One of the major obstacles in the treatment of pancreatic cancer is the ‘defense wall’ that is formed around the tumor. This ‘desmoplastic stroma’ prevents chemotherapy from reaching the tumor. Scientists of the University of Twente now found out which part of the stroma can best be attacked. Furthermore, they discovered a new peptide that can serve as the attacker. In ‘Science Advances’ of 4 September, they show that using the combination of the peptide and cytostatics, tumor volume can be drastically reduced. In four to five years, the combination therapy may be available for patient tests.
Pancreatic cancer is the cancer with the worst survival rates. After the – often late – diagnosis, most of the patients die within a few months. Surgery for removing the tumor is, in many cases, not possible because of the risk of damaging other vital organs. Chemotherapy, using gemcitabine, often isn’t successful, because the tumor cells are surrounded by a fibrous matrix network called desmoplastic stroma, that can be much bigger in size than the tumor itself.
Can we reduce the stroma and, first of all, find the key element that can be attacked? That was the question Jai Prakash and his team started with. After many comparative studies, a protein called integrin alpha 5, ITGA5, proved to be decisive in the survival rate of patients with pancreatic cancer. For this, tumor tissues of around 140 patients were examined. Furthermore, with extensive biological experiments the team proved that attacking ITGA5 biologically would reduce the stroma and give a better access to the tumor. The next crucial question was: can we find a substance for effectively attacking ITGA5?
In their Science Advances paper, the researchers now discovered a short crucial sequence of seven amino acids, that is hidden in a large protein from our own body named fibronectin, of over 1000 amino acids, after laborious screening work. This sequence is named AV3 peptide which turned to be the best candidate for blocking ITGA5. First tests, with tumor tissue and stroma in a petri dish developed in a three-dimensional culture, showed that tumor volume could be reduced after AV3 and gemcitabine were added. Tests with a human tumor inserted into a mouse also showed reduction of up to 80 percent of the tumor volume. Reducing the tumor in size, could already open the way for surgery. But according to Jai Prakash, higher doses of AV3 with cytostatics could even remove the tumor as a whole.
Effect on humans
Before testing this on humans, it is necessary to determine the response of healthy humans on AV3. Until now, there are no signs of toxicity. After AV3 proves to be safe, there will be a procedure for approval, followed by clinical trials using both AV3 and cytostatics. Jai Prakash patented the peptide and started a company called ScarTec Therapeutics, with EU support, for accelerating the introduction of the new type of medication. With the necessary financial means, he expects first therapeutic tests on patients will be possible in 2023 or 2024.
Professor Jai Prakash is leading the Targeted Therapeutics section of the Biomaterials, Science and Technology group. The group is part of UT’s TechMed Centre.
The paper ‘ITGA5 inhibition in pancreatic stellate cells attenuates demoplasia and potentiates efficacy of chemotherapy in pancreatic cancer’ by Praneet Kuninty, Ruchi Bansal, Susanna de Geus, Deby Mardhian, Jonas Schnittert, Joop van Baarlen, Gert Storm, Maarten Bijlsma, Hanneke van Laarhoven, Josbert Metselaar, Peter Kuppen, Alexander Vahrmeijer, Arne Östman, Cornels Sier and Jai Prakash appears in Science Advances of 4 September 2019.