Personalized medicine: from bombing to sniper shooting

Haute couture medicine
Galina Kostina, "Expert" No. 9-2009

Perhaps each of us had to face a situation when pills did not help. Even if they were not falsifications. Doctors know that patients may be immune to certain medications. The World Health Organization cites the following facts: from 30 to 80% of cancer patients do not respond to traditional therapy, from 40 to 75% of patients with bronchial asthma, 30-60% with migraine, 70-75% with diabetes mellitus. The list is large. The main reason for this pharmacotherapeutic problem is that many drugs are aimed at the symptoms, not the cause, pharmacists target the disease, not the patient, whose features are due to his unique genome. Modern scientific knowledge of molecular biology has allowed in recent years to develop a new direction, which is called targeted or targeted therapy. Research by pharmaceutical companies is aimed at finding a target, if not the only one, then one of the key ones in a particular disease. And the diagnostic methods being created allow us to find out whether the disease of a particular patient will respond to treatment. Actually, the goal of personalized medicine is to find the right medicine for a particular person based on new diagnostic methods, as well as optimize the treatment regimen, literally watching the disease disappear. Personalized medicine is among the leading trends in the global pharmaceutical industry: some companies specialize in the creation of innovative drugs and develop precisely targeted drugs, others – the latest diagnostic systems. The Roche Group of companies, where both diagnostic and pharmaceutical directions have been historically developed, is one of those who sets this trend.

From bombing to sniper shootingThe evolution of therapy, which led to a personalized approach, is very well traced on the example of oncology.

Doctors are already calling the first antitumor therapy carpet bombing, because the drugs against cancer cells were worn down and healthy. Scientists have tried to modify such drugs in order to somehow reduce the side destructive effect. One of these drugs, xeloda, was released at Roche: the substance selectively accumulated in the tumor tissue and, under the influence of a special enzyme, activated and killed the diseased cell. In the 70-80−ies of the twentieth century, it was possible to identify some genes that take a key part in the formation of various tumors. The identification of specific targets launched the era of targeted therapy. Almost all the world pharmaceutical giants aimed at these targets and developed drugs for them, which appeared already in the 90s. Some of them belong to the class of so–called monoclonal antibodies - they block receptor proteins on the cell surface. Others belong to the class of so–called small molecules that are able to penetrate into the cell and block the necessary proteins inside it. A new class in oncology – products based on small RNAs – is just emerging in development. These drugs will be able to act at earlier stages, blocking not proteins, but their very appearance.

The history of the creation of the Roche drug herceptin based on monoclonal antibodies has already become a classic example demonstrating how the advances of molecular biology allow individualizing therapy. This medicine is created for the treatment of one of the most common oncological diseases – breast cancer (breast cancer). Before him, doctors noted that about a third of patients affected by this disease either responded very poorly to traditional therapy, or did not respond at all. The disease proceeded rapidly and aggressively, characterized by early metastasis. It was clear to the doctors that they were dealing with some special form of breast cancer caused by special mechanisms of development in a certain group of patients. In 1987, scientists led by Dennis Slamon managed to find out that this group has much more HER-2 neu receptors on the surface of tumor cells than in other cases. It is a receptor from the group of epidermal growth factors. It is involved in transmitting signals to the cell for proliferation (division): the more signals there are, the more intensively the tumor cells multiply. It became clear that HER-2 neu could be an ideal target for drugs from a number of monoclonal antibodies. It was necessary to create an antibody that would capture the surface part of the receptor and thereby block the transmission of signals for proliferation. Such monoclonal antibodies to HER-2 neu receptors were created by Roche in collaboration with a partner – the well-known American company Genentech (Roche owns a controlling stake). These antibodies became the main herceptin. It was a huge success. A very selective drug was found for a specific form of breast cancer, moreover, based on antibodies that differ from other drugs in another feature. Monoclonal antibodies cause an immune response of the body: a bundle of antibodies with a receptor acts for the immune system as a flashing alarm light. Immune killer cells begin to crack down on the tumor cells marked with "light bulbs".

Herceptin does not treat any breast cancer, but only a certain, but very vicious subtype. Now, with the help of special tests, you can identify this subtype and fight it quite successfully. Based on the action of herceptin and tests that detect breast cancer with HER-2 neu, a new standard was written for the treatment of this disease, which is used all over the world.

When it became known that the HER-1 receptor could become a target for the treatment of certain types of cancer, in particular non-small cell lung cancer, scientists began to select the appropriate drug for it. Since this receptor is not located on the surface of the cell, like HER-2, but inside, where a large monoclonal antibody cannot penetrate, a tartseva drug based on a small molecule was created. Penetrating into the cell, the drug blocked the transmission of a signal to the proliferation of tumor cells.

Roche associates great hopes on the way to personalized medicine with the use of a completely new class of targeted drugs based on small RNAs. They will be able to stop the development of the disease at earlier stages than do, for example, the same monoclonal antibodies and small molecules, they can be selected taking into account the genetic characteristics of patients.

Ten years ago, the phenomenon of RNA interference was discovered, and in 2006, American geneticists who discovered it received the Nobel Prize. The essence of RNA interference is the destruction of RNA molecules carrying information about the structure of the gene, after attaching to them small RNAs circulating in the cytoplasm of the cell. Small RNAs are specially produced in the body that can block the work of matrix RNA, which carries information to create a certain protein. This prevents the creation of such a protein. In scientific research, this method produces lines of model animals with knocked out (knocked out, non-functioning) genes and drugs are tested on them. It became clear that this mechanism can be used not only in basic science, but also in medicine: to try to "knock out" overly active genes that produce a lot of proteins that lead to disease. Theoretically, it is possible to stop the reproduction of viruses, the genome of most of which is represented by RNA. RNA interference can also be used in oncology, blocking signaling pathways not at the receptor level, but at the level of their production. And although here, as in any new direction, there are a number of problems, for example, on the delivery, selection of selective small RNAs and their survival in the body, scientists believe that they are technical and solvable. In any case, the Roche Group of companies is already testing drugs based on small RNAs.

"We want to get away from practice when the patient starts taking more and more new drugs. A week passes, another, he takes up a new drug, which also does not help," says Lee Babbiss, president and head of the global research division of Roche–Pharma. – This problem covers three aspects: time, money and the well-being of a patient who is not getting better. With the help of molecular studies, it is possible to determine whether a particular drug will help a particular patient. Ten years ago we realized that this direction has a great future."

Now Roche is trying to approach the problem comprehensively, creating both drugs and test systems. Thus, the COBAS-Amplicor test system created by the company, used, in particular, in virology, allows you to identify subtypes of viruses, accurately determine the so-called viral load – the number of viral particles in the blood. This makes it possible to make a prognosis, determine the treatment regimen, and also monitor its effectiveness. One of these tests complements the highly successful drug pegasis from the interferon group, used in the treatment of hepatitis C, and is included in the standard of treatment. The test reveals the subtype of the virus, the level of viral particles, as a result of which the duration of treatment is precisely determined, which can take from 16 to 48 weeks.

The new Elecsys S100 test system determines the level of the S100B protein, which serves as a biomarker of malignant melanoma metastasis. The level of this protein greatly increases as soon as the growth of metastases begins. Using Elecsys S100 allows you to learn about the beginning of metastasis earlier than other methods and start specific treatment. The same system allows you to monitor the effectiveness of the use of medicines, in particular, Roshevsky roferon.

The evolution of the creation of diagnostic tests and drugs of a new class for targeted therapy has brought the company to a new scheme of innovation.

Strategic cabinetsAt a press conference dedicated to the results of 2008, Severin Schwan, Chief Executive Officer of the Roche group of companies, made journalists smile with the unfinished phrase "We will not expand ...".

It is known that for the last few years the group has only been expanding by buying other companies, and even now it is in a state of negotiations. However, Schwan still finished the sentence: "... but we will go deeper." The Roche Group has already spent several tens of billions of dollars on the acquisition of small, usually biotech companies. In the opinion of an outsider, these companies are quite heterogeneous. For example, the American Piramed Limited attracted the attention of Roche by developing inhibitor drugs for the treatment of breast and lung cancer, as well as rheumatoid arthritis (now these drugs are in the preclinical stage and the first phase of the clinic). Another American company, NimbleGen Systems, is interested in its microchips. 454 Life Sciences is known as one of the leaders in the market of tools for high-performance DNA sequencing. Ventana Medical Systems has been successfully developing and creating diagnostic tools to detect pathology at the tissue level (histological diagnostics). However, all these diverse companies fall into line with the new strategy of personalized therapy developed recently by Roche, which is impossible without the close connection of the best diagnostics and targeted therapy. In this regard, Roche decided to focus on five areas – oncology, neurology, metabolic diseases, inflammatory diseases and virology – which make it possible to integrate diagnostics and pharmaceuticals. The new strategy required a revision of not only the priorities, but also the structure of the company.

"Despite the fact that the company was doing well, we felt that we were stuck in the traditional approach to the creation of drugs, and felt the need for change," says Lee Babbis. "The mass of structures made it increasingly difficult for researchers, developers, and managers to communicate freely and seemed to corrode the spirit of creativity." In each of the five areas, the management created teams of four people, their main task was to organize the process, starting with the selection of the goal and ending with the justification of the concept: one was responsible for R&D, the second for applied research at early stages, the third for clinical trials at late stages, the fourth for strategic placement on the market. These "four" were called strategic cabinets. They receive the support of the entire group of companies, as well as the help of numerous partners – scientific and pharmaceutical companies with which Roche has long-term ties. "Previously, everything went along a well–worn track for decades, the participants of one stage of research did not interfere in the affairs of the participants of the other," continues Lee Babbiss. – This traditional scheme of creating medicines has become cumbersome and inert." Now, thanks to the new in vitro and in vivo research technologies acquired and created within the company, the tests are conducted not sequentially, as before, but in parallel. This gives confidence in its effectiveness already at the earliest stages of the creation of a new drug, allows you to invest more in the most successful projects and accelerate the process of bringing a promising drug to the market.

"The new strategy is aimed at the widest access to innovations," says Lee Babbiss, "And it doesn't matter where we get them – in our company, in the companies being acquired, or from partners, which, based on this task, we have a great many. We are looking for the best that is around us, and we try to support this best." For example, three years ago, Roche opened one of its research centers in China, about which Lee Babbiss says: "We take great care of the people who work there, trying to preserve their views, their culture, their open-mindedness. We support them financially, allowing them to try out many scientific concepts. This center, in particular, is working on a promising direction for the use of therapeutic RNAs."

For Roche, it is important that new scientific knowledge be transferred to the practical plane as soon as possible. New approaches, according to Severin Schwan, give the company an advantage, especially in the current crisis time: "We expect that in the huge market of medicines created by us – very accurate and therefore effective and the safest – will be most in demand."

Portal "Eternal youth" www.vechnayamolodost.ru10.03.2009