Development of New Drugs and Diagnostics: Hope for a Better Life

To understand the underlying causes of cancer, infectious, and inflammatory diseases and to develop future medicines and diagnostics – this is the mission of the Institute of Molecular and Translational Medicine (IMTM), which develops excellent basic and applied biomedical research in Olomouc. The journey leading to the chance for patients with often fatal diseases is, however, a marathon journey, landscaped with millions of molecules, thousands of exacting experiments and endless hours in the laboratory.

The principle of molecular medicine is in finding answers to the basic question: How does the human body work in health and in illness? “We study diseases in terms of their pathogenesis, aiming toward the very basis of what is the cause of the disease. When you understand the cause, you can suggest correct treatment, or the most suitable diagnostics. On the molecular level, there is a potential targeted treatment that will fight the disease with the best probability and efficiency,” explains Marián Hajdúch, Director of the IMTM.

It is a study of diseases that may have similar mechanisms, so similar types of therapy or diagnostics may be applied. “Diseases resemble each other on the molecular-cellular level more than it seems. A similar pathophysiology can be found in a variety of diseases, only details or the localisation of the process may differ,” adds Hajdúch.

The transfer of information from basic research to the patient is the task of translational medicine. “It is a closed cycle called the ‘bench to bedside and back approach’. It transfers the needs of clinical medicine into research, and at the same time it transfers projects that have relevant outcomes in research and may satisfy a relevant medicinal need into the validation phases of clinical studies as soon as possible – called ‘proof of concept’. This allows answering the question whether the chosen path is right or wrong,” says the IMTM Director.

Discovery: It begins with a molecular target

During the development of new drugs, the IMTM scientists focus on the first two stages: drug discovery and preclinical research, which ends shortly before the first administration of the drug to human subjects. There are six research programmes for this purpose, starting with research of the molecular basis of diseases and molecular targets. “In order to have well-targeted drugs and good diagnostics, we must know our target. The first steps lead to its detection and identification – of the proper gene, protein or mechanism,” describes Hajdúch. “For example, once Prof Bártek’s (the programme leader’s) group finds a new key protein or gene, active in the repair of nucleic acids, we can launch screening for identification of substances that are able to inhibit this molecular target, or to activate it. It depends on what the specific disease requires.”

Such discoveries in the area of the molecular basis of diseases facilitate finding possible medical strategies which are within the competence of other research programmes. One of them is Medicinal Chemistry, in the area of which large groups of chemists from the Czech Republic and abroad are collaborating, sending substances to Olomouc to have them tested for biological activity. The extensive chemical library in the IMTM currently consists of 120,000 compounds, occupying a chemical space of roughly 15 million molecules. “Other research groups then investigate how complicated the compound is to prepare or its pharmacological properties. The chemical structure has to be very often further modified and optimised for future medicinal application,” adds Hajdúch.

According to him, the main contribution of the IMTM research groups and programmes is in the close connection and continuity of their R&D activities, allowing the management of all key phases of the development of medicinal products. “In order to have a competitive advantage against the rest of the world, we need yield from our combination of knowledge, interdisciplinary research, and unparalleled technologies. Excellent basic research is a necessity, but there is no guarantee that the findings will have practical applications,” sums up Hajdúch.

A good example of a complete research, from discovery to phase 1 clinical trial, is fenretinide, a drug with a potential use in the treatment of cystic fibrosis. It is able to partly regulate a metabolic disorder which is accompanied with vulnerability to certain types of infection that are eventually the cause of death for patients with this serious disease. Olomouc scientists developed fenretinide in collaboration with their colleagues in Canada, where the evaluation of a phase 1 clinical trial has been completed in 2015 with very encouraging results.

Personalised medicine and tailored drugs

The development of drugs in the IMTM is closely connected to the research of biomarkers – molecular indicators used in in-vitro diagnostics – diagnostics in laboratory conditions. The goal is to develop biomarker assays, or ‘biomarker test kits’, used to identify specific diseases.

“For example, a special kit recently developed in our laboratories and certified for use in the European Union allows testing for the Her-2 gene amplification in highly degraded samples of breast carcinoma. It means that a patient with such amplification will receive a special treatment that may result in full recovery for some of these women,” explains Hajdúch.

By means of biomarkers, it is possible to identify a group of patients who are most likely to have a therapeutic response. “It is the principle of ‘treatment for the right patient’ – which I have been trying to promote in the Czech Republic with Prof Vladimír Mihál, Head of the Children’s Clinic at the UP Faculty of Medicine and Dentistry and the Olomouc Teaching Hospital since the 1990s. Such a treatment is maximum patient-friendly, has minimum side effects, and higher probability of therapeutic response. It works as a magic bullet – the drug hits a corresponding molecular target in the tumour. The target, in order to be hit, has to be present in the tumour tissue, and this is why it is necessary to be examined with an appropriate biomarker,” explains Hajdúch. “Personalised medicine and tailored drugs make it possible for the patients to receive what is best for them at the moment. This approach will undoubtedly dominate in medicine one day, because administering drugs to targeted patient groups increases the efficiency and safety of the treatment. This principle is quickly spreading from oncology to other branches of medicine.”

Taking the lead

The array of successful research activities includes a number of new diagnostic methods within a broad spectrum of cancers. For instance, Olomouc scientists develop new biomarkers for identification of cancers of the colon, ovaries, prostate, and upper gastrointestinal tract – stomach, oesophagus, and pancreas. “Pancreatic cancer is almost always deadly, with a very short life expectancy – less than five percent of the patients survive for five years or more. The only chance for cure is a very early diagnosis. We also search for possibilities of earlier diagnosis of lung carcinoma, which can only be treated in the early stage, too,” underlines Hajdúch. These fascinating projects bring together researchers and their colleagues from the Surgical Clinic and the Tuberculosis and Respiratory Disease Clinic in Olomouc. New biomarkers are identified by means of tumours transplanted from the patient to a mouse with suppressed immunity. “The tumour and its treatment thus may be studied on the level of the whole organism, with the prospect of finding new diagnostic and therapeutic possibilities.”

Very promising are the programmes to screen brain tumours, infections, and other pathological processes. “Our colleague Miloš Petřík works on screening of insidious Aspergillus infection, which may be life-threatening for patients after bone marrow transplants. We also investigate screening of brain tumours, which will be further used in collaboration with the Copenhagen laboratory of Jiří Bártek in his research into brain tumours,” says Hajdúch.

One of the important prerequisites for a successful translational research is to identify in advance the potential problems in the patients before their treatment begins. This has been confirmed by a recent discovery of a new mechanism how cancer cells resist the olaparib treatment. This drug was approved in 2015 for patients with a hereditary type of ovarian cancer. “It was evident that there is a great medical future for olaparib and similar drugs and that it will very important to monitor the ways in which cancer cells will resist it. Last year’s publication of Prof Bártek’s team in the journal Cell identified one of these mechanisms, which enabled us to look for ways how to go round this resistance. In other words, you need to have a solid lead,” explains Hajdúch.

No false hope

The demanding research work requires knowledge and erudition as well as immense patience and endurance, thus being a permanent challenge for scientists. Despite many blind alleys that are often the outcome of basic research, “It is a complicated, yet for most of us a very intriguing and exciting process. You have to be really keen on science to be willing to go through what it takes,” confirms Hajdúch.

It also involves the responsibility for more or less real expectations on the side of the patients that are heard from even beyond the walls of research labs. All of the news in the media about a discovery or a promising treatment are always followed by a flood of letters – patients asking for help. “We’re trying to give our patients hope, but it cannot be false. Our goal should be deepening all our knowledge that makes their lives better and longer – and this is the vision we’re working on,” says Hajdúch.

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