Novel effectors of ERK signaling and their potential roles in the treatment of en

子宫内膜癌是女性最常见的生殖道癌。大多数子宫内膜 癌症是在早期发现的，表现为绝经后出血。这些患者最初是 采用综合外科分期治疗。这种治疗通常是对疾病的程度和程度的诊断 有治疗作用。然而，子宫癌患者治疗中的一个关键临床问题是如何 最好的分期和侵袭性的病理组织类型 死亡率。 高分期或复发癌症的患者有系统性疾病，需要新的治疗方法 干预措施。有效的治疗方法在很大程度上是缺乏的。更好地了解癌症生物学，例如 信号转导通路，将导致新的治疗策略，将提高这些患者的存活率 病人。丝裂原激活通路的激活在很大程度上有助于 子宫内膜肿瘤的发生。我们的团队已经通过三部分确定了30种新的ERK底物 线虫模型中的功能基因组方法。这些蛋白的人类同源基因在 子宫内膜癌细胞系是ERK的候选底物。到目前为止，在被研究的候选人中，我们展示了 GSK3n对多种子宫内膜癌细胞系中的细胞生长是重要的，并具有潜在的 治疗性干预..在这项提案中，我们将继续表征新的ERK候选底物 子宫内膜癌。在目标1中，我们将评估候选ERK1/2底物在正常人中的表达 子宫内膜、原发子宫内膜癌和子宫内膜癌细胞株的检测 磷酸化依赖于ERK。然后在目标2中，我们将确定ERK底物之间的关系 子宫内膜癌和子宫内膜癌组织中磷酸化状态及上游ERK信号通路的激活 ERK底物表达的临床病理意义最后，在目标3中，我们将探索GSKSD 抑制作为子宫内膜癌的潜在治疗方法，并评估抑制其他ERK底物的作用 在子宫内膜癌细胞系中发挥作用。总而言之，这些研究应该能更好地理解 ERK通路在子宫内膜癌发生中的作用及其临床生物学意义 治疗。 相关性(请参阅说明)： 拟议的工作将导致对子宫内膜癌生物学的更好理解和新的 可减少癌症的子宫癌的检测、预防和治疗方法 发病率和死亡率。

Endometrial carinoma is the most common cancer of the female reproductive tract. Most endometrial cancers are found at an early stage and present with postmenopausal bleeding. These patients are initially treated with comprehensive surgical staging. This treatment is often diagnostic ofthe extent of disease and therapeutic. However, a key clinical problem in the management of patients with uterine cancers is how to best fre¿t~ab\r¿rhced'stagieclisease ahdlhe aggressive pathoTogic histotypes that account for signficant mortality. Patients with high stage or recurrent cancers have systemic disease requiring novel therapeutic interventions. Effective therapies are largely lacking. A better understanding ofthe cancer biology, such as signal transduction pathways, will lead to new treatment strategies that will improve the survival of these patients. Activation of the Mitogen Activating Pathway Kinase signaling pathway contributes substantially to endometrial tumorigenesis. Our group has identified thirty novel ERK substrates through a three-part functional genomic approach in the C. elegans model. The human orthologs of these proteins expressed in endometrial cancer cell lines are candidate ERK substrates. Thus far, of the candidates studied, we showed that GSK3n is important to cell growth in multiple endometrial cancer cell lines and has potential for therapeutic interventions.. In this proposal, we will continue to characterize novel ERK candidate substrates in endometrial cancer. In Aim 1, we will assess expression of candidate ERK1/2 substrates in the normal endometrium, primary endometrial cancers and endometrial cancer cell lines and determine if substrate phosphorylation is ERK-dependent. Then in aim 2, we will determine the relationship between ERK substrate phosphorylation status and upstream ERK signaling pathway activation in primary endometrial cancers and clinicopathologic significance of ERK substrate expression. Finally in aim 3, we will explore GSKSD inhibition as potential therapy for endometrial cancer and assess the role of inhibiting other ERK substrates plays in endometrial cancer cell lines. Together these studies should provide a better understanding of the role the ERK pathway plays in endometrial carcinogenesis and may lead to improved clinical biological therapies. RELEVANCE (See instructions): The work proposed will lead to both an improved understanding of endometrial cancer biology and new approaches to the detection, prevention and treatment of uterine cancers which will result in reduced cancer morbidity and mortality.