Targeting STAT3 in Ovarian Cancer- Center for Integrated Biomedical and Bioengineering (CIBBR)

卵巢癌中的 STAT3 靶向治疗 - 综合生物医学和生物工程中心 (CIBBR)

• 批准号: 10395120
• 负责人: Rick H Cote
• 金额: $ 30.07万
• 依托单位: UNIVERSITY OF NEW HAMPSHIRE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395120
• 关键词: 3-Dimensional; Address; Affect; Attenuated; Benign; Biomedical Engineering; Cancer Center; Cancer Cluster; Cancer Patient; Cells; ChIP-seq; Cholesterol; Cisplatin; Data; Disease; Drug Design; Female; Female Genital Diseases; Female of child bearing age; GAK gene; Gene Expression; Genes; Growth; Health; Human; Immunofluorescence Immunologic; Infertility; Knowledge; Lead; Life; Longevity; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Maps; Mesothelial Cell; Metastatic Malignant Neoplasm to the Ovary; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Ovarian; Ovarian Endometriosis; Pathway interactions; Patients; Peritoneum; Pharmaceutical Preparations; Pharmacotherapy; Play; Recurrence; Regulation; Reporter; Research; Resistance; Retrospective Studies; Risk; Role; STAT3 gene; Signal Pathway; Signaling Protein; Simvastatin; Small Interfering RNA; Stat3 Signaling Pathway; Strategic Planning; United States National Institutes of Health; Woman; Women' s Health; Work; cancer cell; chemotherapy; endometriosis; genetic signature; inhibitor/antagonist; insight; mortality; single-cell RNA sequencing; success; transcription factor; treatment strategy

PROJECT SUMMARY Ovarian cancer remains a deadly disease in part due to ovarian cancer metastasis. Spheroids, clusters of ovarian cancer cells, interact and clear the protective mesothelial layer that lines the peritoneum in the early stages of ovarian cancer metastasis. There is a gap in knowledge regarding the signaling pathways and genes involved in mesothelial clearance. By not knowing these pathways, this may affect the ability to design drugs to target ovarian cancer metastasis. The STAT3 signaling pathway plays a role in mesothelial clearance. However, it is not known how the interaction of ovarian spheroids with mesothelial cells affects STAT3 activation in ovarian cancer cells. Endometriosis, a benign disease that may promote infertility and increase risk for ovarian cancer, has some similarities to ovarian cancer as the endometrioid cells also interact with the mesothelial cells, and STAT3 activation is elevated in patients with endometriosis. Statins, inhibitors of HMGCR, are often used to lower cholesterol; however, there is evidence that statins also inhibit STAT3. The long-term objective of this work is to develop drugs for the treatment of metastatic ovarian cancer. The central hypothesis is that interaction with mesothelial cells modulates STAT3 activity that can be attenuated with statin treatment. Aim 1 will determine the effects of interacting with mesothelial cells on STAT3 activation and define the mechanism of STAT3 inhibition by statins. Aim 2 will determine STAT3 target gene expression changes during mesothelial clearance that are blocked by statin treatment using single cell RNA-seq. Ovarian cancer cells will be compared to endometrioid cells to potentially identify cancer specific STAT3 target genes. Overall, the outcomes of the proposed work may provide a more complete understanding of the role of STAT3 in ovarian cancer metastasis and provide insight into the role of STAT3 in endometriosis, two gynecologic diseases that may greatly impact women across their lifespan.

项目概要 卵巢癌仍然是一种致命的疾病，部分原因是卵巢癌转移。卵巢球体、簇 癌细胞相互作用并清除早期阶段腹膜上的保护性间皮层 卵巢癌转移。关于所涉及的信号通路和基因的知识存在差距 在间皮间隙。由于不了解这些途径，这可能会影响设计靶向药物的能力 卵巢癌转移。 STAT3 信号通路在间皮清除中发挥作用。然而，它是 尚不清楚卵巢球体与间皮细胞的相互作用如何影响卵巢中 STAT3 的激活 癌细胞。子宫内膜异位症是一种良性疾病，可能会促进不孕并增加患卵巢癌的风险， 与卵巢癌有一些相似之处，因为子宫内膜样细胞也与间皮细胞相互作用，并且 子宫内膜异位症患者的 STAT3 激活水平升高。他汀类药物是 HMGCR 抑制剂，通常用于 降低胆固醇；然而，有证据表明他汀类药物也会抑制 STAT3。这项工作的长期目标 是开发治疗转移性卵巢癌的药物。中心假设是相互作用 间皮细胞调节 STAT3 活性，可通过他汀类药物治疗减弱这种活性。目标 1 将确定 与间皮细胞相互作用对 STAT3 激活的影响并确定 STAT3 抑制机制 通过他汀类药物。目标 2 将确定间皮清除期间 STAT3 靶基因表达的变化 使用单细胞 RNA-seq 通过他汀类药物治疗进行阻断。卵巢癌细胞将与子宫内膜样细胞进行比较 细胞可能识别癌症特异性 STAT3 靶基因。总体而言，拟议工作的成果可能 更全面地了解 STAT3 在卵巢癌转移中的作用并提供见解 STAT3 在子宫内膜异位症中的作用，子宫内膜异位症是两种可能对女性一生产生重大影响的妇科疾病 寿命。