Copper-mediated metabolic reprogramming and ECM alterations in TNBC metastasis

TNBC 转移中铜介导的代谢重编程和 ECM 改变

• 批准号: 10398970
• 负责人: Vivek Mittal
• 金额: $ 53.53万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10398970
• 关键词: 5' -AMP-activated protein kinase; Affect; Animal Model; Architecture; Atomic Force Microscopy; Binding; Bioenergetics; Biological Markers; Breast Cancer Patient; Breast cancer metastasis; Cells; Chelating Agents; Clinical; Clinical Trials; Collagen; Copper; Deposition; Development; Disease; Distal; ERBB2 gene; Enzymes; Exhibits; Extracellular Matrix; FRAP1 gene; Future; Genetic; Glycolysis; Goals; Human; Impairment; Investigation; LOXL2 gene; Link; Lung; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Metals; Mitochondria; Modality; Molecular; Molecular Chaperones; Mus; Neoplasm Metastasis; Oral; Organ; Outcome; Pathway interactions; Patients; Pharmacology; Phase; Phase II Clinical Trials; Phenotype; Population; Pre-Clinical Model; Primary Neoplasm; Progression-Free Survivals; Protein Kinase; Protein-Lysine 6-Oxidase; Proteins; Randomized Clinical Trials; Recurrence; Reporting; Role; Sampling; Serum; Signal Transduction; Testing; Therapeutic; Therapeutic Agents; Trace Elements; Tumor Angiogenesis; Work; amine oxidase; anti-cancer therapeutic; base; cancer cell; clinically significant; cofactor; combat; complex IV; crosslink; effective therapy; genetic approach; genetic manipulation; high risk; human data; hypocupremia; metabolic phenotype; metabolomics; metalloenzyme; mouse model; mutant; neoplastic cell; novel; novel therapeutic intervention; patient subsets; pre-clinical; prevent; randomized trial; response; response biomarker; second harmonic generation imaging; stem cells; targeted treatment; tetrathiomolybdate; thiomolybdate; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; uptake

Triple negative breast cancer (TNBC) patients present a formidable clinical challenge, as they exhibit higher rates of metastatic recurrence, and respond poorly to available targeted therapies. Given the clinical significance, it is imperative to develop effective targeted anti-metastatic therapies for the treatment of TNBC. Metals serve as co-factors for tumor promoting pathways and targeting metals to disable these pathways has emerged as a potential anti-cancer therapeutic strategy. Copper, an essential trace element functions as a catalytic cofactor for a host of metalloenzymes/proteins that contribute to tumor angiogenesis and metastasis. In addition, increased copper uptake by malignant cells has led to the development of copper-specific chelators as therapeutic agents. In a potentially transformative discovery, we have identified within the primary tumor, a discrete population of highly metastatic OCT4+ SOX2+ cells. We show that these metastatic cells have significantly elevated levels of intracellular copper and exhibit increased sensitivity to copper deficiency. We have also shown that copper depletion alters the architecture of extracellular matrix in the metastatic lungs of both mouse and human. Our central hypothesis is that copper contributes to two key aspects of metastasis: cancer cell intrinsic metabolic pathways that directly contribute to metastasis; and the “pre-metastatic niche” that supports colonization, and outgrowth of disseminated metastatic tumor cells. To test this hypothesis, we will use pre-clinical models to elucidate cellular and molecular mechanisms of oral copper chelator tetrathiomolybdate (TM) and leverage banked samples from our completed phase II TM clinical trial to develop collagen remodeling products as biomarkers of TM response. The central goal of this proposal is to understand the mechanistic basis of copper depletion as a viable treatment approach against TNBC metastasis. We expect to make significant advances through the following aims. Aim 1 will establish the direct link between copper-mediated metabolic reprograming and metastasis in TNBC and dissect key cellular and molecular mechanisms, and Aim 2 will investigate how copper deficiency reprograms the extracellular matrix in the distal metastatic organs to generate an inhospitable microenvironment to impair metastasis and develop clinically valuable biomarkers of response to TM. Fundamental discoveries from these integrated pharmacological and genetic investigations has the potential not only to advance TM into larger randomized trials, but to identify new copper pathways for the development of novel therapeutic strategies against TNBC.

三阴性乳腺癌（TNBC）患者提出了一个艰巨的临床挑战，因为他们 表现出更高的转移复发率，并且对可用的靶向治疗反应差。 鉴于其临床意义，开发有效的靶向抗转移药物势在必行 用于治疗TNBC的疗法。金属作为肿瘤促进途径的辅助因子 靶向金属来破坏这些通路已经成为一种潜在的抗癌治疗方法 战略铜是一种必需的微量元素，是许多生物的催化辅因子 金属酶/蛋白质有助于肿瘤血管生成和转移。此外，本发明还提供了一种方法， 恶性细胞对铜的摄取增加导致了铜特异性 螯合剂作为治疗剂。在一个潜在的变革性发现中，我们发现了 在原发性肿瘤内，高转移性OCT 4 + SOX 2+细胞的离散群体。我们 显示这些转移性细胞具有显著升高的细胞内铜水平， 表现出对铜缺乏的敏感性增加。我们还表明， 改变小鼠和人转移性肺中细胞外基质的结构。 我们的中心假设是，铜有助于转移的两个关键方面：癌细胞 直接导致转移的内在代谢途径;以及“转移前小生境” 支持扩散转移性肿瘤细胞的定殖和生长。为了验证这一 假设，我们将使用临床前模型来阐明细胞和分子机制， 口服铜螯合剂四硫代钼酸盐（TM）和杠杆库存样品从我们完成 II期TM临床试验，以开发胶原重塑产品作为TM反应的生物标志物。 该提案的中心目标是了解铜耗竭的机械基础， 针对TNBC转移的可行治疗方法。我们希望在未来的几年里 通过以下目标。目标1将建立铜介导的 代谢重编程和转移，并剖析关键的细胞和分子 机制，目标2将研究铜缺乏如何重新编程细胞外 基质中的远端转移器官，以产生一个不适宜的微环境，损害 转移并开发对TM响应的临床上有价值的生物标志物。基本 这些综合药理学和遗传学研究的发现有可能 只是为了将TM推进到更大的随机试验中，而是为了确定新的铜途径， 开发针对TNBC的新型治疗策略。