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治疗效果不佳的结合，造成固有的和获得性的治疗耐药性。传统方法的失败，提供有效的治疗卵巢癌表明，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对手。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来支持其生长和生存。我们建议用“铁瘾”这个词来描述这种状态。铁代谢的改变可能是癌症的一种新的靶向标志。我们提出三个具体目标来检验这一假设。在Aim 1中，来自患者样本的正常卵巢干细胞和卵巢肿瘤祖细胞之间铁代谢的关键差异将使用RNAseq和蛋白质组学进行表征。这些蛋白在癌细胞铁代谢的重要途径中的作用将被确定。在Aim 2中，致癌信号的改变驱动卵巢肿瘤祖细胞铁代谢的关键差异

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.