Biomarkers (medicine)
In medicine, a biomarker is a measurable indicator of the presence or severity of a disease or other physiological condition of an organism. For example, a biomarker indicates a change in the expression or condition of a protein that correlates with the risk or progression of a disease, or with the response of the disease to a given treatment. Biomarkers can be molecules that can be detected and measured in parts of the body (such as blood or tissue). They can show normal or abnormal processes in the body.
Biomarkers can be, for example, specific molecules or genes, gene products, enzymes or hormones. Complex organ functions or characteristic changes in biological structures can also serve as biomarkers. Although the term biomarker is still relatively new, biomarkers have been used in preclinical research and clinical diagnostics for some time. For example, body temperature is a well-known biomarker for fever. Blood pressure is used to determine the risk of stroke. Cholesterol levels are used as a biomarker and risk indicator for coronary and vascular disease, and C-reactive protein (CRP) is a marker for inflammation. The presence of an antibody can also indicate an infection. Finally, a biomarker can also be a substance that is introduced into an organism in order to study organ functions or other aspects of health. For example, rubidium chloride is used in isotopic labeling to assess the perfusion of the heart muscle. Biomarkers are useful in a number of ways. For example , in cancer, tumor markers are used to measure disease progression, evaluate the most effective therapeutic approaches for a particular cancer, and determine long-term susceptibility to cancer or its recurrence.
Classification and application of biomarkers
Biomarkers can be classified based on various parameters. They can be classified as imaging biomarkers (for CT, PET, MRI) or molecular biomarkers based on their properties. Molecular biomarkers have biophysical properties that allow their measurement in biological samples (e.g. plasma, serum, liquor, biopsy). There are also markers based on DNA such as B. gene mutations or polymorphisms, but also transcripts, peptides, proteins, lipids, metabolites and other small molecules. Biomarkers can also be classified according to their application, such as: B. diagnostic, prognostic or predictive biomarkers, cf. above. Another category of biomarkers are those used in decision making in early drug development. For example, pharmacodynamic biomarkers (PD biomarkers) measure the pharmacological response, which is of particular interest for studies on dose optimization.
Biomarkers of diseases and biomarkers of the effect of drugs
A distinction is often made between disease-related and treatment-related biomarkers. Disease-related biomarkers indicate whether a disease exists (diagnostic biomarkers) or how such a disease can develop in individual cases, regardless of the type of treatment (prognostic biomarkers). Treatment-related biomarkers give an indication of the likely effect of a specific treatment on the patient (predictive biomarkers). In other words, predictive biomarkers help assess the most likely response to a particular type of treatment, while prognostic markers show disease progression with or without treatment. In addition to long-known biomarkers, such as. B. in the blood count, there are numerous novel biomarkers that are used in various medical fields. Intensive work is currently underway to discover and develop innovative and effective biomarkers. Many of these biomarkers have become the basis for prevention , i.e. for medicine that detects diseases or the risk of disease at an early stage and takes targeted countermeasures against the development of diseases. Biomarkers are also seen as the key to personalized medicine. With them, it is possible to tailor treatments to specific patients in order to intervene in disease processes in a highly efficient manner.
In the past, biomarkers were primarily physiological indicators such as blood pressure or heart rate. The term biomarker is now often a synonym for a molecular biomarker, such as increased prostate-specific antigen as a molecular biomarker for prostate cancer. Recently there has been an increasing interest in the importance of biomarkers in oncology, for example the role of KRAS in colorectal cancer and other EGFR- associated cancers. In patients whose tumors express the mutated KRAS gene, the KRAS protein, which is part of the EGFR signaling pathway, is always “switched on”. This overactive EGFR signaling means that signaling continues downstream - even if signaling upstream is blocked by an EGFR inhibitor such as cetuximab (Erbitux) - which leads to further growth of the cancer cells. Examining a tumor for its KRAS (wild type vs. mutant) status helps identify those patients who will benefit most from treatment with cetuximab. Changes in the P53 gene and MMPs, for example, are also relevant.
Effective treatment is currently only available to a small percentage of cancer patients. In addition, many cancer patients are diagnosed at a stage when the cancer is too advanced to be treated. Biomarkers have the ability to significantly improve cancer discovery and the drug development process. In addition, biomarkers can enable doctors to develop individual treatment plans for their cancer patients, and so doctors can tailor drugs specifically to their patient's tumor type. This can significantly improve the response rate of the drug and / or limit the toxicity of the drug and reduce the costs associated with testing various therapies and the resulting treatment for side effects.
In the case of chronic diseases, the treatment of which can force patients to take medication for years, an accurate diagnosis is particularly important if severe side effects are expected from the treatment. In these cases, biomarkers are becoming increasingly important because they can confirm a difficult diagnosis or even make it possible in the first place. A number of diseases such as Alzheimer's disease or rheumatoid arthritis often start with an early, symptom-free phase. In these cases, biomarkers help identify high-risk patients reliably and in good time so that they can be treated either before the onset of the disease or as soon as possible afterwards.
Biomarkers in drug development
Biomarkers are also used in drug development. Here biomarkers are used in both preclinical and clinical research. When evaluating potential drug therapies, a biomarker can be used as a substitute for a natural endpoint such as irreversible morbidity or mortality. When treatment alters a biomarker that is directly related to disease progression, the biomarker serves as a surrogate marker for evaluating clinical benefit. For example, biomarkers are used in Phase I trials to determine dosages and dosing regimens for future Phase II trials. To determine biomarkers, test systems for animals and humans are automated as far as possible. The most common tests include the determination of liver (e.g. transaminases, bilirubin, alkaline phosphatase) and kidney functions (e.g. serum creatinine, creatinine clearance, cystatin C). Other biomarkers record injuries to skeletal muscle (e.g. myoglobin) or cardiac muscle cells (e.g. CK-MB, troponin I or T).
Imaging biomarkers
Many new biomarkers are being developed that incorporate imaging techniques. Imaging biomarkers have many advantages. They are usually non-invasive and produce intuitive, multidimensional results. They provide both qualitative and quantitative data and are usually relatively comfortable for patients. When combined with other sources of information, they can be very useful for doctors trying to make a diagnosis.
Cardiac imaging is an active area of biomarker research. The coronary angiography , an invasive procedure that requires catheterization, has long been standard for the diagnosis of arterial stenoses. However, scientists and doctors are developing non-invasive techniques. It is believed that cardiac computed tomography (CT) has great potential in this area. In doing so, researchers need to overcome problems related to calcium blooming . This is a phenomenon in which limescale deposits interfere with image resolution. Other intravascular imaging techniques, including magnetic resonance imaging (MRI), optical coherence tomography (OCT), and near-infrared spectroscopy , are also being investigated.
Another new imaging biomarker includes radiolabeled fluorodeoxyglucose as a tracer . The positron emission tomography (PET) can be used to determine the location of glucose uptake in the body. By tracking glucose, doctors can pinpoint sources of inflammation as macrophages ingest the sugar in high concentrations. Tumors also have a high consumption of glucose and are therefore often suitable for monitoring by this method.
Individual evidence
- ^ The Biomarkers Consortium . Foundation for the National Institutes of Health.
- ↑ Archived copy, whatisabiomarkers.html . Archived from the original on October 25, 2009. Retrieved January 27, 2010.
- ^ Biomarker Technology Platforms for Cancer Diagnoses and Therapies . TriMark Publications, LLC. July 2014.
- ↑ Clinical and pathologic relevance of p53 index in canine osseous tumors . In: Vet. Pathol. . 40, No. 3, May 2003, pp. 237-48. doi : 10.1354 / vp.40-3-237 . PMID 12724563 .
- ^ Matrix metalloproteinase-2 and -9 involvement in canine tumors . In: Vet. Pathol. . 40, No. 4, July 2003, pp. 382-94. doi : 10.1354 / vp.40-4-382 . PMID 12824510 .
- ^ Advances In Pharmaceutical Cell Therapy: Principles Of Cell-based Biopharmaceuticals , ISBN 981461680X .
- ↑ Pharma Matters White Paper: Establishing the standards in biomarker research (2008). Thomson Reuters
- ↑ Biomarkers of Alzheimer's Disease . In: Neurobiol. Dis. . 35, No. 2, August 2009, pp. 128-40. doi : 10.1016 / j.nbd.2008.10.003 . PMID 19010417 . PMC 2747727 (free full text).
- ↑ The serological diagnosis of rheumatoid arthritis: antibodies to citrullinated antigens . In: Dtsch Arztebl Int . 106, No. 10, March 2009, pp. 159-63. doi : 10.3238 / arztebl.2009.0159 . PMID 19578391 . PMC 2695367 (free full text).