We convert tumour wall cells from ‘baddies’ to ‘goodies'.
Pancreatic cancer is one of the most aggressive and unassailable forms of cancer. Its highest mortality rate has to do with the fact that tumours on the pancreas are hard to reach, while surgical intervention introduces a high risk of cancer cells spreading to other parts of the body. Another, very important obstacle is that pancreatic tumours, like other solid tumours, are surrounded by a tough, fibrous matrix, that is virtually impenetrable to the anticancer drugs administered in chemotherapy. ‘This matrix, or desmoplastic stroma – a kind of fibrous network – can be compared to the defensive wall around a fort’, says UT scientist Jai Prakash. ‘It can even take up more space than the tumour cells themselves. The tumour cells hide themselves inside this fort, and almost nothing can penetrate it. As surgical removal is often impossible, the only remaining alternative is chemotherapy – but unfortunately, its efficacy is very low.’
Prakash and his team see a possible solution: dismantling or neutralizing the defensive wall. The results of their research have been hailed as an important step forward in the fight against pancreatic cancer and were published in Science Advances, a scientific journal, in September this year. ‘It is clear that we cannot break down the wall, because then the cancer cells would have free reign and could threaten the whole environment,’ Prakash explains. ‘What we have discovered, though, is that we can make tiny holes in the wall at a sub-nano scale: the anti-cancer medicine can get in through them, but the much larger cancer cells can’t get out.’
Staging an attack on the defensive wall is not easy. After much comparative research, Prakash’s team discovered that the chance of success would be greatest if they managed to break down a specific protein in the stroma: ITGA5. But how? Further research has shown that the desired perforations can be made with a peptide already present in the human body, known as AV3. In the first tests, AV3 injections, combined with chemotherapy, reduced tumour size by at least 80%. Prakash: ‘Reducing the tumour size so dramatically can already open the way for surgery. We think it may even be possible to completely remove the tumour through this method.’
Although many rounds of testing are still to follow, Prakash has already patented AV3 and set up a company, ScarTec Therapeutics, to prepare the new drug for practical application within the next five years or so.
Prakash’s research group at the University of Twente is one of three or four groups worldwide attempting to penetrate the wall surrounding pancreatic tumours. ‘This area of research has only emerged in the last seven to ten years’, says Prakash, who came to UT seven years ago to start this research. ‘Other researchers focus primarily on medication that dilates blood vessels, in the hope that this will allow the anticancer medication to enter the tumour more easily. With our perforation method, we are the first to actually attack the wall itself by targeting ITGA5. The pharmaceutical market worldwide offers hundreds of chemotherapy treatments – but none of them can effectively beat pancreatic cancer, because of the defence wall. The dosages keep increasing, but the outcomes remain low. We hope to change this.’
Prakash, previously carried out successful research on kidney and liver fibrosis – which is somewhat similar due to its accumulation of connective tissue in the scar tissue surrounding a damaged liver – now sees many more possibilities in working with tumour walls. ‘The wall around a tumour is made up of many layers with lots of different types of cells. And it appears that the wall not only protects the tumour against external attacks, but also feeds it and allows it to spread. We are now directing our attention to this aspect. We are experimenting with new peptides to ‘brainwash’ or reprogramme some of these wall cells so that they will turn from protecting and nourishing the tumour to helping us in attacking it. Tumours require cells around them that they can turn into ‘slaves’. We believe we can free the slaves and train them to fight back. You might say we aim to convert them from bad guys to good guys.’
Prakash is organizing a conference on the tumour micro-environment in Twente in 2020 in order to stimulate worldwide research in this field.