Iron addiction and the biology of ovarian cancer

描述（由申请人提供）：卵巢癌仍然是一种致命的疾病。这是由于晚期发现和边际有效治疗的结合，这是由固有和获得性治疗抗性引起的。传统方法未能为这种卵巢癌提供有效治疗，这表明需要新的思维方式。我们的初步观察表明，卵巢肿瘤细胞获得和保留更多的铁比他们的非恶性同行。铁利用增强的证据在卵巢肿瘤组织和卵巢肿瘤祖细胞中是明显的。我们假设卵巢癌细胞依赖于维持超正常水平的代谢可用的细胞内铁，以支持其生长和活力。我们建议用“铁成瘾”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关键差异。这些蛋白质在癌细胞铁代谢必不可少的途径中的作用将被确定。在目标2中，致癌信号的改变驱动了卵巢肿瘤祖细胞铁代谢的关键差异， 通过询问c-myc的作用来评估。患者数据库分析将用于评估c-myc驱动的铁代谢变化的患病率及其与预后的相关性。目标3，我们将使用系统生物学来确定关键的铁调控节点和机制，通过这些节点和机制，其他致癌驱动因子靶向铁。这项研究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联系起来。这可能为卵巢癌治疗提供新的和新颖的靶点。

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.