Immunomodulatory action of demethylating agent SGI-110 in ovarian cancer

去甲基化剂SGI-110对卵巢癌的免疫调节作用

• 批准号: 1770870
• 金额: --
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1770870
• 关键词: Immunomodulatory; action; demethylating; agent; SGI

Ovarian cancer (OC) is regarded as being an immunogenic cancer, however, the bulk of the immune responses associated with OC are inflammatory and suppressive in nature. This suggests that strategies to overcome these suppressive mechanisms and enhance immune function in patients will confer benefit and improve prognosis. Immunotherapy has been shown to be most promising when combined with other therapeutic approaches to combat the disease. Recent evidence in the field and preliminary data from our group suggest that treatment with epigenetic drugs, such as cytidine analogs, can lead to improved immune activation in several cancers including ovarian. We hypothesise that the global demethylating and DNA damaging effects of treatment with cytidine analogs can induce the re-expression of immunomodulatory genes and endogenous retroviral elements (ERVs), which shifts ovarian cancer cells towards a more immunogenic expression profile. We plan to identify and validate such immunomodulatory genes and ERVs by RNA-sequencing of ovarian cancer cell lines treated with novel cytidine analog SGI-110; to investigate the contribution of DNA demethylation and DNA damage in the proposed immunomodulatory effect of this class of epigenetic drugs and to test a novel combination epigenetic-immunotherapeutic strategy for the treatment of ovarian cancer using SGI-110 and T-cells. This project will, for the first time, use a genomic approach to study the immunomodulatory potential of SGI-110 and provide genome-wide transcriptional data for previously unstudied ovarian cancer cell lines which better represent the real disease. Additionally, it will identify potential gene targets and/or biomarkers and test a novel combination therapy which may, ultimately, be developed into a clinical trial.

卵巢癌（OC）被认为是一种免疫原性癌症，然而，与OC相关的大部分免疫应答本质上是炎症性和抑制性的。这表明克服这些抑制机制和增强患者免疫功能的策略将带来益处并改善预后。免疫疗法已被证明是最有前途的，当与其他治疗方法相结合，以打击这种疾病。该领域的最新证据和我们小组的初步数据表明，用表观遗传药物（如胞苷类似物）治疗可以改善包括卵巢癌在内的几种癌症的免疫激活。我们假设胞苷类似物治疗的整体去甲基化和DNA损伤效应可以诱导免疫调节基因和内源性逆转录病毒元件（ERVs）的重新表达，这使卵巢癌细胞向更具免疫原性的表达谱转变。我们计划通过用新型胞苷类似物SGI-110处理的卵巢癌细胞系的RNA测序来鉴定和验证这种免疫调节基因和ERV;研究DNA去甲基化和DNA损伤在这类表观遗传药物的拟议免疫调节作用中的作用，并测试使用SGI-110和T细胞治疗卵巢癌的新型组合表观遗传免疫策略。该项目将首次使用基因组方法研究SGI-110的免疫调节潜力，并为以前未研究的卵巢癌细胞系提供全基因组转录数据，这些细胞系更好地代表了真实的疾病。此外，它将确定潜在的基因靶点和/或生物标志物，并测试一种新的联合疗法，最终可能会发展成临床试验。