治疗功效 用于原发性和转移性TNBC肿瘤模型（AIM 3）。 为了响应RFA-CA-21-007，此修订应用程序将引入尖端技术 线粒体分离和表征以仔细检查与线粒体相关的细胞功能改变 经过CDN治疗（例如凋亡和代谢），并揭示了基本的机理见解 线粒体异质性可能有助于抗铜耗尽处理（新目标4）。这 研究将是父母R01的PI与Peter J Burke教授之间的合作努力 加利福尼亚大学 - Irvine大学，通过IMAT资助的线粒体分析技术的开发商 应用IMAT技术以分析铜耗尽时单线粒体的功能。这 R01-IMAT统一将在很大程度上扩展对与铜耗尽相关的生物学的当前理解和 帮助将父级R01的范围扩展到TNBC以外的其他癌症类型。