The fight against cancer is an "arms race"

How Russian scientists are looking for medicines at the bottom of the ocean

Oleg Sokolenko, Forbes, 04/16/2021

Vladimir Katanaev, a biochemist and specialist in translational medicine, told Forbes Life how the World Ocean became a pharmacological treasure trove, why we are unlikely to be able to completely defeat cancer and what chances of success a biomedical startup has.

Vladimir Katanaev is a professor of translational medicine at the University of Geneva (Switzerland), Head of the Laboratory of Natural Compounds at the School of Biomedicine of the Far Eastern Federal University (Vladivostok). A specialist in the study of WNT signaling pathways, the activation of which in the body of adults becomes one of the causes of cancer.

– Do you think humanity will be able to completely defeat cancer in the near future?

– "Cancer" is a generalizing concept for many different diseases. By and large, each of them requires its own medicine. Certain forms of cancer can already be considered defeated, in the sense that we have learned either to prevent them or to treat them effectively. The former include, for example, cervical cancer caused by the human papillomavirus, the latter – chronic myeloid leukemia. That is, we see some progress in a number of areas, but it is premature to say that we have defeated all forms of cancer. And, probably, this, unfortunately, will never happen. 

- why?

– Firstly, because each of the cancers needs to be dealt with separately. Secondly, cancer even in the same patient before the start of treatment and after his (cancer) return is also, in fact, different diseases. Cancer is very dynamic, it evolves, developing, with more or less efficiency, resistance to each new therapy that we "offer" to it. Therefore, the fight against cancer in each individual patient is an ongoing "arms race", the winner of which is not obvious.

– Tell us about your research. How are they related to oncological diseases?

– In my laboratories in Geneva and in Russia, we study, among other things, the intracellular mechanisms of signal transmission when cells communicate with each other. I will briefly explain what it is about. 

Our body consists of trillions of cells, and they need to coordinate their work. To do this, cells and tissues send chemical signals to each other. Most of these signals do not penetrate into the cell, but bind to receptors-proteins on its surface. This triggers a cascade of reactions, as a result of which cells can grow, divide, migrate or turn into other types of cells.

Cells become cancerous if one of the oncogenic signaling pathways is mistakenly triggered in them. Normally, these pathways do not work in adulthood or work only in a limited way, since their main function is the regulation of processes during embryonic development. The embryo needs its cells to grow and divide quickly, but the adult organism as a whole does not. But sometimes his cells "seem" – for example, because of some mutation in the genes - that they have received a signal for active growth and division, and a tumor arises.

We are studying one of such oncogenic signaling pathways – the WNT cascade. Its activation leads to cancer degeneration of intestinal cells, breast, ovaries, liver and some other organs and tissues. The main interest at the moment is the so–called triple negative breast cancer - the deadliest form of cancer in women.

– What prospects do your research open up in the treatment of cancer?

– Many cancers can be effectively treated by blocking oncogenic signaling pathways in cells. There are several ways to do this. For example, it is possible to block receptor proteins on the cell surface using antibody-based drugs. Or inhibit (suppress) certain signal transmission components already inside the cell, such as some kinase enzymes, with the help of their inhibitors.

However, there are no approved drugs that would be inhibitors of the WNT signaling pathway. Why? The fact is that it is not "turned off" in all tissues in the adult state: there are important exceptions. For example, bone tissue or intestinal epithelium, which need to be constantly updated. Hematopoiesis also depends on the controlled activation of the WNT pathway. Therefore, its rough blocking leads to very unpleasant side effects, which was confirmed by experiments not only on mice. One drug, a WNT pathway inhibitor developed in the USA, reached the first phase of clinical trials, but failed – patients began to develop osteoporosis (apparently, we are talking about two experimental drugs, vantictumab and ipafricept, developed by OncoMed Pharmaceuticals. – Forbes Life).

My team is looking for a drug that would effectively suppress exactly the variant of the WNT pathway that causes thrice-negative breast cancer, but would not block – or almost block – other variants of this signaling pathway necessary for the normal functioning of the body. Such a drug will treat the tumor without causing side effects. To do this, we target one of the ten receptors that trigger the WNT cascade. It is critically important for cancer cells, but it has "stand-ins" in healthy tissue cells. And we have already found several substances that can block it.

– Will it be possible to start clinical trials of the drugs you found soon? 

– One of them is already ready for the start of clinical trials, and now I am trying to solve a number of administrative difficulties so that this becomes possible. We are talking about an already well-known drug called clofazimine and is used to treat leprosy (leprosy) and some forms of tuberculosis. We have shown both in cell cultures and in laboratory animals that clofazimine effectively blocks the WNT signaling pathway in cancer cells.

Clofazmin is already an approved drug, its pharmacokinetics, metabolism, all side effects, dosages are well known. It is known that its reception can be combined with chemotherapy. This practice, when existing drugs are used against new diseases – it is called "repositioning" – allows us to significantly accelerate the development of new treatment methods.

Other drugs that we are developing from scratch are not yet ready for clinical trials. They have shown their effectiveness in experiments on laboratory animals. But before testing them on humans, it is necessary to conduct a whole series of studies: to study in detail the toxicity of the drug, its pharmacokinetics, and so on.

– Will these drugs only work against that aggressive breast cancer?

– A very important and good question. We hope that, in any case, some of the drugs we are developing can be applied to other WNT-dependent forms of cancer. For example, our preliminary preclinical trials of the same clofazimine have shown that it is also effective against a number of forms of intestinal cancer and about half of the forms of hepatocellular carcinoma (liver cancer) studied by us. But again, more research will be needed to assert something with certainty.

– How quickly do you think it will be possible to start mass use of clofazimine as an anti-cancer drug?

– It's hard to say. It depends not only on us as researchers. In principle, in those countries where clofazimine is approved for the treatment of other diseases, it can already be prescribed by the attending oncologist to patients with a thrice negative form of breast cancer. This practice is called the use of off-label medication. But clofazimine, in principle, is not approved in all countries. In Russia, the situation is uncertain: fellow clinicians have not been able to answer my question for two months whether clofazimine is allowed or not.

My colleagues and I are working to ensure that clofazimine is approved specifically for the treatment of triple-negative breast cancer, on a global scale. But this requires approval from regulatory authorities in different countries, and for him, in turn, the successful completion of clinical trials by the drug. 

One of the main problems is financing. Clinical trials are expensive. And the problem with clofazimine is that it has been known for several decades, and almost everything that could be assumed about it has already been publicly stated. Therefore, it will not be possible to obtain such a patent for the use of this drug for the treatment of breast cancer: we simply do not have intellectual property rights to this idea, it is a public domain. This means that we will not be able to attract funds from investors for such clinical trials. Why would they invest in the development of a drug that will then be in the public domain? Therefore, we are now looking for a non-profit foundation that would finance our research.

– Have there been any examples of successful repositioning of existing drugs for the treatment of cancer? 

– Yes, of course. For example, the drug imatinib (glivec) It was originally developed for the treatment of chronic myeloid leukemia. This is a fairly rare form of cancer, so the market for the drug was small. However, imatinib was saved by the fact that it turned out to be repositioned against gastrointestinal stromal malignant tumors, which are much more common. After it became clear, and the drug passed new clinical trials, it began to be sold very successfully.

– What other promising cancer treatment methods are developing now, can you identify?

– The most fashionable direction now is immunotherapy. Cancer cells have "learned" to suppress the body's immune system so that it does not kill them. Scientists have figured out how they do it, a couple of years ago they were awarded Nobel Prize (to James Ellison and Tasuku Honjo). Based on this discovery, drugs have now been created that reactivate the body's immune response. Against a number of tumors – for example, some types of melanoma – such drugs are very effective: a complete cure is quickly achieved without significant side effects. But still, immunotherapy does not help with all forms of cancer, so this is not a panacea, but only another weapon in the arsenal of oncologists. 

I will also name photodynamic therapy. This method is based on the use of special substances – photosensitizers, which, when irradiated with light with a certain wavelength, begin to release active oxygen radicals that kill cells. These substances are introduced into the affected tissue and then activated by a laser beam. This method, of course, is also not universal: it is not possible to introduce a photosensitizer into any organ accurately enough, and then properly irradiate it. But photodynamic therapy works well against some types of skin cancer.

My team recently isolated a substance from the porphyrin class from the tissues of deep-sea echinoderm animals ophiur, which kills cancer cells. This substance is an interesting candidate for the role of a natural photosensitizer for photodynamic therapy. To understand whether it is possible to make a medicine out of it, further research is needed. In the meantime, we have published our first results in Marine Drugs, the No. 1 journal in the world in the field of studying natural compounds from marine sources as candidates for medicines (a peer–reviewed scientific journal with an impact factor of 4.07 and open access, published by the Swiss publishing house MDPI. – Forbes Life).

– How did this deep-sea animal get into your laboratory?

– This is another big project of mine. I am trying to promote what I call the national program for the development of medicines from marine natural compounds. Organisms living in the oceans are colossally understudied, while they can serve as a rich source of new medicinal substances for medicine, including oncology. The world Ocean is, in fact, a huge pharmacological treasure trove that requires research and development.

And Russia has a huge advantage in this sense. Few countries permanently send research vessels to different areas of the world's oceans and take samples from different depths there. Now China and the USA are doing this, The European Union as a whole, a little bit – Japan and Australia. And in Russia, such oceanic expedition activity exists and has great traditions.

My labs are now participating in this activity. We send our employees to complex expeditions organized by the Academy of Sciences, collect samples from the depths and isolate natural chemical compounds from them, which we then test for activity against breast cancer and blocking the WNT signaling pathway in cancer cells. Here, too, interesting results have already been obtained with an extract of the same ophiura tissues, now we are trying to isolate an active substance from it that gives the desired effect.

– Have you thought about launching your own startup that would monetize the results of your research?

– Yes, there are plans for a startup based on the connections that we are developing against the WNT path. I have held a lot of negotiations with potential investors, they have already brought the first results. I can't tell you anything else yet.

– Biomedical startups are now considered one of the most promising in the United States, investors are willing to invest money in them. Do you think such hype is justified?

– In America, it is easier to attract investments in risky startups, and biomedical ones are just among them. After all, what is a biomedical startup? This is a small enterprise that is based, say, on the development of one molecule or one class of molecules that has shown effectiveness in preclinical trials. The founders' goal is to reach clinical trials and successfully pass the first phase. After that, the startup can already be sold.

But the probability of a successful transition to the first phase of clinical trials, according to statistics, hardly exceeds 10%. Accordingly, there cannot be more than 10% of successful startups with such a rough calculation. And in reality, I think there are even fewer of them. Because the development of drugs is a complex process in which there are other important stages.

Startups themselves are at risk. It is quite easy to get funding at the R&D stage, after completing at least the second phase of clinical trials, too. But between these two points lies the so-called valley of death, when it is very difficult to attract financing. Few startups pass through this valley.

Of course, there are successful biotech startups. For example, the German BioNTech, which helped Pfizer develop a vaccine against coronavirus based on matrix RNA. In fact, they developed an innovative technology that the pharmaceutical giant bought. There are such success stories, but they are few. This does not mean that it is not necessary to move in this direction, and I'm going to do it. But you need to be aware of the risks.

– Do you think biomedicine will be able to make people immortal in the foreseeable future, or at least significantly slow down our aging?

– I think we will not achieve immortality. Aging is another difficult topic. Practice shows that when we defeat some deadly diseases or postpone their arrival, others appear instead of them. After we achieved success in the fight against cardiovascular and the same cancers, neurodegenerative diseases began to come to the fore in the aging population. The probability that a person at the age of 100 will develop Alzheimer's disease is approaching 100%. What to do about it is still unclear.

I hope that we will also move forward in the fight against Alzheimer's disease. But when we learn to postpone her arrival, some new age-related diseases will surely "pop up". Therefore, it is indisputable that we will be able to increase life expectancy in the coming decades. Some futurologists predict that already in this century we will live for 120 years – which I doubt, because I don't see any biological reasons for this. But I think we will never achieve immortality.

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