11 May 2011

Cancer prevention: waiting for the results of phase II clinical trials

Big cleaning
Alla Astakhova, the magazine "Results" No. 19-2011

The study of the nature of cancer and biotech are two passions that can individually absorb a person entirely. Andrey Gudkov, one of the most successful Russian biologists currently living abroad, scientific director of the Roswell Park Cancer Institute in Buffalo, USA, combines both these topics in life. At one time, he and his friends made a startup in this area, because he did not want to give discoveries into the hands of indifferent managers too early, in which he saw grains capable of yielding an unprecedented harvest. One of these seeds can come up in Russia.

– Andrey, you were originally a theoretical scientist, how did you get into the biotech?

– Until the end of the 90s, I didn't even think that I would deal with medicines. Moreover, at the university where I studied in the 80s, it was self-evident that applied science was something not entirely pure.

– An unworthy thing for a scientist?

– In a sense, yes. Having concocted something utilitarian, you probably won't understand the true mechanism of the phenomenon. Well, medicine is generally the lot of talented artisans. In some ways, of course, I exaggerate this point of view, but the meaning was this. It was believed that the real occupation of a scientist was to comprehend the mechanisms of phenomena. There is even the term "reductionist science". You divide the complex into simple parts, as if you are disassembling an alarm clock. When we studied, science was in exactly this state – we investigated what it consists of. And now we have come to a new phase of knowledge. For most of my scientific life, the role of a hypothesis in biological research has been to inspire a scientist to experiment, which will show that it is wrong, but will allow us to propose a new one. You get used to the fact that reality is much more complicated than your idea of it. And suddenly one day you put forward a hypothesis, checked – and cured a laboratory mouse! This moment changes the psychology of the researcher forever. You can no longer return to the state of a child disassembling an alarm clock. It turns out that the mechanism can be repaired, or you can come up with a new one. The engineer who creates the new is the next, higher level after the scientist. This word was devalued in the Soviet country by the army of technical employees at engineering rates. But in fact, there is nothing more interesting than inventing something that did not exist before.

– How did you first take this step?

– At the end of the 90s, one of the mechanisms that protect a person from cancer was already quite well studied. We knew about the so-called guardian of the genome, the p53 protein. It turned out that when it turns on in response to DNA damage, it is able to give a signal to trigger apoptosis – programmed cell death.

– Thanks to this mechanism, cells with genome errors that appear in the body every now and then are removed from it?

– If an individual cell makes a mistake, it can kill itself "with its own hands", with the help of apoptosis. But imagine a situation where we provoked billions of cells to make a mistake. If they all commit suicide together, it will turn out badly.

– Are you talking about radiation treatment for cancer?

– Any exposure that damages DNA, including cancer treatment with radiation and chemotherapy. Sometimes it is difficult to say whether people suffer more from the disease or from treatment. Then I thought: what if we stop the mechanism of cellular suicide for a while? Maybe this will allow the body to tolerate a very high dose of radiation, because the cells will not go into apoptosis? After all, this is exactly what tumors do by "turning off" the p53 gene. In 1998, this idea seemed ridiculous, because it contradicted the "light appearance" of the guardian of the genome. However, the result of testing this hypothesis was stunning: the mouse, which we injected with a substance blocking the activity of p53, showed resistance to radiation.

– And you started creating medicines?

– It was still a long way from medicines. The p53 inhibitor perfectly protected the hematopoietic system, but could not save the intestines from radiation and chemotherapy. And we began to think further, deciding once again to learn from cancer cells. The idea here was this. One of the first things cancer cells learn to do is to turn off their apoptosis functions in order to "untie their hands" for the accumulation of new mutations. I was trying to figure out: maybe it was already profitable for someone in nature to come up with their own way to combat apoptosis? The answer was yes. To whom? Those whose life depends on the life of the cell. Viruses. Why? They need time so that the cell does not die too early and they can give offspring, ending their reproductive cycle. Therefore, the first thing that all viruses do, with the rarest exceptions, when they get into the cell, is to remove the sentries – block apoptosis.

– You didn't use this mechanism?

– Alas, it was impossible. Viruses synthesize anti-apoptotic proteins inside the cell. And we don't know how to deliver them inside it. It turned out that the idea was a good one, but it was impossible to deliver protein to the cell. I was quiet with this thought for a couple of years. But then I thought: maybe there are other microorganisms that live not inside, but on the surface of cells, but are just as much dependent on them? They had to find a mechanism to block apoptosis from the outside. And then I remembered a story that happened in the mid-80s, when I worked at the Moscow Cancer Center. Boris Kopnin and I, the current director of the Research Institute of Carcinogenesis of the same center, discovered then a fact that at one time we were simply ashamed of. We obtained cells that had a previously unknown mechanism of resistance to chemotherapeutic drugs. Having understood, we realized to our horror that resistance is associated with chronic infection of cells with mycoplasma, the smallest of bacteria. It was called dirt in the samples. A cell with mycoplasma on the surface for a biologist is like a person who has lice.

– Apoptosis does not take this "lousy" cell?

– Exactly. But I appreciated the significance of these experiments only after 20 years and began to systematically look for anti-apoptotic factors in bacteria. It turned out that one of the first radioprotectors we made was a product of mycoplasma. As a result, we opened a whole direction – we began to check the microflora that is usually present in humans. For example, we take the protein of E. coli, from which its flagellum is composed. Our immunity, which has been dealing with this or similar salmonella proteins for millions of years, does not make sense to relearn each time meeting them. Therefore, an apparatus for recognizing these flagella, the so-called toll-like receptor 5, is encoded in our genome. This device is needed in order to find out that the bacterium has penetrated the tissue. As soon as it is detected, the NF-kappaB protein, which includes the innate immunity program, begins to work. However, the same protein temporarily turns off apoptosis: if you need to repel an enemy attack, not to suicide. We used this mechanism. What did you get as a result? You can take a tiny dose of the protein that makes up the flagellum of salmonella, inject it under the skin of the mouse, and in about half an hour it will become resistant to lethal doses of radiation. At the same time, both the intestines and blood will be protected.

– Have you made a medicine on this basis?

– The fastest way was to register this drug as a means of civil defense – to protect a person from radiation. Simply because that's how the bureaucratic system of drug approval works. In parallel, we started a medical program in the USA. We are currently conducting clinical trials.

– Will you also test it in Russia?

– Here we brought other substances from the category of direct antitumor agents. It is hoped that they will become the first means of active cancer prevention. However, we started developing them for a more modest purpose. We wanted to learn how to turn off the p53 protein in cancer cells in order to cause apoptosis in them and destroy the tumor.

– Turn it off – I imagine. You can block some kind of receptor. But how to turn on protein?

– Katya Gurova and I, who works at our institute and played a key role in this development, found that in many tumors the p53 protein is physically preserved, but its function is suppressed by the mechanism acquired by the tumor cell. What to do? It seems to be looking for a mechanism. But we are impatient people and acted differently: we carried out the screening overkill. One hundred thousand molecules of different chemical compounds were added to the cells in turn, hoping that some would work.

"That doesn't sound very scientific."..

– The scientific method here was the very method of detecting the awakened p53. Besides, winners are not judged. In modern conditions, it takes only a month of work to check one hundred thousand connections. As a result, we found a dozen working chemical compounds. One of them suspiciously resembled a well-known and forgotten medicine that was used from the late 30s to the early 70s of the last century to treat malaria. Very cheap, by the way. We synthesized it anew and found that it is an amazing activator of p53 in tumor cells and can trigger the mechanism of apoptosis in them. And later it turned out that if we had followed the traditional scientific path, we would never have come to the result that we received.

– What do you mean?

– The "unscientifically" found compounds led us to a goal that could not have been guessed. Studying our find, we found that in addition to p53, it hits at least two more targets. However, the substances found belonged to DNA intercalators: their molecules "get stuck" in the gaps between the strands of the DNA double helix. The problem is that they tend to cause mutations. Therefore, any large pharmaceutical company would immediately put an end to such a substance, considering it unpromising. But we were sorry to part with our find, and we continued to study it. And then it turned out that our substances do not damage DNA and do not cause mutations. Note – unlike most standard anti-cancer drugs. Therefore, no one, even in a terrible delirium, has ever thought of using radiation or chemotherapy to prevent cancer in healthy people. But our finding allows us to think about it.

– Cancer prevention? How?

– Cancer is a social disease. In the sense that our body is a society of cells that keep their selfish aspirations in check. Cancer cells are typical antisocial elements. They behave badly: they take away space, food and oxygen from others, do not support professional functions, multiply indefinitely. At the same time, as in the case of any social disease, the subject does not immediately become a criminal. The cell goes through successive stages of progression – from bad to worse. It is impossible to turn a normal cell into a cancerous one with the help of a single mutation. It takes at least five to six mutations for their combination to lead to aggressive cancer. In reality, even more.

– It turns out that this is a rare event?

- of course. Any mutation is rare, and a combination of certain mutations is already a very unlikely event. That's why we live so long with hundreds of billions of cells. But this means that each of us carries cells that have already gone through two, three, four steps to malignant transformation. Another mutation is only a matter of time. But having cancer in the "preparatory stage" creates an amazing opportunity. You can just kill precancerous cells from time to time. For example, once every few years to do preventive, cleansing therapy. After all, we already, in fact, know what the first steps a cell takes to become bad – these are the cells to destroy.

– In some ways, this task is easier than destroying a mature, mature cancer?

– I really hope so. So far, no one has ever done this, because they didn't know how. Our substances can work here. I will tell you "news from the front" – these results have not yet been published. We asked ourselves: is it possible to prevent cancer in normal, healthy animals? Katya Gurova's laboratory at our institute conducted experiments on a special line of genetically modified laboratory mice: all their females die within a year from breast cancer. When the mice were a month old, they were put on water, to which our drug was added. By the time the last mouse in the control group died of cancer, half of our animals had no cancer. Another experiment was made in Russia in one of the laboratories of the Cancer Center, which is headed by Marianna Yakubovskaya. There, it was possible to fundamentally reduce the frequency of tumors that occurred in mice that had previously been fed the chemical carcinogen hydrazine.

– Do you think we will use additives in water over time? How is fluoride so that there is no caries?

– Hardly. In any case, first you need to bring the drug to cancer patients, show that it works, and only then you can think about prevention.

– Is it about destroying cancer cells at the root?

– It's nice to dream about it, but let's stop here. Please do not forget that all experiments have so far been conducted only on mice: no one knows how these substances will behave in humans. In addition, to create a medicine, you need to have not only a formal opportunity to make it and demonstrate activity on animals. It is important to determine the side effects, find the optimal way of delivery to the body, make sure that the compound is stable… A lot of money is needed for all this. For example, after the crisis, we had to partially freeze work. It continued after the founder of one of the Russian investment funds heard my lecture at a seminar of young scientists in Zvenigorod. As a result, we opened a joint Russian-American venture company. The funds invested in it should be enough to bring the project to the end of the second phase of clinical trials. By this point, the main thing will become clear. For the creators of the drug, the second phase is like the Hamburg account. There is success – the drug has a real chance to become a medicine. No – it can be buried, no matter how much money and hopes were invested in it.

Portal "Eternal youth" http://vechnayamolodost.ru11.05.2011

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