Triple blow to cancer
Cancer has no way out
Galina Kostina, "Expert" No. 8-2013
Many anticancer drugs hit one target, but the tumor cunningly bypasses the blocked channel. American scientists of Russian origin are creating a unique anti-cancer drug that hits three goals at once. Russian institutes of innovative development help them
In the early 1990s, molecular biologist Andrey Gudkov was full of prospects and ideas, but Russian biology was rapidly losing them. Therefore, Gudkov left for the USA and has been working there for more than twenty years. He is a well-known scientist, senior vice president of the Roswell Park Cancer Institute in Buffalo, author of more than 200 scientific papers. For many years he has been working on the mechanisms of cell death and oncology. In his laboratory, Gudkov gathered a lot of talented scientists, mainly from Russia. At home, he considered himself a pure theorist, and in the USA he matured to create products based on his ideas with colleagues. In 2003, he organized the Cleveland BioLabs company with an uncharacteristic startup's plump portfolio of developments. Along with the financial crisis, it became clear that the most realistic way of development is to create several small companies with one or two products. Since there was noticeably less venture capital money in the US during the crisis, some companies received a residence permit in Russia, where the money appeared. One of them, Incuron, was created by Cleveland BioLabs together with Bioprocess Capital Ventures, one of the funds of the Russian Venture Company (RVC), to study two leading molecules that can give rise to a new class of cancer drugs.
Went against the rulesOne of the objects of study of the Gudkov laboratory was the famous protein p53. In 1989, scientists found out that p53 plays the role of a guardian of order in the cell.
If there are breakdowns in it, if it is attacked by enemy agents, p53 evaluates whether there are chances of recovery, and if not, then it is better for the cell to die in order not to produce mutant offspring. In most tumor cells, this protein does not work, and the cells do not die, but constantly divide. Hundreds of laboratories around the world are engaged in the p53 protein – it is very attractive in terms of its impact on it.
Gudkov's student and associate, and now the head of the laboratory, Professor Katerina Gurova, who studied the details of the cellular mechanisms of tumor formation, was looking for how to revive this "guardian": "It is well known that in about half of all tumors, this protein is broken and does not work. Cells divide uncontrollably, no one sends them to death. However, we were occupied with the other half of the tumors, where p53 was not broken, but the tumors nevertheless grew. We wanted to find out what was going on and find a way to wake up p53 so that it would send cancer cells to death." The search for the mechanism of action of the entire chain, or signal path, is like unwinding an unimaginably tangled tangle of thin threads. This process can take years. In parallel, scientists decided to use a simpler method – sorting through hundreds of thousands of chemical compounds from libraries: suddenly there will be one among them that will activate the desired protein! The first compound from the library being tested that activated p53 turned out to be an already well–known drug used against malaria - quinacrine, better known in Russia as akrikhin. However, according to Gurova, it had one drawback – it accumulated most actively in the liver. "Potentially, quinacrine can be used against liver cancer," the scientists thought and began to study the mechanism of its action. "And then we made a very unexpected discovery. It turned out that quinacrine not only activates our beloved p53, it also suppresses the action of another important protein for the tumor," says Katerina Gurova. This other protein, NF-kappaB, in contrast to p53 inhibits cell death – apoptosis. Normally, it is designed to make our cells more resistant to various stresses: if, for example, a virus attacks, NF-kappaB signals the immune system to engage in battle, and the protein postpones apoptosis during the fight. The tumor actively uses NF-kappaB to protect against cell death and intensive division.
The ability of quinacrine to simultaneously awaken dormant p53 in a tumor cell and put NF-kappaB to sleep so that it does not interfere with apoptosis was an unexpected and extremely important discovery. And scientists decided to go a completely non-standard way. Usually screening is not practiced on several targets, but if the experiment shows that this is possible, why not look for a compound that will hit two targets at once? "If we had gone the standard way and tried to theoretically justify the existence of one small molecule that would act on two targets at once, we would have achieved nothing. And we went against all the rules," says Andrey Gudkov. In Gurova's laboratory, they began to look for substances similar to quinacrine, but affecting not only the liver, but also other tissues. "During the screening process, we found compounds that, from my point of view, were spatially similar to quinacrine, although they belonged to a different class. These molecules belonged to carbazoles. One of the charms was that they were more active and at the same time patent–free - unlike quinacrine, from which an antimalarial agent was made a long time ago," Gurova continues. With the help of a team of talented chemists, researchers were able to go a long way to improve the properties of carbazoles and come to an understanding of what their structural elements are important for anti-cancer activity. As a result, they obtained molecules that not only showed the necessary molecular activity, but also met other important requirements for the drug: they were highly soluble, stable, etc. These several molecules were called kuraxins (from the English cure – "to heal").
Andrey Gudkov and Katerina Gurova call themselves the parents of the Kuraksin project. Gudkov, the author of many projects, jokes that "the father left to make other children, and the mother remained to raise the kuraksins. And he continues to do it so well that I only admire."
Screening brought good luck, but it was necessary to sum up the theory and explain where the bridge connecting them was. Scientists went deep into the search and came to a certain protein complex known as FACT. Previously, it was not associated with cancer or other diseases. "Since this was a new character in our story, we began to look for his possible connection with some other important proteins for the tumor. And they found it!" – says Andrey Gudkov. FACT turned out to be associated with the so-called heat shock factor HSF1. During growth, often in a hurry, the tumor produces many different proteins. To monitor these proteins, numerous assistants are needed, the so-called heat shock proteins. The additional synthesis of these assistants initiates just the heat shock factor. Without it, the tumor is nowhere.
It turned out that through FACT it is possible to hit three targets in a tumor cell at once! No one has ever received such a unique molecule. The so-called targeted approach involves the search for a drug acting on a single target. "Cancer, unlike all other diseases, lives in the body as a living being. And, like any living being, it evolves according to the Darwinian principle – it is looking for ways of survival. The tumor quite easily finds a way to bypass one signal pathway blocked by the drug. It will be more difficult for her if two paths are blocked, and it will be very bad if three. In any case, so far we have not been able to obtain a tumor resistant to kuraxins experimentally," explains Andrey Gudkov. The mechanism is clear to scientists so far in general terms (see diagram).
For an investor in RussiaThese scientific discoveries have greatly excited scientists – their unique leader molecules can become a fundamentally new class of cancer drugs.
Usually at this stage there are business angels or seed venture funds that are invested in the initial research of a potential drug. But our scientists guessed right to the financial crisis of 2008, when many American venture capitalists were in no hurry to take risks. However, Russian researchers who maintain close relations with Russia knew that national programs and institutes for the support and development of scientific achievements were being developed in the country. At the same time, it turned out that there are catastrophically not enough promising projects in some areas of science. And the sponsors' eyes were turned not only to domestic, but also to world achievements. So the Kuraksins got together with the money. However, first Andrey Gudkov, who came as a lecturer to the school of young scientists in Zvenigorod, met with his friend Mikhail Mogutov, a shareholder of the management company of the Bioprocess Capital Ventures fund, whose shareholders are RVC and Vnesheconombank. The Foundation, established in 2007, was designed to support startups aimed at creating promising medicines.
In 2010, Andrey Gudkov's company Cleveland BioLabs transferred its intellectual property – two leader molecules to Incuron, and Bioprocess Capital Ventures promised investments in the amount of 550 million rubles. A successful team of Russian and American specialists formed in the small "Inkuron", who immediately got down to business.
Remembering that quinacrine accumulates in the liver, testing of its antitumor properties (the drug was called "Kuraxin CBLC102") began with the first phase of clinical trials against cancers that metastasize to the liver. In the first phase, the dose of the drug must be determined very accurately – in order to avoid toxic effects. "Starting the first phase in Russia is a new and difficult thing. We practically do not produce our own original funds, and foreign companies usually carry out the third phase here, less often the second. The first phase requires a lot of diligence and work, more flexibility, control, attention and experience to distinguish the side effect of the drug from the manifestations of the disease itself," says Andrey Leonov, CEO of Incuron. The first phase of clinical trials involves several cohorts of patients, each of which, as a rule, consists of three people. If the first dose is found to be safe, the dose will be increased in the second cohort. And so on, until they notice the toxic effects associated with taking the drug. As a rule, you need to go through about five cohorts, although in the case of quinacrine this was not enough, and the researchers decided on higher doses with a higher chance of success. Currently, research is being conducted at the Blokhin Russian Research Center and at the Yaroslavl Cancer Center. "Although in the first phase we aim to determine only the dose, not the effectiveness, the doctors noted that two patients in Moscow and one patient in Yaroslavl showed signs of a response to therapy," says Leonov.
The second molecule, kuraxin No. 137, was obtained by Inkuron at the initial stages of preclinics. Preclinical trials have now been completed both in Russia and in the USA. The safe dose interval of molecule 137 was determined by two laboratories – the Ukrainian laboratory (working with mice) and the laboratory at the Adler Institute of Primatology. In the spring of last year, the Ministry of Health of the Russian Federation gave permission for the first phase of clinical trials initiated at the RSC and at the Chelyabinsk Regional Cancer Center. The Incuron company decided to divide the clinical research program into two parts: an injectable form will be tested in the USA, and a capsule form for oral administration in Russia. This kuraxin is launched against so-called solid (solid) tumors. Despite the signs of a response to the drug, noted already in the first cohort, it is too early to draw conclusions about its effectiveness. "Firstly, it is not customary to do this in the first phase, and secondly, it is impossible to draw conclusions based on one result. That's when the data from all the studies are summarized and they turn out to be positive, it will be possible to be optimistic," says Oleg Gladkov, head of the department of the Chelyabinsk Cancer Center.
Knock out a chair from under cancerClinical trials in the USA are about to begin.
Two parallel programs are a good tactical solution. Russian innovators have practically no experience in bringing original medicines to the world market. "We do not know how the FDA will treat the results of our preclinical and clinical trials. But we hope that our Russian dossier, coupled with the American one, will convince the American regulatory authority to allow the testing of capsules in the United States. We will create a precedent. Let's see which Russian studies will satisfy and which will not. This is an ambitious task. Even if we do not get permission from the FDA right away, we will not be very upset, because the capsule form is planned for sale in our and Asian markets. In the USA, preference is given to injectable forms," admits Andrey Leonov.
Another tactical move is to launch studies of kuraxin in the USA in combination with already known drugs. "This practice has been gaining momentum in the USA lately: not only the company requests permission for clinical trials, but also individual doctors interested in new drugs. By the way, doctors can receive grants from the National Institutes of Health (NIH) for such research. We give them the medicine and get a broader dossier on our molecule. In addition, after applying kuraxin in combination and getting good results, the doctor can try it separately," says Leonov. This is also important so that a new drug, which many doctors may simply not trust, can take its rightful place in the standards of treatment. And the more doctors receive their own positive information about an innovative drug, the faster the entire medical community learns about it.
In parallel with the drug, scientists are also investigating the FACT marker, which, they hope, will determine how much treatment with kuraxin is indicated. "FACT is active only in the most malignant variants of tumors. Therefore, there is a chance that we have found both a marker and a cure for those tumors that are still poorly treated or not treated at all," says Katerina Gurova. If it is confirmed that FACT is a marker of aggressive tumors, then the marker test will be another candidate for commercialization. And the duet "marker plus medicine" as a personalized approach is very attractive to potential buyers from big pharma.
Inkuron received 550 million rubles from Bioprocess Capital Ventures – just enough to complete the first phase of clinical trials. Another 150 million – to search for the next generations of kuraxins – was given by Skolkovo, whose resident was the company "Inkuron". If the results are encouraging, there should be buyers for the molecules. "In the last few years, bigpharma has been very actively buying molecules, especially anticancer ones, from small innovative companies. Last year, for example, there were a lot of such deals – from $ 100 million after the first phase of the clinic to more than a billion after the second. However, it still depends on the prospects of the candidate for the drug. We are targeting about $150-200 million after the first phase," says Leonov.
Innovators have another trump card: experiments show that curaxins can be used not only for the treatment, but also for the prevention of cancer. The human body consists of about a trillion cells. "Cancer, as a rule, arises from a single cell, which is the first to stochastically gain the necessary combination of mutations. This means that every adult organism has many cells that have already entered the path of accumulation of dangerous mutations. It is these cells that make up the high-risk population, it is among them that the malignant variant will eventually arise. It is impossible to find such a cell by diagnostic methods as a needle in a haystack today. But it seems that such a diagnosis is not necessary if we learn how to cleanse the body of such cells with the help of drugs. The luck is that the activation of NF-kappaB and HSF1 and the acquisition of dependence on them are the necessary conditions for the transformation of normal cells into cancer cells. And this means that you can try to clean them with kuraxins, then the cancer can be pushed away. And if you clean it every five years, cancer may not occur at all. There are very few cancers that would not activate those proteins that are affected by kuraxin. So, if we kill all the cells that depend on the heat shock factor and NF-kappaB, we will immediately knock out the stool from under the cancer. Luck is also in the fact that kuraxins so far show that they are safe in normal cells, which means that they can be prescribed to still healthy people for prevention," says Andrey Gudkov.
Portal "Eternal youth" http://vechnayamolodost.ru05.03.2013