In 2019, a group from the National Center for Cardiovascular Research published in the magazine Nature relevant data on the involvement of the p38gamma protein in the development of the main type of primary liver cancer. This is hepatocellular carcinoma, which affects more than one million people a year worldwide and for which there are currently few pharmacological options. Nowthe international tribunal that awards the Dr. Antoni Esteve Foundation Research Award every two years has considered this scientific article as the most important pharmacological publication published by a Spanish author between 2019 and 2020. Antonia Tomás Loba, on behalf of the team led by Guadalupe Sabio, has received this award, endowed with 18,000 euros, as the first author of the article, in an award ceremony held at the CNIC.
The article p38γ is essential for cell cycle progression and liver tumorigenesis not only discovers how the p38gamma protein is related to cell division in the liver but has also studied in mice what happened when liver cancer was chemically induced with or without this protein. “Whether this protein was missing or its activity was blocked with a drug, we managed to delay the development of the tumor,” says Tomás Loba. “These results could be extrapolated to people, since we have seen that p38gamma is increased in human samples from patients with liver cancer,” explains Guadalupe Sabio, director of this CNIC research group.
“These results could be extrapolated to people, since we have seen that p38gamma is increased in human samples from patients with liver cancer”
The CNIC team has been studying a family of proteins, the p38 kinases, which are activated when cells are under any type of stress, for several years. “Studying in detail the three-dimensional structure of the proteins, we observed that one of them, p38gamma, was very similar to that of another group of proteins known as CDKs.
In laboratory studies in collaboration with scientists from the Spanish National Cancer Research Centre (CNIO), they delved into these similarities with CDKs. In this way, using the inhibitor blocked its activity and exerted a tumor suppressive action.
In collaboration with the University Hospital of Salamanca, this CNIC group has also found that the amount of this protein in the liver increases with liver fibrosis. A condition that precedes cancer and is much higher in patients with liver cancer. “In the future, this type of cancer could be treated with a drug that specifically inhibits p38gamma,” the researchers suggest. “The advantage over other pathways is that our results suggest that the inhibition of p38gamma would not affect other tissues that are in proliferation such as the intestine or hair,” they add.
The members of the international jury of the Dr. Antoni Esteve Foundation Research Award also wanted to recognize with an honorable mention the article published in 2019 in the journal Nature Metabolism by the group of the Instituto de Investigación Sanitaria de Santiago and the University of Santiago de Compostela, coordinated by Rubén Nogueiras, in which they discover the mechanism by which some drugs that are used for the treatment of other diseases they also reduce body weight. This honorable mention is in addition to the Dr. Antoni Esteve Foundation Research Award that Nogueiras’ team already received in 2017 for demonstrating the efficacy of a diabetes drug in weight reduction.
This is the seventeenth edition of the Dr. Antoni Esteve Foundation Research Award, which is awarded to the best pharmacology work published by a Spanish author in the last two years in any of its aspects (design, synthesis, galenic development, clinical or laboratory evaluation, use, etc.).
KEYWORDS | Basic pharmacology, Research Award, cancer
Interview with Guadalupe Sabio and Antonia Tomás
What is the role played by the p38gamma protein in the development of this type of liver cancer?
Guadalupe Sabio: What we discovered is that p38gamma is activated when the cell is stressed. This stress, in some cases, is a trigger for liver cancer as it will produce an increase in cell proliferation, that is, the cells begin to multiply. It is this p38gamma that is activated that controls cell proliferation, this increase in the number of cells that will eventually trigger a tumor.
What novelty does it mean for its treatment and why is this finding so important?
Antonia Tomás: It is important because the work we did puts the p38gamma protein on the cell cycle map, which is the process that regulates cell division, which is well established and known, and places it as an important regulatory actor. Knowing where p38gamma acts we can go directly to this point, looking for targets, which we have also described in the article, and looking for specific drugs for that target. The innovation is that p38gamma is a main player in the regulation of the cell cycle and proliferation.
How could action be taken to inhibit the p38gamma protein and thus delay the development of these liver tumours?
Guadalupe Sabio: p38gamma has the advantage that it is activated by stress, unlike other known ones that control cell cycles. Until now, cell cycle control has been talked about as physiological control, meaning that your cells must be constantly dividing. If we inhibit these proteins that control the physiological cell cycle of your cell, we inhibit the proliferation triggered by tumor cells but also your cells in the intestine, skin, all the cells in your body that must reproduce continuously. What is the advantage of p38gamma? That it only acts when the promoter of this division is not physiological but harmful. If you inhibit p38gamma you are being a little more specific in the type of proliferation you attack. In this study we evaluate known inhibitors of p38gamma, but from this moment until now we are trying to develop new inhibitors that are more specific to this target, since this ability to act only when the proliferation is not physiological could help to be a little more specific against the proliferation that appears in tumors.
The paper was published in Nature in 2019. Where is this research now?
Guadalupe Sabio: Well, we are trying to study a little more what function p38gamma has in the normal physiology of our body because this will help us to know what side effects an inhibitor that goes to the whole body could have. Another of the main avenues we are working on is to develop new inhibitors, since we need new inhibitors of this kinase to be able to take it to the clinic. Right now we are collaborating with a Galician foundation. We already have some inhibitors and we are starting to test them in mice. But it is a slow investigation.
We know that the result of this research has been very complex to obtain and that it has had to be approached from very different approaches. How would you summarize the process of obtaining these results?
Antonia Tomás: The word that best defines it is passion. You have to have a lot of passion for science, for discovery, for knowledge, a wonderful work team, a boss who was very clear about what was going on in her mind and wonderful collaborators. This is what has allowed us to be such a complete scientific article, which has provided a study of the role of p38gamma in the control of the cell cycle, or the proliferation of liver cancer, from many points of view: a more clinical point of view, of bioinformatics studies, mouse models and even more experiments that have not been reflected in the published article, since it has been seven years of work. But the key has been a great passion and a great work team.
Guadalupe Sabio: And a great perseverance, since Antonia has infinite perseverance. A capacity for resilience, to fall and get back up, to receive criticism that is not easy to resolve, because we didn’t come from this field. We are more from the physiological field. Delving into a whole new field and discovering something so important is always very difficult. But Antonia’s passion for science is endless.
Antonia Tomás: Guadalupe has also been very persevering and very inspiring. When you see that your reference in the laboratory does not decline, it helps a lot. When you have a hypothesis, you believe in it and when there are really signs that verify it, you keep working on it, no matter how much the reviewers and experts in the field tell you. The passion, of course, is multiplied.
To what extent has collaboration between different research centres been important?
Guadalupe Sabio: It has been very easy to collaborate with all those who have worked on this study, from computational chemistry, which we had no idea about, to collaboration with hospital doctors. They have always been there to help us. Also the collaboration with the CNIO, where the established experts in the cell cycle were and whom we had physically next to us. This is one of the advantages of having research in Spain. It is so difficult to collaborate with people who are very far away and so easy when they are close and to be able to interact with them. Much more critical mass is needed in science in Spain for collaborative work to be possible because in the end collaboration is achieved on a day-to-day basis. That is why it is essential to create a research fabric in Spain, with young people, with people who have energy and give them support, give them money, because in the end we are competing with mini cars against Ferraris.
Finally, how has the Dr. Antoni Esteve Foundation Research Award been received?
Antonia Tomás: When Guadalupe told me… It is like the culmination of a job, an effort, a team, a passion, many hours in the laboratory and a lot of sacrifice. That’s like a smile on science. It is also a hug to so much work, to so much effort. When I heard the news I didn’t know how to react. Then you metabolize it and say “how nice it was to work on it and how nice that it ends this way”. Guadalupe Sabio: In addition, it was a lot of effort. I think this award is also a recognition of Antonia, now that she is starting her independent stage. That these younger faces are visible, this new hope for science in Spain, these new groups. I hope it opens doors for more funding because in the end without it scientists can do nothing. This type of award at least puts you on the map of Spanish science and I think it will be very important for your career.