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常见的癌症，占英国癌症死亡的25％。食道和胰腺腺癌的预后特别差，5年的存活率仅为5％。胃蛋白基因在胃肠道腺癌的发展早期表达，从而促进了预抗病变的进展。除了充当生长激素外，它还可以保护细胞免受凋亡，刺激血管的形成，并通过增加浸润和粘附来增加转移的潜力。胃蛋白的抗体能够抑制这些生物学作用，并最近成功完成了一项III期临床试验，用于治疗胰腺癌。尽管这是概念证明，但它们仅部分中和胃蛋白基因的产物。反义方法为下调涉及疾病的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地到达了诊所，作为CMV视网膜炎的局部治疗方法，但由于需要使用高系统性剂量以在当地实现有效剂量的需要，其成功受到了限制。事实证明，胃泌素反义可有效阻断胃蛋白介导的癌变。 siRNA是由于使用细胞内的天然催化过程而导致基因下调基因的一种更有效的手段。因此，只要可以开发稳定和传递sirnas'in in sirnas'in'的方法，从而开发了这种方法的成功机会。该提案中所述的工作旨在为与基于RNA的治疗剂相关的稳定性和递送问题提供化学解决方案。我们将使用胃蛋白基因作为测试系统研究主链修饰对siRNA的水解稳定性的影响，并评估其在肿瘤细胞系中启动siRNA反应的能力。我们还将通过与已知的“分子转运蛋白”肽结合的许多靶向胃蛋白/CCK-2受体的配体的共价附着来解决细胞特异性靶向和细胞质递送的问题。