Returnees: Peter Chumakov, specialist in molecular biology of cancer

Viruses against cancer
Maria Rogovaya, STRF.ru

One of the mega-grants, which was won by Novosibirsk State University, involves the development of drugs for the treatment of oncological diseases. The principle of action of future drugs is the destruction of cancer cells by strains of viruses that are not dangerous to humans. The work will be led by one of the world's leading experts in the field of molecular biology of cancer, Pyotr Chumakov (left). Over the past few years, he planned to organize research in this direction together with the Vice-rector of the NSU for Science, Professor Sergey Netesov (right). The State Scientific Center of Virology and Biotechnology "Vector", the Institute of Chemical Biology and Fundamental Medicine and the Institute of Cytology and Genetics SB RAS will also take part in the project.

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Pyotr Mikhailovich Chumakov, Doctor of Biological Sciences, Professor, Head of the Cell Proliferation Laboratory of the V. A. Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, head of the laboratory in the Department of Molecular Genetics of the Lerner Research Institute of the Cleveland Clinic Foundation in the USA and the research group at Case Western University. His work made a great contribution to the discovery and study of the protein p53 (recognized as a molecule in 1993 by the journal Science), which causes apoptosis – programmed self-destruction of a cell, including when it is infected with dangerous viruses. Since the mid-90s, he began to conduct active scientific activities abroad, continuing to study various aspects of apoptosis and without losing close scientific contacts with Russia.
Netesov Sergey Viktorovich, Doctor of Biological Sciences, Professor, Corresponding Member of the Russian Academy of Sciences, Vice-Rector for Scientific Work of Novosibirsk State University. Until 2007, he was in charge of the Laboratory of Molecular Biology of RNA viruses of the FGUN SSC Virology and Biotechnology "Vector". Specialist in the field of structures and functions of human and animal virus genomes. Since the mid-90s, he has been developing strains of oncolytic viruses. Under his leadership, a weakened strain of adenovirus was constructed with a complete deletion of one of the genes, it was tested on various cell cultures and on animals with human tumors implanted. The resulting drug is currently undergoing clinical trials at the N. N. Blokhin Russian Cancer Research Center.

Sergey Netesov:

– There is a science fiction story by Ivan Efremov about a rich man and a poor man who got sick with the same type of cancer. The rich man was treated in the best clinics, but they could not save him. And the poor man was not treated at all, but simply, being hungry, found somewhere a bunch of rotten potatoes infected with a virus, ate it and recovered. In fact, plant viruses that decompose human tumor cells are not yet known, but some animal and human viruses can do this.

The oncolytic effect of a number of viruses was discovered at the beginning of the XX century on some bird tumors, but scientists failed to uncover the mechanism of this phenomenon at that time.

The results were unstable, and the research stopped, and in the 50s, due to the mass development of vaccines, this topic was returned again. By the way, Pyotr Chumakov's mother was engaged in this topic (although based on polio vaccine) – he showed me her materials in the late 90s, and then we decided to work on this area together, but it was not possible to provide sufficient funding in those difficult times. Other researchers abroad analyzed a similar effect of enteroviruses, but the molecular nature of cancer had not yet been studied, which seriously complicated the task. Much later it turned out that, for example, there are dozens of types of lung cancer alone, and it was necessary to look for a virus against each of them. Some scientists sometimes got promising results, but they were poorly reproduced, and it was unclear how to create a technology that guarantees the absence of failures. And the unknown, even if its minimal degree, is "prohibited" in practical medicine: it is impossible to inject a drug to a patient, which, in case of failure, will not only not help, but also worsen his well-being. So they put a second cross on these studies. And only in the mid-90s, when the genome structures of many viruses were deciphered, it became possible to observe their action at the cellular level. This time they returned to the question fully armed with knowledge, which increased the chances of success by orders of magnitude.

The first drug based on an adenovirus strain devoid of one of the genes was tested in the USA on humans back in the 90s and found to be highly effective in the treatment of certain oncological diseases.

However, scientists failed to achieve mass use due to problems with the stabilization of viral strain preparations during their storage. The medicine did not always retain the necessary titer of viruses, and therefore its quality decreased. Nevertheless, in the USA today, this drug is used with the consent of the patient as an additional therapy. In China, this idea was quickly picked up and managed to bring to the final result: now a similar American strain of adenovirus is used there in combination with chemotherapy to treat certain types of cancer. There is no doubt about the prospects of the technology: around the world today, about twenty such drugs are already being tested at various stages, including clinical ones. It will not be easy for us to compete with them, but we are not going to duplicate foreign works – we have our own promising strains. I would like to note that neither in Russia nor abroad we are talking about the appearance of a panacea. The oncolytic effect of such strains can only be used as an additional means accompanying the main treatment – surgical, chemical or radiation. But it can be crucial for saving the patient's life when it is necessary to prevent metastases – the spread of cancer cells in the body. Today, protection against them is provided insufficiently and in much less sparing ways, including prolonged chemotherapy, which not all patients are able to successfully tolerate.

Over the past 12 years, the development of strains of oncolytic viruses has been carried out in my laboratory at the Vector World Health Center, where I worked at that time. These studies were funded by grants from Moscow with the support of academicians G.P. Georgiev and G.N. Vorozhtsov, but due to insufficient funds, it took a lot of time to develop this drug.

Thanks to the megagrant, three or four years may be enough for us to develop a line of several promising drugs. However, 5-7 years will pass before the stage of their clinical trials, one way or another – this is world practice.

There are a lot of types of cancer, and the cause of each is different mutations in the cellular genome. Therefore, many different viruses are needed to destroy them. Since the emergence of immunity to almost any virus occurs after two to three weeks, it is important to have several serotypes of each virus, the alternate reception of which will prolong therapy up to several months. So far, we can confidently say that we will conduct such work with adenovirus. There are plans to work with other virus families – some avian viruses, herpes virus derivatives, smallpox vaccine modifications and a number of others, the details of which are too early to disclose.

Even before animal testing, we will have complete information about the genomes of the viruses being created and tested, and this is a very expensive part, for which we have always lacked funds before. The tests themselves also require expensive equipment, a modern vivarium and skills to work with immunodeficient mice. In the world's leading laboratories, hundreds of mice are no longer dissected to find out how the drug affected them. The animal is euthanized and examined on a high-resolution tomograph. Fortunately, such a device is available in the new SPF-vivarium of the Institute of Cytology and Genetics SB RAS.

The low level of the domestic pharmaceutical industry will not interfere with the implementation of the project, since technologically the production of these drugs is similar to the production of live or inactivated vaccines.

In order to provide personnel for the full development cycle – from the laboratory to patients – we plan to create educational programs at NSU for future specialists in medical biotechnologies, including the development and production of vaccines. In the next six months, both at the university and in the institutes participating in the project, on the basis of our specialized departments, we will prepare specialized premises, purchase new equipment and materials: reagents, culture media. Pyotr Chumakov plans to organize lecture cycles of the world's leading scientists on oncology and virology in Novosibirsk. We want to attract to our work not only students and postgraduates of NSU, but also graduates of leading universities throughout the region.

Now a lot of people write and talk about the shortcomings of the past competition. They certainly exist, but sometimes they are exaggerated. The choice was not always in favor of scientists with a higher citation index, because the largest Hirsch index is mainly among people already of deep retirement age, and to work on projects you need a lot of energy over the next 5-7 years.

In the case of foreign participants, the commission probably leaned in favor of those who cooperated more with Russia, which is quite understandable by the desire to leave intellectual property rights to our country. The decision on the two phases was also competent. It will allow you to get at least some experience, evaluate the feasibility of the competition and make the necessary changes to the rules of the game. For example, to make its terms more transparent, to increase the time for preparing applications and exclude from them not very necessary information. Abroad, they give it a couple of months, not three weeks. Of course, those who did not win should know the reasons and have at their disposal the arguments of experts pointing out the shortcomings. By the way, there are few criteria for evaluating grant applications abroad and they are extremely clear. But this system has existed there for a long time, and it appeared in our country only a few years ago and, I am sure, it will evolve rapidly.

Portal "Eternal youth" http://vechnayamolodost.ru26.11.2010