Chemically Modified siRNAs for the Treatment of Gastrointestinal Cancer

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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.