Copper-depleting nanotheranostics for treating triple negative breast cancer

摘要 在女性所有类型的癌症中，乳腺癌是第二大死因。最致命的亚型 由于耐药，三阴性乳腺癌的转移风险最高，预后最差。 到目前的治疗方法。三阴性乳腺癌(TNBC)是一种本质异质性疾病。 在TNBC治疗中，靶向单一生物标记物或癌基因的治疗效果往往不理想。至 要获得更广泛的治疗益处，我们的起点是铜离子，这是一种关键的金属离子 在广泛的生化反应中发挥着不可替代的作用。血清和癌组织中铜含量过高 很早就在乳腺癌患者中得到了认可。铜金属蛋白的失调被发现是 参与不受控制的生长、侵袭、癌细胞扩散、血管生成和继发性肿瘤 在遥远的地点形成队形。尽管公认的重要性，但成功的治疗癌症的尝试 铜的络合作用相当有限。 我们的母公司R01项目旨在建立一个自我报告的铜枯竭纳米平台，以有效地枯竭 铜在TNBC中的作用，并通过设计最终抑制原发肿瘤的进展和转移形成 高效、低毒、自报告的贫铜纳米络合物作为TNBC的功能 Theranostics(目标1)，确定耗铜纳米络合物的治疗效果，并确定 体外治疗机制(目标2)，确定贫铜纳米络合物的治疗效果 用于原发和转移性TNBC肿瘤模型(目标3)。 为响应RFA-CA-21-007，本次修订申请将在 线粒体的分离和鉴定以观察线粒体相关的细胞功能改变 在CDN治疗(例如，细胞凋亡和新陈代谢)之后，并揭示了对如何 线粒体的异质性可能有助于抗铜耗竭治疗(新目标4)。这个 这项研究将是家长R01的PI和来自 加州大学欧文分校，通过IMAT基金开发线粒体分析技术 应用IMAT技术分析单个线粒体在铜缺乏时的功能。这 R01-IMAT的统一将在很大程度上扩展目前对与铜枯竭和铜消耗相关的生物学的理解 帮助将亲本R01的范围扩大到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.