Iron addiction and the biology of ovarian cancer

描述(申请人提供)：卵巢癌仍然是一种致命的疾病。这是由于后期发现和边际有效的治疗相结合，这是由先天和后天治疗耐药造成的。传统方法无法为卵巢癌提供有效的治疗，这表明需要新的思维方式。我们的初步观察表明，卵巢肿瘤细胞比非恶性肿瘤细胞获得和保留更多的铁。在卵巢肿瘤组织和卵巢肿瘤前体细胞中，铁利用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细胞内代谢可用铁的超正常水平来支持其生长和生存。我们建议用“铁瘾”一词来描述这种状态。铁代谢的改变可能代表了癌症的一个新的靶标。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来自患者样本的正常卵巢干细胞和卵巢肿瘤前体细胞中铁代谢的关键差异。这些蛋白质在癌细胞铁代谢所必需的途径中的作用将被确定。在目标2中，导致卵巢肿瘤前体细胞铁代谢关键差异的致癌信号的变化将 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流行率及其与预后的关系。目的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，其他致癌驱动因素通过这些机制靶向铁。这项建议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的新靶点提供洞察力。

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.