Targeting cytosolic helicases with modified siRNA for immunotherapy of hepatocellular carcinoma

使用修饰的 siRNA 靶向胞质解旋酶用于肝细胞癌的免疫治疗

• 批准号: 224057855
• 负责人: Professor Dr. Simon Rothenfußer
• 金额: --
• 依托单位: Abteilung für Klinische Pharmakologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/224057855?language=en
• 关键词: Targeting; cytosolic; helicases; modified; siRNA

Immune responses are able to influence tumor growth in HCC. Type I interferon (IFN) in conjunction with other inflammatory cytokines plays a key role in tumor immune surveillance and boosts tumor immunity. The ubiquitously expressed RIG-I-like helicases (RLH) retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein-5 (MDA-5) are immunoreceptors that signal the presence of viral RNA in the cytosol of cells and activate innate and adaptive immunity via type I IFN. Furthermore, RLH activate the intrinsic, mitochondrial pathway of apoptosis in tumor cells. The combination of immune activation and apoptosis induction via RLH ligands has great potential in cancer therapy. Synthetic RNA molecules containing a triphosphate group at the 5' end (ppp-RNA) induce RIG-I signaling. Modifying siRNA to ppp-siRNA allows to combine gene silencing with RIG-I activation and has shown therapeutic efficacy in several tumor models. The proposed project aims at evaluating RLH as targets and specific RLH ligands as therapeutic agents for HCC. Bi-functional ppp-siRNA molecules designed to specifically silence tumor promoting targets regulating angiogenesis, proliferation and immune suppression will be developed and validated in mouse models of HCC. In addition, means for optimizing siRNA delivery for effective tumor targeting will be investigated. Our goal is the preclinical development of bi-functional siRNA molecules as novel therapeutic option for patients with HCC.

免疫应答能够影响HCC中的肿瘤生长。I型干扰素（IFN）与其他炎性细胞因子一起在肿瘤免疫监视中起关键作用并增强肿瘤免疫。广泛表达的RIG-I样解旋酶（RLH）、视黄酸诱导基因I（RIG-I）和黑色素瘤分化相关蛋白-5（MDA-5）是免疫受体，其发出细胞胞质溶胶中病毒RNA存在的信号并通过I型IFN激活先天性和适应性免疫。此外，RLH激活肿瘤细胞中细胞凋亡的内在线粒体途径。通过RLH配体的免疫激活和细胞凋亡诱导的组合在癌症治疗中具有巨大的潜力。在5'端含有三磷酸基团的合成RNA分子（ppp-RNA）诱导RIG-I信号传导。将siRNA修饰为ppp-siRNA允许联合收割机将基因沉默与RIG-I活化结合，并且已经在几种肿瘤模型中显示出治疗功效。该项目旨在评估RLH作为HCC靶点和特异性RLH配体作为HCC治疗剂的作用。双功能ppp-siRNA分子被设计为特异性沉默调节血管生成、增殖和免疫抑制的肿瘤促进靶点，将在HCC小鼠模型中开发和验证。此外，将研究优化siRNA递送以有效靶向肿瘤的方法。我们的目标是临床前开发双功能siRNA分子作为HCC患者的新治疗选择。

项目成果

RIG-I-basierte Immuntherapie des Hepatozellulären Karzinoms

基于 RIG-I 的肝细胞癌免疫治疗

• DOI: 10.1055/s-0035-1559022
• 发表时间: 2015
• 期刊: Zeitschrift Fur Gastroenterologie
• 影响因子: 1.3
• 作者: Böhmer D;Posselt L;Lazic I;König L;Endres S;Duewell P;Mayr D;De Toni E;Rothenfusser S;Schnurr M.
• 通讯作者: Schnurr M.

ITOC2 – 015. Therapy of hepatocellular carcinoma (HCC) with immunostimulatory RNA activating RIG-I

ITOC2 â 015 使用免疫刺激性 RNA 激活 RIG-I 治疗肝细胞癌 (HCC)

• DOI: 10.1016/j.ejca.2015.01.028
• 发表时间: 2015
• 期刊: European Journal of Cancer
• 影响因子: 8.4
• 作者: Posselt L;Lazic I;Boehmer D;Hoffmann S;Endres S;Duewell P;Rothenfusser S;Schnurr M.
• 通讯作者: Schnurr M.

Targeting RIG-I with 5'ppp-modified RNA for immunotherapy of hepatocellular carcinoma (HCC)

使用 5ppp 修饰的 RNA 靶向 RIG-I 用于肝细胞癌 (HCC) 的免疫治疗

• DOI: 10.1055/s-0034-1386661
• 发表时间: 2014
• 期刊: Zeitschrift Fur Gastroenterologie
• 影响因子: 1.3
• 作者: Posselt L;Lazic I;Boehmer D;Funk A;Kirchleitner S;Hoffmann S;Adunka T;Endres S;Düwell P;Rothenfusser S;Schnurr M.
• 通讯作者: Schnurr M.