"Most cancers will never be cured; the goal is to make them chronic"

Serendipity is defined as a 'valuable finding that occurs accidentally or chance'. And many scientific milestones that have changed our lives are written with 's' for serendipity, for example, the famous penicillin. By one of those chances of life, in 1979 the molecular biologist Tony Hunter studied the polyomavirus, a small virus capable of producing tumors in mice, to understand what protein gave the virus the ability to cause cancer and instead of preparing a new one Ph buffer solution did the experiment with an expired solution. That oversight allowed him to discover tyrosine kinase phosphorylation, since the good formula masked that unknown type of enzyme.

Tyrosine kinases are enzymes that catalyze the transfer of phosphates from the ATP molecule (adenosine triphosphate) to certain proteins and play a fundamental role as they open a specific door in the cell membrane and send signals within the cell that are involved in different cellular processes. such as cell growth. Tyrosine phosphorylation works like a kind of chemical on/off switch that can tell cells to multiply out of control, and that's when cancer occurs.

This discovery marked a before and after in cancer treatment, giving way to precision medicine in this area and promoting drugs such as imatinib (Gleevec in the US, Gleevec in Europe).. Such is the potential that the FDA has approved more than 50 anticancer drugs inhibitors of the tyrosine kinase (TKI) pathways and even today much of the research is devoted to the search for new antitumor TKIs.. And yet it was an oversight.

“Luck is involved in many discoveries, but luck must be recognized. If you see something unexpected you might think you did something wrong and ignore it. You have to be able to recognize something important. As Louis Pasteur said, chance only favors the prepared mind,” says Hunter, who is a professor at the Salk Institute and the University of California, San Diego.

Tony Hunter. SERGIO GONZALEZ VALERO

Although he is British, he has spent most of his life in California.. Perhaps that is why his appearance is casual, with a beard that he has worn for more than half a century.. “July 14, 1972 was the last time I shaved. You can't shave at the bottom of the Grand Canyon and that day the descent started, so after two weeks I liked the way it looked and kept it on, it saves me a lot of time not having to shave every morning,” he explains.

Due to his affable and informal appearance, he could be your neighbor, but this 'king of kinases', as he has once been called, has received numerous prestigious international awards for his work, including the Prince of Asturias Award in 2004 and the Frontiers of Knowledge Award in 2014 in Spain. This pioneer of 'precision' cancer treatments visited the National Cancer Research Center (CNIO) at the end of June to give a talk and this newspaper was able to talk with him about his career.

His talk is titled 'Journey from phosphotyrosine to phosphohistidine and what it has revealed about the mechanisms of cancer'. What has this journey revealed, what has it been like? How do I go from tyrosine phosphorylation to histidine phosphorylation? It helps to understand how the structures of the different amino acids are. Tyrosine has a benzene ring, a six-sided ring with a hydroxyl group, made up of hydrogen and oxygen, which is where phosphate is added.. Histidine is one of the other 20 amino acids and it has a five sided ring with two nitrogens and phosphate can be added to any nitrogen so it's a different type of phosphate addition not to an oxygen but to a nitrogen. Histidine phosphorylation has been known for more than 60 years, longer than tyrosine phosphorylation, and because of the similarities in the chemical structures of tyrosine and histidine, we became interested in the possibility that phosphate addition to histidine could be a regulatory mechanism, just like the addition of phosphate to tyrosine, which could do the same. And could this research lead to new drugs like tyrosine phosphorylation once led to the development of imatinib? ?Potentially. That would be great, but it's hard to tell. We have focused on the possible role of histidine phosphorylation in cancer, specifically in four different types of cancer where, from the evidence we have, it could be important.It is hopeful…It is and I often like it pointing out that I am near the end of my career, I will be 80 in August, so this could be the last new research I will develop.As responsible for one of the great turning points in oncology that allowed treatments such as imatinib and others, what do you think have been the next tipping points and what are to come? Imatinib was designed to block a particular type of what we call oncogenic cancer that drives tyrosine kinase, by mutations in the BCR-ABL gene, and is found in chronic myeloid leukemia cells. Although TKIs, tyrosine kinase inhibitor drugs, have been very successful, apart from imatinib, they are not cures.. And what usually happens is that a cancer with an active tyrosine kinase, such as an EGFR receptor lung cancer, responds for a few months and then the tumor cells become resistant to the TKI.. There are many ways they can become resistant, so while they help, TKIs are not a cure. What would you say is the most important thing you have discovered in your career? I guess I would have to say tyrosine phosphorylation, I don't see what It could be something else, that's why people have recognized me for a long time.. I hope we have discovered many other things along the way, but nothing as important as that, I would say. In these 50 years of your career, what would you have liked to find or discover in the laboratory? What we did not discover. Look, if I started over, I'd be a neurobiologist.. I believe that the brain, how it works, is the last frontier.. I believe that great strides have been made at the molecular level. When Francis Crick came to finish his degree at the Salk Institute, he switched from molecular biology to neurobiology and raised the problem. You have to understand the neuron at the individual level and what is special about it at the molecular level. He had a scientific perspective when exposing this and we have finally been able to do it, we can take individual neurons and look for RNA, DNA sequences, how the soma or cell body identifies individual neurons and what they connect with inside, that is, the brain and what other neurons do they come into contact with. We are getting a diagram of the neural connections (connectome); another challenge now is to see how they work together, although there are neuroimaging techniques.. This is what I would have done now. When I looked at it obviously it wasn't a possibility, but I'm happy with the way my career has gone. The development of the precision treatments was due to the basic research he did. How important is this part of Science and why should we continue betting on it, even if the investment does not have a direct return as in a clinical trial? From my perspective, being a basic science researcher, I think it is essential to have funds for make discoveries. It is what is known as Blue Sky Research, where very specific questions are not asked, but instead tries to understand how something works. We didn't set out to discover tyrosine kinases, we just set out to understand how a simple virus with just six genes (polyomavirus) can cause cancer. Although we have learned a lot about how cells work, how cancer occurs, or the genes involved, there is still much more to discover.. And for that you need funding.
It is essential to continue funding basic research, understanding that whatever is learned may take 20-30 years to translate, although it is faster than it was before.. For example, since the discovery of tyrosine phosphorylation in the 1970s, it took 20 to 22 years for a first drug to be approved, so that's a lot longer in the eyes of people who would like to see immediate returns on their money, but not it always happens like this. Perhaps the most exciting thing in cancer treatment right now is the possibility of designing an mRNA vaccine, something that came out of much of the covid vaccine development effort, where mRNA vaccines have proven very successful. That could to be the future of cancer research….There is still some skepticism and we are not there yet. I mean, the vaccines will depend on there being changes in some protein in the cancer and I think there will be resistance as well, so it won't be a panacea.. One way the tumor has apparently become resistant to immune checkpoint therapy is by removing a protein called MHC on the surface of cells, which allows T cells to recognize the antigen.. By killing it, the tumor cell becomes 'silent' to the immune system. Despite these possible resistances, I believe in any case that mRNA vaccines against cancer will undoubtedly be important for us. With therapies such as CAR-T, cancer is cured, but with others we only buy more time or corner the tumor without removing it. How close are we to making cancer a chronic disease? I think that should be the goal. Most cancers will never be cured. CAR-T cells – and here I have to make a little note: my son Sean is actually in cancer biology, which makes me very happy, and now he's at Stanford doing postdoctoral studies and designing CAR-T cells – they are very interesting in leukemias, where they do not always work, but can be curative. In fact, there are some cases where patients appear to be cured.. The main challenge for CAR-T cells is that they don't work on solid tumors, they are great against leukemias possibly because CAR-Ts have access to affected cells in the circulation, while getting T cells into tumors can be difficult. and, for example, pancreatic cancer, which we are working on, is a so-called cold tumor where the tumor cells are small nests surrounded by a rigid, dense matrix, and the T cells cannot enter the tumor to attack the cells. tumors. That is one of the biggest challenges, although I think progress is being made, but slowly. I was precisely going to ask you what happens with the most aggressive tumors, pancreas, liver, some brain…. because in these cases we are not even close to buying more time for the patients. There are many new ideas about how to treat solid tumors with cell therapies. It is taking advantage of the fact that natural killer (NK) cells do not work in the same way; CAR-T cells target the cell with a particular protein (the expression of tumor antigens via the MHC), but NK cells recognize the cells they need to kill in a different way. An antibody is created with two halves, one that recognizes tumor cells and the other recognizes NK cells, and when the antibody binds them close enough for the NK cell to kill the tumor cell. This is one of the ideas, but there are lots of smart people out there with lots of other good ideas.. I believe that there will be advances in the treatment of solid tumors with cell therapies, but surely it will not be tomorrow. What are the lines of research that you are focusing on now? Apart from histidine phosphorylation, which is what most of my team works, we are with a project on pancreatic cancer in which we found that leukemia inhibitory factor (LIF), which is a cytokine, is a possible driver of pancreatic cancer in a mouse model. Based on our work, at least in part, they generated antibodies that neutralize LIF and used them in a phase I trial. AstraZeneca acquired the program and they are now in a phase II trial for pancreatic cancer. This is the most translational thing I've ever done, is to really focus on trying to find something that could be targeted to a specific cancer. What about histidine phosphorylation? It's still early days. In pediatric neuroblastoma there is an aggressive form in which there is an amplification of one of the arms of chromosome 17 and that region of chromosome 17 has two genes that we think are histidine kinases, so it is probably the cancer with the greatest potential for us to be able to do something with an inhibitor of this enzyme.