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Synthetic drugs for pancreatic cancer treatment

Pancreatic cancer is characterised by poor diagnosis, high aggressiveness and a low survival rate. European scientists initiated a long-term effort in order to improve on available diagnostic and therapeutic tools.
Synthetic drugs for pancreatic cancer treatment
Pancreatic cancer is the fourth most common cause of cancer deaths in the world. Its poor and late prognosis combined with very low survival rates makes it one of the most fatal and aggressive cancers. Gastrin, which is a peptide hormone that stimulates secretion of gastric acid, was found to be involved in related tumour development.

A recently developed anti-gastrin vaccine successfully increased the survival time and the quality of life of a limited number of pancreatic cancer patients. Despite the promising preliminary results, the limited number of positive responses as well as the slow development of antibodies indicate the need for more intensive efforts.

European scientists joined their forces within the EU-funded project ‘Therapeutic synthetic antibodies -binding bodies- against gastrin to treat pancreatic cancer’ (Binding Gastrin) to develop alternative strategies immediately effective in all patients. For that purpose, they developed synthetic antibodies of high affinity and low cost in order to reduce the gastrin concentrations.

The synthetic antibodies created by Binding Gastrin consist of two peptides that represent two different complementary determining regions (CDRs) of an antibody. These peptides are stably bound on a small chemical scaffold and in preliminary tests showed high binding specificity and affinity. Further optimisation and evaluation tests will significantly improve the performance of these binding bodies.

Binding Gastrin scientists discovered many inconsistencies in the already available information on antibody mimicry. The antibodies and protocols described in published data were evaluated by Binding Gastrin researchers, showing lower affinity and specificity than was initially demonstrated. These findings uncover the need for common evaluated procedures for the synthesis, validation and interpretation of antibody mimicry data. Therefore, Binding Gastrin had to re-plan its objectives to include the re-evaluation of known procedures and reagents.

The project successfully developed proof-of-principle small binding bodies for gastrin of high affinity and specificity, able to bind gastrin in a tumour-cell bioassay. The novel CDR peptides were synthesised by validated procedures and reagents within Binding Gastrin. This is a major achievement since it is the first time that a small target like gastrin was successfully captured by a binding body. Previous similar studies were limited to large proteins bound with low specificity and affinity.

Despite overcoming major obstacles towards a selective and effective recognition of gastrin by small binding bodies, there are still some technical difficulties. Self-aggregation is the main hurdle in synthetic antibodies, which is not an issue in natural antibodies. In this project a variety of possible solutions for this problem were advanced and are currently under evaluation. More specifically, there is an obvious need for structural characterisation of binding bodies in solution, in order to optimise their characteristics.

Binding Gastrin pushed forward research in the field of binding bodies for the elimination of gastrin and other target molecules. It established the fundamental base ground for the further development of these strategies and provided the required motivation.

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