Chemically Modified siRNAs for the Treatment of Gastrointestinal Cancer

用于治疗胃肠癌的化学修饰 siRNA

• 批准号: EP/D50368X/1
• 负责人: Christopher Hayes
• 金额: $ 40.96万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FD50368X%2F1
• 关键词: Chemically; Modified; siRNAs; Treatment; Gastrointestinal

Gastrointestinal (GI) malignancy is the second most common cancer in the UK and accounts for 25% of UK cancer deaths. Oesophageal and pancreatic adenocarcinomas have a particularly poor prognosis, with 5-year survival rates of only 5%. The gastrin gene is expressed early in the development of gastrointestinal adenocarcinomas, promoting the progression of premalignant lesions. In addition to acting as a growth hormone, it protects,cells against apoptosis, stimulates blood vessel formation and increases the potential for metastasis by increasing invasion and adhesion. Antibodies to gastrin are able to inhibit these biological effects and have recently successfully completed a Phase III clinical trial for use in the treatment of pancreatic cancer. Whilst this is proof of concept, they only partially neutralise the products of the gastrin gene. The antisense approach offers hope of downregulating key oncogenes involved in disease establishment and progression. Traditional antisense technology has successfully reached the clinic as a topical treatment for CMV retinitis but its success has been limited by the need to use high systemic doses to achieve effective doses locally. Gastrin antisense has proven to be effective in blocking gastrin-mediated carcinogenesis. siRNAs are a more potent means of downregulating genes due to use of a naturally-occurring catalytic process within the cell. Thus the chances of success with this approach are considerably higher, provided that methods of stabilising and delivering siRNAs'in vivo' can be developed.The work described in this proposal aims to provide chemistry solutions to both the stability and delivery problems associated with RNA-based therapeutic agents. We will study the effects of backbone modifications upon the hydrolytic stability of siRNAs using the gastrin gene as the test system and assess their ability to initiate an siRNA response in tumour cell lines. We will also address the problem of cell-specific targeting and cytoplasmic delivery by covalent attachment of a number of ligands targeted at the gastrin/CCK-2 receptor in conjunction with known 'molecular transporter' peptides.

胃肠道 (GI) 恶性肿瘤是英国第二大常见癌症，占英国癌症死亡人数的 25%。食管腺癌和胰腺癌的预后特别差，5年生存率仅为5%。胃泌素基因在胃肠道腺癌发展的早期表达，促进癌前病变的进展。除了作为生长激素外，它还可以保护细胞免于凋亡，刺激血管形成并通过增加侵袭和粘附来增加转移的可能性。胃泌素抗体能够抑制这些生物效应，并且最近成功完成了用于治疗胰腺癌的 III 期临床试验。虽然这是概念证明，但它们仅部分中和胃泌素基因的产物。反义方法为下调参与疾病建立和进展的关键癌基因提供了希望。传统的反义技术已成功进入临床，作为 CMV 视网膜炎的局部治疗，但其成功受到需要使用高全身剂量才能达到局部有效剂量的限制。胃泌素反义已被证明可以有效阻止胃泌素介导的致癌作用。由于使用细胞内自然发生的催化过程，siRNA 是下调基因的更有效方法。因此，只要能够开发出“体内”稳定和递送 siRNA 的方法，这种方法的成功机会就会相当高。本提案中描述的工作旨在为与 RNA 相关的稳定性和递送问题提供化学解决方案。为基础的治疗剂。我们将使用胃泌素基因作为测试系统，研究骨架修饰对 siRNA 水解稳定性的影响，并评估它们在肿瘤细胞系中启动 siRNA 反应的能力。我们还将通过将许多靶向胃泌素/CCK-2受体的配体与已知的“分子转运蛋白”肽共价连接来解决细胞特异性靶向和细胞质递送的问题。

项目成果

Stereoselective synthesis of highly functionalised P-stereogenic nucleosides via palladium-catalysed P-C cross-coupling reactions

通过钯催化 P-C 交叉偶联反应立体选择性合成高功能化 P-立体核苷

• DOI: http://dx.10.1016/j.tetlet.2008.09.102
• 发表时间: 2008
• 期刊: Tetrahedron Letters
• 影响因子: 1.8
• 作者: Whittaker B