9 minute read
Effective Biomarkers in Uncovering Novel Target Molecules for a Drug The Revolution in New Drug Targets
The Revolution in New Drug Targets
Biomarkers have always played a pivotal part in the detection and treatment of diseases. However, recent studies suggest that the use of biomarkers in drug discovery would unquestionably facilitate and accelerate the process of drug development through analysis of the pharmacodynamics of the specific drug. This article focuses on the role of effective biomarkers in uncovering novel target molecules for a drug.
Ashish Wadhwani*
Head, Department of Pharmaceutical Biotechnology, JSS Academy of Higher Education & Research - College of Pharmacy Salvi Wahidna, School of Pharmacy, JSS Academy of Higher Education and Research
Biological markers or the more commonly used term ‘Biomarkers’ was first heard of in the 1950s. In the coming years, this term gained unprecedented popularity as myriad studies were carried out regarding the efficacy of biomarkers in the drug discovery and development process as well as in the medical diagnosis of diseases. However, the use of biomarkers is not limited to solely these two fields; chemistry, geology, and astrobiology are only a few of the other domains in which the term ‘biomarker’ makes an appearance.
Over the years, the Food and Drug Administration (FDA) has approved a plethora of biomarkers to be used in drug development through the three-stage submission process of the Biomarker Qualification Program (BQP), an occurrence which has revolutionized the process of drug discovery from being a tedious, time-consuming task to one which is significantly less challenging. Owing to this, there have been several research which has been
conducted related to drug targets for better therapeutic development of diseases such as Type 2 Diabetes, AIDS, and neurological disorders like Alzheimer’s disease, among others.
Roles of Different Biomarkers
A biomarker, in accordance with the Biomarkers, Endpoints and other Tools (BEST) Resource, is said to be “a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions.” The seven categories in which these measurements can be majorly classified into are susceptibility/risk, diagnostic, monitoring, prognostic, predictive, and pharmacodynamic/response, and safety biomarkers.
Susceptibility/Risk Biomarkers
These characteristics serve to encompass the possibility of contracting a particular disease, prior to the development of that disease in the individual. In the case of Alzheimer’s disease, changes in the genome of Apolipoprotein E (APOE) demonstrate the onset of this neurological disorder in the patient. To further illustrate the use of susceptibility biomarkers, patients with
elevated levels of C-Reactive Protein (CRP) in the blood are at more peril of being diagnosed with coronary heart disease.
Diagnostic Biomarkers
As its name suggests, a diagnostic biomarker plays a leading role in establishing the presence of a disease in a patient coupled with the subtype of the medical condition. The most basic example to denote a situation in which a diagnostic biomarker is employed is in the detection of essential hypertension, where repeated patterns of raised blood pressure will be observed. On the other hand, Type 2 Diabetes Mellitus is concurrent with a high blood glucose level.
Monitoring Biomarkers
This signifies continuous measurement to evaluate and judge the rate at which the disease is progressing or to oversee the way the body reacts to a drug. Monitoring biomarkers are especially beneficial in gauging the response in a Hepatitis C-positive patient through the quantification of Hepatitis C virus ribonucleic acid (HCV RNA) levels. Prostate cancer can also be monitored by indulging in the use of prostate-specific antigens as a biomarker.
Prognostic Biomarkers
This biomarker’s purpose is to define the odds of a recurring or progressing disease in a specific group of people. A shift in the gene sequence of BReastCAncer genes 1 and 2 (BRCA1/2) are likely to be used as a prognostic biomarker to show the possibility of relapse in breast cancer in women.
Predictive Biomarkers
After administration of a drug or exposure to environmental factors, predictive biomarkers distinguish between people who are inclined to react to it from those who do not. One such example is the use of Human leukocyte antigen allele (HLA)–B*5701 genotype to judge the severity of adverse effects on the skin of HIV positive patients prior to exposure to abacavir.
Pharmacodynamic Biomarkers
It is also known as a response biomarker which shows the effects of a drug on the processes occurring in the body. The International normalized ratio (INR) of a patient is checked as a pharmacodynamic biomarker when the latter is administered warfarin to minimize the risks of a thrombus.
Safety Biomarkers
This biomarker has the crucial role of measuring whether a certain drug is noxious to the body, and if so, the degree of it. Bilirubin is one such example when used to check for hepatotoxicity.
Biomarkers in Target Validation
Following target identification, the drug development process undertakes target validation as the next substantial step. This phase is vital in gaining knowledge about the medical effects encountered when a drug binds with its target molecule. This is essential to assess the efficacy of the drug while it is still under the development process.
Pharmacodynamic biomarkers as mentioned above, help establish the pharmacodynamics and pharmacokinetics profile of a specific drug during pre-clinical trials. Lack of effective biomarkers in this phase would lead to insufficient information obtained regarding the properties of the drug, hence affecting the dose and dosage form selected. The choice of target molecule will also be negatively influenced.
Individual biomarkers are used in each phase of the drug discovery and development process, some of which might not necessarily be interrelated to each other. Nevertheless, the properties the biomarkers should possess to be termed as an effective biomarker remain the exact same; easily attainable, robust, readily replicated and the ability to differentiate between real and fake results. The biomarker employed should be able to show both the progression of the disease and the effects of the drug on that disease. To test whether the biomarker meets these criteria, in vivo testing of the biomarker should be performed.
Type 2 Diabetes
Advanced genetic studies in 2015 by Nelson and group have shown that new drug targets can be discovered through the genomics of an organism. In this study, the gene SLC16A11, coding for monocarboxylate transporters (MCTs), was examined. MCTs act as a drug target while it is majorly involved in the transfer of monocarboxylic acids across the plasma membrane of cells. To substantiate this view, pyruvate was used in the assay, hence proving MCTs to be a valuable drug target.
The transporter has also proven to be engaged in the release of insulin by beta-cells of the pancreas when stimulated by the presence of pyruvate and in regulating the absorption of pyruvate into cells. Several questions have aroused regarding monocarboxylate transporters as a valid drug target in showing curative properties particularly about the use of MCTs in the treatment of Type 2 Diabetes. These questions can only be answered after additional
research has been carried out, which will clearly be a fruitful activity, seeing that MCTs have shown their potential as a drug target.
Challenges and Opportunities for Drug Development
So far, only the positive aspects regarding the development of biomarkers have been portrayed. Regardless, it cannot be denied that there are several oppositions to be countered before launching into biomarker development. Included in the challenges is the fact that scientific explanations of biomarkers are not always verified, leading to a certain reluctance to approve the biomarker by regulatory bodies. Assessment of biomarker characteristics can also be wrongly defined, hence incorrectly setting up the link between the biomarker and a specific disease.
Another truth about biomarker development is that it can prove to be quite time-consuming, and it will additionally take up significant assets and funds to be able to contribute to an early decision-making process. More extensive and prolonged clinical trials will have to be considered to prove the greater benefits of biomarkers as compared to their risks. Regulatory bodies as well do not make the development of biomarkers an easy task with their continuously varying requirements to qualify a biomarker for approval.
To balance out these challenges, biomarker development involves numerous opportunities as well:
The Way Forward…
The latest buzzword heard when biomarkers are discussed is exosomes, extracellular vesicles derived from the endosomal structure of cells and containing proteins and nucleic acids that symbolize the Figure: Biomarkers: Opportunities for Drug Development
pathological processes occurring in the body. Being ever-present under any conditions leads to exosomes being an indispensable part of biomarkers discovery. The effortless isolation of these vesicles has only encouraged their use as a diagnostic biomarker in several diseases like cancer, neurodegenerative diseases, as well as liver and kidney diseases.
A 2013 study by Yoshioka and team led to the revelation of lower levels of CD63, an exosomal protein marker of the tetraspaningroup, in cases of benign tumor cells being present as opposed to when cancerous cells proliferate in the body. Another finding by Graner et al.established the accumulation of amyloid proteins from exosomes in the brain plaques in the case of Alzheimer’s Disease along with elevated levels of phosphorylated Tau proteins, an essential biomarker in the premature diagnosis of the disease.
Coming to exosomal nucleic acids, much research has led to the conclusion that exosomal miRNAs can be of great significance in detecting various cancers. The year 2013 showed that increased exosomal miR-21 levels in the blood plasma of patients suffering from esophageal squamous cell cancer (ESCC) can be used as a crucial biomarker, as proven by Tanaki et al.
This goes to show that indulging in further research on exosomes is of paramount importance and it would undoubtedly prove to be a huge advancement in exposing novel drug targets.
To conclude the pharmaceutical and health sector is shifting focus from a “one-drug-fits-all” to a “personalized approach”, the state-of-the-art roadmap for biomarker-driven drug development is the way forward and the biomarkers will surely bring the revolution in new drug targets for this approach.
Ms.Salvi Wahidnais Researcher at the School of Pharmacy, JSS Academy of Higher Education and Research, Mauritius. Her interest lies in the vast field of research and drug development specifically the pharmacological aspects of drugs. In these lines, she has authored articles on ‘Diabetes In sipidus’ and ‘The Drug Development Process’.
AUTHOR BIO
Dr Ashish Wadhwani did his MPharm and PhD in Pharmaceutical Biotechnology from JSS University, Mysore. After completing his PhD he worked as a Research Associate at National AIDS Research Institute, Pune for DBT-ICMR joint project. He has handled six projects as PI/Co-PI from the Government of India, published 67 research/review papers in peer-reviewed journals and published 03 Patents. He has received various awards at National and International conferences for his research findings. Currently, he is working as a Professor & Head at the School of Pharmacy, JSS Academy of Higher Education and Research, Mauritius.
