Copper-depleting nanotheranostics for treating triple negative breast cancer

摘要 乳腺癌是妇女所有类型癌症中的第二大死亡原因。最致命的亚型 三阴性乳腺癌的转移风险最高，由于耐药， 目前的治疗方法。三阴性乳腺癌（TNBC）是一种本质上异质性的疾病。 靶向单一生物标志物或癌基因通常在TNBC治疗中产生不令人满意的治疗结果。到 为了获得更广泛的治疗益处，我们的出发点是铜离子，一种关键的金属离子， 在广泛的生物化学反应中具有不可替代的作用。血清和癌组织中的铜过量 在乳腺癌患者中早已被认可。铜金属蛋白的失调被发现是 参与癌细胞的不受控制的生长、侵袭、扩散、血管生成和继发性肿瘤 在遥远的地方形成。尽管公认的重要性，成功的尝试治疗癌症与 铜螯合作用相当有限。 我们的母公司R 01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 铜在TNBC中的作用，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自报告功能的铜消耗纳米络合物 治疗诊断学（目的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（目的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（Aim 3）。 作为对RFA-CA-21-007的回应，本修订申请将引入尖端技术， 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 CDN治疗后（例如凋亡和代谢），并揭示了如何 线粒体异质性可能有助于对铜耗竭治疗的抗性（新目标4）。的 研究将是R 01的PI和来自英国的Peter J Burke教授之间的合作努力。 加州大学欧文分校，线粒体分析技术的开发者，通过IMAT资助 将IMAT技术应用于分析单个铜离子对铜贫化的作用。这 R 01-IMAT的统一将在很大程度上扩展目前对与铜消耗相关的生物学的理解， 有助于将亲本R 01的范围扩展到TNBC以外的其他癌症类型。

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.