Iron addiction and the biology of ovarian cancer

铁成瘾与卵巢癌的生物学

• 批准号: 8928096
• 负责人: Suzy V Torti
• 金额: $ 37.9万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-16 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8928096
• 关键词: Affect; Biological Models; Biology; Cancer Patient; Cells; Data; Databases; Disease; Engineering; Failure; Future; Goals; Growth; Health; Heme; Iron; Lead; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Metabolic; Modeling; Non-Malignant; Normal Cell; Oncogenes; Oncogenic; Ovarian; Pathway interactions; Patients; Phenocopy; Prevalence; Proteins; Proteomics; Recurrence; Research Personnel; Resistance; Role; Sampling; Shorthand; Signal Transduction; Staging; Stem cells; Sulfur; Systems Biology; Techniques; Testing; Therapeutic Intervention; Thinking; Transcript; Tumor Suppressor Genes; Tumor Tissue; addiction; c-myc Genes; cancer cell; cancer therapy; differential expression; effective therapy; insight; iron metabolism; neoplastic cell; novel; outcome forecast; ovarian neoplasm; research study; stem; transcriptome sequencing; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Ovarian cancer remains a deadly disease. This is due to a combination of late stage discovery and marginally effective therapy, resulting from both inherent and acquired treatment resistance. Failure of conventional approaches to provide effective treatment for this ovarian cancer suggests that new ways of thinking are required. Our preliminary observations show that ovarian tumor cells acquire and retain more iron than their non-malignant counterparts. Evidence of enhanced iron utilization is evident in ovarian tumor tissue and in ovarian tumor progenitor cells. We hypothesize that ovarian cancer cells become dependent on maintaining supra-normal levels of metabolically available intracellular iron to support their growth and viability. We propose the term "iron addiction" to characterize this state. Altered iron metabolism may represent a new targetable hallmark of cancer. We propose three specific aims to test this hypothesis. In Aim 1, key differences in iron metabolism between normal ovarian stem cells and ovarian tumor progenitor cells derived from patient samples will be characterized using RNAseq and proteomics. The roles of these proteins in pathways essential to cancer cell iron metabolism will be determined. In Aim 2, alterations in oncogenic signaling that drive critical differences in iron metabolism in ovarian tumor progenitor cells will be assessed by interrogating the role of c-myc. Analysis of patient databases will be used to assess prevalence of c-myc-driven changes in iron metabolism and association with prognosis. Aim 3, we will use systems biology to identify key iron regulatory nodes and mechanisms through which other oncogenic drivers target iron. The overall goal of this proposal is to understand mechanisms underlying iron addiction in ovarian cancer and how changes in iron metabolism link to oncogenic signaling. This may provide insights into new and novel targets for ovarian cancer therapy.

描述（由申请人提供）：卵巢癌仍然是一种致命的疾病。这是由于固有的和获得性的治疗耐药性导致晚期发现和勉强有效的治疗相结合。传统方法无法有效治疗这种卵巢癌，这表明需要新的思维方式。我们的初步观察表明，卵巢肿瘤细胞比非恶性细胞获得并保留更多的铁。在卵巢肿瘤组织和卵巢肿瘤祖细胞中铁利用率增强的证据是明显的。我们假设卵巢癌细胞变得依赖于维持代谢可用的细胞内铁的超正常水平来支持其生长和活力。我们提出“铁瘾”一词来描述这种状态。铁代谢的改变可能代表癌症的一个新的可靶向标志。我们提出了三个具体目标来检验这一假设。在目标 1 中，将使用 RNAseq 和蛋白质组学来表征正常卵巢干细胞和源自患者样本的卵巢肿瘤祖细胞之间铁代谢的主要差异。这些蛋白质在癌细胞铁代谢必需途径中的作用将被确定。在目标 2 中，致癌信号的改变会导致卵巢肿瘤祖细胞中铁代谢的关键差异 通过询问 c-myc 的作用来评估。对患者数据库的分析将用于评估 c-myc 驱动的铁代谢变化的发生率及其与预后的关系。目标 3，我们将利用系统生物学来确定其他致癌驱动因素针对铁的关键铁调节节点和机制。该提案的总体目标是了解卵巢癌铁成瘾的潜在机制以及铁代谢的变化如何与致癌信号传导相关。这可能为卵巢癌治疗的新靶点提供见解。