Exploration of SIK2-signaling in ovarian cancer with CCNE1-amplification3

通过 CCNE1 扩增探索卵巢癌中的 SIK2 信号传导3

• 批准号: 397659447
• 负责人: Professor Dr. Stefan Knapp
• 金额: --
• 依托单位: Institut für Pharmazeutische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/397659447?language=en
• 关键词: Exploration; SIK2; signaling; ovarian; cancer

Despite a high overall initial response to standard chemotherapy, the majority of epithelial ovarian cancer (EOC) patients die from the progressive growth of recurrent chemotherapy-resistant disease. The most significant advance in the chemotherapy was the introduction of paclitaxel to the treatment of EOC patients. The toxicity profile favoring the carboplatin/paclitaxel regimen has now established this as standard of care in the first-line setting. However, it appears that a therapeutic ceiling with these drugs has been reached. Recent evidence make a compelling case for targeting salt-inducible kinase 2 (SIK2) for therapy in ovarian cancer. SIK2 is over-expressed in omental metastases compared with primary tissues. Overexpression of SIK2 promotes abdominal metastasis in vivo. Although the established function of SIK2 is in the regulation of cellular metabolism, it’s role for the progression of ovarian cancer cells with CCNE1-amplification (30% of all ovarian cancers) through mitosis remains elusive. In this project, we plan to establish a structural model of the SIK2 catalytic domain, which is a prerequisite for an improved understanding for the regulation of the SIK2 catalytic activity and for the rational design of inhibitors. The detailed analysis of the role of SIK2 in the development of ovarian cancer with CCNE1-amplification in vitro and in vivo requires the use of specific SIK2 inhibitors. To further our understanding of SIK2 signaling in different stages of the cell cycle including mitosis, we plan to analyze the interactome and the phosphorylation of SIK2 in conjunction with the crystal structure of SIK2. Novel interacting partners will be functionally characterized. Importantly, we will also test novel inhibitors for targeted and combinatorial therapies (taxane/carboplatin) of ovarian cancer cells with CCNE1-amplification. Small molecules targeting SIK2 will have the potential to block two major pathways involved in metabolic regulation and the crosstalk between cancer cells and the microenvironment that both contribute to the establishment and growth of tumor metastasis.

尽管对标准化疗的总体初始反应很高，但大多数上皮性卵巢癌(EOC)患者死于复发的化疗耐药疾病的进行性增长。化疗方面最显著的进展是将紫杉醇引入卵巢癌患者的治疗中。支持卡铂/紫杉醇方案的毒性描述现在已将其确立为一线治疗的标准。然而，这些药物似乎已经达到了治疗的上限。最近的证据为以盐诱导蛋白2(SIK2)为靶点治疗卵巢癌提供了一个令人信服的理由。与原发灶组织相比，SIK2在大网膜转移灶中高表达。SIK2过表达可促进体内腹壁转移。尽管SIK2的功能已经确立，但它对CCNE1扩增的卵巢癌细胞(占所有卵巢癌的30%)通过有丝分裂的进展的作用仍不清楚。在这个项目中，我们计划建立SIK2催化结构域的结构模型，这是更好地理解SIK2催化活性的调节和合理设计抑制剂的先决条件。通过体外和体内CCNE1扩增，详细分析SIK2在卵巢癌发生发展中的作用，需要使用特定的SIK2抑制剂。为了进一步了解SIK2信号在细胞周期的不同阶段，包括有丝分裂，我们计划结合SIK2的晶体结构来分析SIK2的相互作用组和磷酸化。新的互动伙伴将从功能上进行描述。重要的是，我们还将通过CCNE1扩增来测试针对卵巢癌细胞的靶向和联合治疗(紫杉烷/卡铂)的新型抑制剂。靶向SIK2的小分子将有可能阻断参与代谢调节的两条主要途径，以及癌细胞和微环境之间的串扰，这两条途径都有助于肿瘤转移的建立和生长。