24 February 2016

Biomarkers and the future of medicine

Sofia Sigmond

Biomarker research has been progressing rapidly over the past decade. Every day millions of people take medications that, in principle, cannot help because they are not individually selected, it is noted on the Nature portal (Nicholas J. Schork, Personalized medicine: Time for one-person trials). The magazine cites data on the top ten most sold–out drugs in the United States and their effectiveness: at best, the drug helps one out of four patients (as, for example, the arthritis remedy "Humira" – 25 percent effectiveness), at worst – one out of 25 (as nexium / esomeprazole - 4 percent). Such disappointing statistics and the state of health of Americans in general probably forced President Obama to announce the national program of personalized medicine, which invests $ 215 million. In particular, within the framework of the program, it is planned to create a database of genetic examinations and other information about the health of one million US residents. Diagnostics based on biomarkers can help the development of personalized medicine around the world.

Doctor of Medical Sciences, Professor of Immunology Gelena Tlaxkalova-Gogenova from the Institute of Microbiology of the Academy of Sciences of the Czech Republic explains in an interview with a correspondent of Radio Liberty that in the future the doctor needs to identify the genetic characteristics of each patient in order to choose the most effective and safe medicine and its dosage. Obviously, such therapy will be more effective and will be accompanied by less pronounced side effects, as well as reduce the cost of expensive, but not able to help this patient medications. So-called biomarkers can help to personalize therapy.

"These are cells, molecules or genes, gene products, enzymes or hormones that are measured in tissues, cells or body fluids and allow you to identify a tissue or organ that is not all right. Diagnostics based on these indicators are more sensitive than many traditional methods," notes Gelena Tlaxkalova–Gogenova. Biomarkers have characteristics that can be objectively measured to identify a pathological process or establish a norm, as well as the body's response to therapy or the use of new drugs. Such indicators are used for early diagnosis and prevention of diseases: for example, when a person just starts to get sick, a certain protein enters the bloodstream, appearing as a result of a violation of the integrity of the organ or "incorrect" tissue metabolism. This protein/biomarker may be the first call warning about the development of various diseases.

Biomarkers can be clinical, image-based (for example, those used in the process of magnetic resonance imaging) or biochemical (found in blood, cerebrospinal fluid, saliva, urine or on the surface of the skin). They are also distinguished by the nature of the disease: neurological (say, biomarkers of Alzheimer's disease), metabolic, cardiovascular diseases, cancer markers, genetic or revealing pathologies of intrauterine development (for example, biomarkers of autism). Radio Liberty has prepared an overview of the main biomarkers used in clinical practice today.

Neurological biomarkers

Antibodies found in the blood of sufferers of Parkinson's disease (PD) and Alzheimer's disease (AD) serve as indicators of the disease at an early stage. Most likely, as noted by Gelena Tlaxkalova-Gogenova, this disease is caused by a combination of genetic and environmental/lifestyle factors. Clinicians use biomarkers to diagnose a mild form of the disease, as well as for prevention at a stage when there are no symptoms yet.

With the development of Parkinson's disease, antibodies to the amyloid-forming protein alpha-synuclein can be detected in the patient's blood – they arise as part of the body's immune response to the disease. Alpha-synuclein analysis will help for prevention: with early detection of PD, vaccination with amyloid antigens and antibodies is possible to support the body's natural ability to resist the disease.

In Alzheimer's syndrome, antibodies to beta-amyloids become biomarkers. There are three hypotheses of the occurrence of AD: a decrease in the synthesis of acetylcholine for reasons unknown to science, the deposition of beta-amyloid, as well as pathological changes in tau protein, which eventually leads to signal transmission disorders in brain cells and their subsequent death. Research by Christopher Rosen from the Salgrenska Academy of the University of Gothenburg shows that tau protein mutations in the cerebrospinal fluid occur 10-15 years before the onset of Alzheimer's, and can also serve as a biomarker of the disease. In order for Alzheimer's biomarkers to be used in clinical practice, the Alzheimer's Association established a quality control commission and recommended the use of cerebrospinal fluid biomarkers for early diagnosis of AD worldwide.

Researchers involved in the development of new drugs need biomarkers of neurodegenerative diseases, says Giovanni Frisoni from the University Hospital of the University of Geneva. After all, in this case, the body's response is measured at the molecular and physiological level, which significantly complements the palette of researchers with new details. The advantages of personalized medicine are that the patient is no longer a guinea pig to whom the doctor offers: "Let's try medicine A, and if it doesn't help, we have more medicines B and C. And if these do not help, well, then science is powerless." The medicine is selected individually.

Cardiomarkers are substances that enter the bloodstream during cardiovascular diseases or severe stress. In clinical practice, they are used as an addition to an ECG and have proven themselves well at an early stage of diagnosis. Currently, such indicators of acute and chronic heart failure as creatine kinase-MV, myoglobin, homocysteine, C-reactive protein (CRP), troponin T (cTnT) and troponin I (cTnI) are widely used. New ones have also appeared: a brain natriuretic peptide, as well as a protein binding fatty acids-3. Such biomarker tests that complement the cardiologist's picture of the disease are prescribed to the patient in case of symptoms of coronary heart block: chest pain that lasts more than a few minutes and increases, pain and discomfort in the shoulders, arms, neck, jaw, chest pain that does not get better after taking nitroglycerin. Of course, any of these symptoms requires a comprehensive examination, and a biomarker test is as important as, say, decoding a detailed blood test or an ECG.

Jiri Kettner, MD, cardiologist from Prague, says that today about 20 biomarkers of atherosclerosis are known, and ideally he would recommend that everyone undergo a multi-marker diagnosis. An expert from the Netherlands, Hans Peter Brunner-La Rocca, professor of cardiology at Maastricht University and director of the cardiology clinic, called the use of cardiobiomarkers useful and reducing the cost of treatment. As Brunner-La Rocca said, Maastricht University is conducting unique research in the field of cardiobiomarkers of heart failure. In general, about 1000 different indicators of diseases are known. However, in his cardioclinic, researchers focused on a set of 20 biomarkers that interact with each other and are associated with heart failure.

In 2014, a comprehensive study was launched to determine how to form a list of medications and their dosage for a particular patient based on biomarker diagnostics. These studies in the field of personalized medicine are designed to show how the body of heart patients reacts to therapy and how the treatment of heart failure interacts with concomitant diseases and the patient's lifestyle. For example, a cardiologist prescribes a blood pressure medication to a patient and observes how the drug works applicable to a particular patient. If a team of clinicians is involved, they can supplement the study with blood tests, the state of biomarkers corresponding to hypertension, details about stress, occupational loads and other necessary information that will be stored in the national database. Thus, each particular case can lead researchers to broader generalizations, possibly applicable after processing the accumulated database to the whole population.

Metabolic biomarkers

According to the American Diabetes Association, type 2 diabetes is predictable and preventable. "Weight loss by 5-10 percent reduces the risk of diabetes by 50 percent," says James Meigs, a biochemist at GlaxoSmithKline. He notes that, in addition to the classic diagnostic trio, namely the assessment of the state of beta cells of the pancreas, skeletal muscles and liver, amicably involved in the creation of prediabetes, it is worth paying attention to such signals of the body as, say, abnormal adipocytes (fat cells), subclinical inflammation, endothelial dysfunction (progressive damage to the inner layer (endothelium) of vascular cells or iron overload: iron deposition in tissues and concomitant increase in ferritin levels in the blood. For example, according to PubMed, there is a high correlation between an increase in ferritin levels, which can be determined by an analysis of venous blood, and type 2 diabetes.

Endothelial dysfunction can also be an early signal of the risk of type 2 diabetes. Professor Angelo Avogaro (American Diabetes Association) notes that endothelial dysfunction can cause various complications in type 2 diabetes, and therefore it is very important to monitor the "behavior" of blood vessels. This can be done, for example, during a simple and inexpensive procedure using temperature sensors (VENDYS), which are fixed on the index fingers of the hands and show the body's ability to regulate blood circulation.

Oncobiomarkers

The development of molecular genetic and information technologies helps modern oncology in many ways. For example, it is now possible to predict the body's response to chemotherapy and create vaccines with a "personal address". Publicly available Oncotype DX (Genomic Health) and Mammaprint (Agendia) tests are based on the correlation between gene expression and prognosis and/or probable response to chemotherapy. At the same time, a number of biomarkers are used directly for the early diagnosis of cancer.

For example, in the case of prostate cancer, it is a biomarker PSA-antigen. The correspondent of Radio Liberty asked the opinion of Thomas Buchler, head of the oncology department of the first Medical Faculty of Charles University. Thomas Buchler cautiously called preventive screening of cancer markers of prostate, ovarian and lung cancer "a method in need of improvement." Nevertheless, in the Czech Republic and the UK, the PSA test is widely used: men after 50 years of age are recommended to undergo this inexpensive analysis (it costs about 10 euros) every two years. If the PSA level is higher than normal, it makes sense to conduct a biopsy. However, doctors urge to treat this diagnostic method with caution. "Two control studies were conducted, and both failed to scientifically prove that in the case of prostate cancer, the survival rate of men who underwent PSA screening is higher than those who did not undergo such screening," says oncologist Professor Lodovico Balducci from Moffit Cancer Center (USA).

Ovarian cancer. Long Nguyen on the Future medicine website says that current diagnostic methods (CA-125 antigen test, ultrasonography and gynecological examination) can detect only 30-45 percent of cases at an early stage of ovarian cancer, and this is the most lethal gynecological disease, often asymptomatic until the condition is irreversible. Nevertheless, CA-125 has a low specificity, so current research is aimed at finding more accurate markers. Scientists from the University of California, San Diego, managed to find a candidate – a highly specific mRNA genetic material. During the study, analysts identified six mRNA messenger isoforms that were present in 296 samples of cancer patients and were absent in 1839 samples of healthy tissue. Sherrill Scientz, one of the project participants, says that more comprehensive clinical studies are now needed to confirm the presence of this biomarker in ovarian cancer patients and the absence in healthy ones. And then, probably, mRNA can become one of the clinically confirmed indicators of an approaching disease.

​Breast cancer. "There is no validated breast cancer biomarker in clinical practice yet," warns Brunna Dos Anjos Pulz from the University of Uberlandia, Brazil. At the same time, a mutation of the BRCA1 gene, as studies show, will cause breast cancer in 55-65 percent of women, according to the National Cancer Institute. Studies of BRCA mutations do not provide an absolutely accurate prognosis, but several medical tests for such a diagnosis have been developed and in many countries are recommended for women with a hereditary history of such a disease. A famous example is actress Angelina Jolie, whose mother, aunt and grandmother died of breast cancer. The BRCA1 gene mutation discovered in Jolie herself prompted her to undergo a double mastoectomy proactively.

Cervical cancer. Geert Van Raemdonsk from the University of Queensland, Australia, conducted a study in 2014 concerning protein biomarkers located in the cervical fluid (CVJ). The results of the study, published on the Plos Org portal, helped to create a self-diagnosis test for cervical cancer, which can help women in underdeveloped countries where it is not possible to undergo regular histological tests. The author of the study notes that biomarkers located in the CVJ are more specific than blood plasma biomarkers. Thus, the new test successfully improves the currently used screening programs.

Rectal cancer. "50 percent of patients with colorectal cancer have metastases. Biomarkers such as epidermal growth factor receptor (EGFR) or KRAS oncogene mutation are able to predict disease progression," Russell Langan and co–authors report in the Journal of Cancer. Medscape informs that from 30 to 50 percent of malignant tumors of the rectum are distinguished by a mutation of the KRAS gene.

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Summing up, we note that today biomarkers work better for the diagnosis of cardiovascular and neurodegenerative diseases at an early stage. As for oncological diseases, biomarker screening data should not be absolutized. "So far, not a single universal cancer marker has been identified, not a single method whose specificity would reach 100 percent," comments Yaroslav Masopust, professor of the second Medical Faculty of Charles University. – So, the "normal" level of any cancer marker does not mean the absence of the disease. Conversely, a positive result does not necessarily indicate the presence of a malignant tumor." However, in some cases, the distinguishing ability of cancer markers allows you to determine a tumor weighing 1 mg (the presence of 10 cells in the 6th degree), while a clinical diagnosis is made only with the development of a tumor in which there are three orders of magnitude (10 in the 9th degree) more cells. In addition, biomarkers help to individually select treatment for cancer, which is much more effective than the "gross" approach.

Many researchers note that the focus on biomarkers and personalized medicine will bring millions of dollars in savings in the future, since medicines will be selected strictly according to "your address". Now these millions are being spent idly on treatment that does not help the patient, as well as the development of new "unaddressed" blockbuster drugs. Wouldn't it be better to encourage pharmaceutical companies and national organizations responsible for healthcare in highly developed countries to invest in personalized medicine with tax discounts? "Research continues, and this is the future," agrees Gelena Tlaxkalova-Gogenova.

Portal "Eternal youth" http://vechnayamolodost.ru 24.02.2015

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