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BIOMARKERS

SUBJECT:PSMEDEPARTMENT : PHARMACOLOGYPROFESSOR : Dr.REMA RAZDAN MADAMPRESENTED BY : ROOHITH

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CONTENTS

I. DEFINATIONII. HISTORY OF BIOMARKERSIII. DISCOVERY OF BIOMARKERSIV. PROPERTIES OF AN IDEA BIOMARKERV. CLASSIFICATIONVI. COMMON BIOMARKERS FOR CANCERVII. APPLICATIONS

3DEFINATION

• Biomarkers (short for biological markers) are biological measures of a biological state. By definition, a biomarker is "a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention.“

• Biomarker is any indicator that is used as an index of the intensity of a disease or other physiological state in the organism.

• A substance that when introduced into the organism serves for the estimation of organ function or some other form of health assessment.

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Impaired fitness

Disturbed population andecosystem stability

Chemical pollution- speciation- bioavailable residues

Sensoryinterference

Absorption

Molecular responsesPhysiological responses

Structural damage

Exposure / effectbiomarkers

Effect / healthbiomarkers

Pred

ictiv

eR

eact

ive

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HISTORY OF BIOMARKERS• The practice of uroscopy — examining a patient’s urine for signs of

disease — dates back to the 14th century when doctors would regularly examine the colour and sediment of their patient’s urine

• In 1960, researchers discovered that some patients with chronic myelogenous leukaemia (CML) have a specific genetic change associated with their cancer. ( i.e. shortened version of chromosome 22)

• This abnormality, known as the Philadelphia chromosome is caused by a translocation between chromosomes 9 and 22. The consequence of this translocation is the creation of the BCR-ABL ‘oncogene’.

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• The word biomarker is a little over 30 years old, having first been used by Karpetsky Humphrey and Levy in the April 1977 edition of the Journal of the National Cancer Institute.

• Reported that the serum RNase level was not a biomarker either for the presence or extent of the plasma cell tumor.

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Discovery of biomarker and validation • Because of diseased tissue/tumour heterogeneity and other biases.

• it is important that the identification of biomarkers should proceed in a systematic manner.

• In 2002, The National Cancer Institute’s ‘Early Detection Research Network’ developed a five-phase approach to systematic discovery and evaluation of biomarkers .

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PHASE I• Refers to preclinical exploratory studies. • Biomarkers are discovered through knowledge based gene selection,

gene expression profiling or protein profiling to distinguish cancer and normal samples.

• In labs nuclear cells, blood, urine, saliva, tissues are analyzed in which the target biomarkers are identified(genes, proteins, enzymes and other substances)

• Obtained values are compared in healthy and diseased subjects in order to establish the extent of correlation .

• After this the very method is perfected, i.e. its reliability and sensitivity.

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PHASE II• An assay is established with a clear intended clinical To document clinical

usefulness. • Firstly, such assays need to be validated for reproducibility and shown to

be portable among different laboratories use. • Secondly, evaluated for their clinical performance in terms of ‘sensitivity’

and ‘specificity

i.e. its ability to identify diseases compared to the gold standard, and the reference values are determined along with intra individual variations

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PHASE III • Implies retrospective epidemiological studies on screening and the

predictive value of the biomarkers

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PHASE IV • includes prospective clinical studies

• investigate the correlation between biomarker levels and the onset of clinical indicators of the disease course.

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PHASE V Evaluates the overall benefits Risks of the new diagnostic test on the screened population.

Phases IV and V are necessary to evaluate benefits and risks of the use of a biomarker in screening and detection.

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PROPERTIES OF AN IDEAL BIOMARKER

IDEAL MARKER FOR DIAGNOSIS:

Should have great sensitivity. Specificity. Accuracy in reflecting total disease

burden. A tumor marker should also be

prognostic of outcome and treatment.

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IDEAL BIOMARKER FOR SCREENING

1. The marker must be highly specific, minimize false positive and negative2. The marker must be able to clearly reflect the different stages of the disease (early) 3.The marker must be easily detected without complicated medical procedures. The disease markers released to serum and urine are good targets for application of early screening4.The method for screening should be cost effective.

17CLASSIFICATION OF BIOMARKERS

• They can be classified as• Genomic biomarkers: based on the analysis of DNA (deoxyribonucleic

acid) profiles, especially the analysis of SNPs (single nucleotide polymorphisms), i.e. identification of punctual variations in genomic DNA.

• Transcriptomic biomarkers: based on the analysis of RNA expression profiles.

• Proteomic or Protein biomarkers: based on the analysis of the protein profiles.

• Metabolomic biomarkers: based on the analysis of metabolites (metabolites are the inter-mediates and products of metabolism).

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GENOMIC OR DNA BIOMARKERS• A measurable DNA characteristic that is an indicator of normal

biologic processes, pathogenic processes, and/or response to therapeutic or other interventions.

• somatic mutations form in the DNA of individual cells during a person's life. Because these somatic mutations are only present in tumor cell DNA, they provide an extremely specific biomarker that can be detected and tracked.

• Mutations in oncogenes, tumour-suppressor genes, and mismatch-repair genes can serve as DNA biomarkers.

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TRANSCRIPTOMIC BIOMARKERS• The transcriptome is the set of all RNA molecules,

including mRNA, rRNA, tRNA, and other non-coding RNA produced in one or a population of cells. It differs from the exome in that it includes only those RNA molecules found in a specified cell population, and usually includes the amount or concentration of each RNA molecule in addition to the molecular identities.

• RNA-based biomarkers undergoing clinical evaluation consist of multi-gene molecular patterns or ‘fingerprints’.

20TRANSCRIPTOMIC BIOMARKERS USE IN CANCER DRUG

DISCOVERY

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PROTEOMIC BIOMARKERS• Proteomics is the large-scale study of proteins, particularly

their structures and functions.• Proteomics technologies are emerging as a useful tool in the

discovery of cancer biomarkers.• These advances overcome in part the complexity and heterogeneity

of the human proteome, permitting the quantitative analysis and identification of protein changes associated with tumor development. With the advent of new and improved proteomic technologies, it is possible to discover new biomarkers for the early detection and treatment of cancer.

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Ongoing & anticipated implications of Proteomics biomarkers in medicine

• Proteomic-based approaches for biomarker investigation can be employed in different aspects of medicine, such as –

1. elucidation of pathways affected in disease,

2. identification of individuals who are at a high risk of developing,

3. identification of individuals who are most likely to respond to specific therapeutic interventions, and prediction of which patients will develop specific side effects

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METABOLOMIC BIOMARKERS• Metabolomics is the "systematic study of the unique

chemical fingerprints that specific cellular processes leave behind", the study of their small-molecule metabolite profiles.

• Metabolomics, was introduced to refer specifically to the analysis of metabolic responses to drugs or diseases.

• Metabolomics has become a major area of research; it is the complex system biological study, used as a method to identify the biomarker for various disease.

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In general, in most disease cases, a metabolic pathway had or has been either activated or deactivated - this parameter can thus be used as a marker for some diseases.

For eg., Serotonin production pathways, activated in a person who has recently consumed alcohol for instance, can be a metabolic marker of recent alcohol consumption.

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DEPENDING ON THEIR APPLICATION THEY ARE CLASSIFIED AS FOLLOWS

1)Diagnostic biomarkers : e.g. cardiac troponins

2)Biomarkers to determine the stage of disease :e.g. Brain natriuretic peptide

3)prognostic biomarkers : e.g. tumor markers

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CLASSIFICATION BASED ON THEIR CHARACTERISTICS

• Imaging biomarkers• Molecular biomarkers/non

imaging biomarkers

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1.Imaging Biomarkers: (CT), (PET), (MRI). CT, PET, MRI and nuclear imaging are already widely used Medical

imaging could have a great impact on slow progressing diseases, such as lymphoma, non-small cell lung cancer, Alzheimer’s disease and rheumatoid arthritis.

• Help monitor drug distribution, pharmacokinetics and pharmacodynamics essential for clinical trials.

Advantages : non-invasive, they produce intuitive, multidimensional results, Yielding both qualitative and quantitative data

Disadvantages: Exposing to radiation, high cost.

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Molecular Biomarkers/non-imaging biomarkers:

• mainly used to monitor treatment, especially in molecular medicine, medical diagnostics, disease prognosis, risk assessment.

• involves measurements in biological samples (plasma, serum, cerebrospinal fluid and biopsy) include nucleic acids-based biomarkers such as gene mutations or polymorphisms and quantitative gene expression molecules .

• levels on which molecular biomarkers can be identified, from formation of protein to degraded products .

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CLASSIFICATION Based on genetic and molecular biology methods

• TYPE 0• TYPE 1• TYPE 2

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1.Type 0- Natural history marker: defined as a marker of disease severity examples of type 0 markers as independent predictors of risk are the CD4' T-cell count and the HIV 1 plasma RNA level.

2.Type 1- Biological activity marker: defined as one that responds to therapy. determined in the context of early phase clinical trials. Example Triple-drug anti retroviral combinations appeared superior to single drugs and double-drug combinations in vitro

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Type 2: Surrogate marker of therapeutic efficacy: (single or composite of several markers)

defined as one that accounts fully for the efficacy of an agent

Ideally, type II markers represent "complete" surrogates of clinical outcome.

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THEY CAN ALSO BE CLASSIFIED AS

• DRUG RELATED BIOMRKERS• DISEASE RELATED BIOMARKERS

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DRUG RELATED…….

• THEY INDICATE WHETHER A DRUG WILL BE EFFECTIVE IN A SPECIFIC PATIENT AND HOW A PATIENT BODY WILL PROCESS IT.

DISEASE RELATED

• THEY GIVE AN INDICATION OF THE PROBABLE EFFECT OF TREATMENT ON PATIENT ( RISK INDICATOR OR PREDICTIVE BIOMARKER)

• IF A DISEASE ALREADY EXISTS (DIAGNOSTIC BIOMARKERS)s

34Types of Biomarkers Based upon application and Use in Drug Development and Disease Management

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COMMON BIOMARKER FOR CANCER

• CEA (>10 ng/ml)• Carcinoembryonic antigen (CEA) is produced during fetal development. After

birth, the production of CEA stops and is undetectable. CEA has also been found elevated in nonmalignant tumors such as pleural effusions. Elevation of CEA after conventional treatment of neoplasms has been correlated with a recurrence of cancer

• AFP (>100 ng/ml)• Alpha fetoprotein (AFP) is typically found in the developing fetus. Because of the

association of the rapid cell growth, this fetal protein is also used as a tumor marker. non cancerous liver diseases such as cirrhosis and viral hepatitis can lead to high level AFP

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CA19-9 (>37 U/ml)Carbohydrate Antigen 19-9 (CA 19-9) is present in the fetus in the epithelium of the fetal stomach. It is primarily used as a marker for pancreatic cancer. High levels also exist in conditions such as non-malignant liver disease and other disorders of the gastrointestinal tract.

HCG (>10 mIU/ml )Human Chorionic Gonadotropin-beta (HCG) is normally produced by the placenta during pregnancy, an indicator of pregnancy. The protein can be detected in serum or urine. Non-malignant elevations may be observed in pregnancy, ulcers, duke’s disease, and cirrhosis. Levels of HCG are useful in monitoring the effectiveness of treatment. Ferr (>120 ng/ml )Ferritin is an iron binding storage found in the liver, spleen, and bone marrow. Elevated levels observed in non-cancerous conditions include rheumatoid arthritis and anemia

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APPLICATIONS OF BIOMARKERS• IN DIAGNOSIS• TREATMENT• DISEASE PROGRESSION• SAFETY BIOMARKERS• Forensic applications. • Biomarkers for Personalized Prevention Strategies.

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DIAGNOSTIC TECHNOLOGIES. • Screening : Screening discriminates the healthy from the asymptomatic

disease state by screening particular groups.• Biomarkers are important for screening and early diagnosis.• E.g. the prognosis of advanced HCC is poor, whereas smaller HCC

suitable for organ transplantation, surgical resection or radio frequency ablation have shown a better prognosis and longer survival.

• For this reason, a surveillance program using alpha fetoprotein (AFP) and ultrasound (US) every six months has been recommended, and is widely practiced.

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DISEASE PROGRESSION• HIV INFECTION IS ASSOCIATED WITH INCREASED RISK OF

CARDIOVASCULAR COMPLICATIONS.• PLASMA LEVELS OF COAGULATION BIOMARKER D-DIMER (DD) HAVE BEEN

CORELATED WITH INCREASED MORTALITY AND CARDIOVASCULAR EVENTS IN HIV PATIENTS.

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SAFETY BIOMARKERS• THE ISOENZYME OF LACTATE DEHYDROGENASE AND CREATININE KINASE

IN COMBINATIOM WITH MORE MORE SPECIFIC MARKERS OF CARDIAC INJURY SUCH AS CARDIAC TROPONINS CAN PROVIDE INFORMATION ON THE RELATIVE SEVEREITY, EXTENT OR DURATION OF MYOCARDIAL INJURY.

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APPLICATIONS• BIOMARKERS CAN REFLECT ENTIRE SPECTRUM OF DISEASE FROM THE

EARLIEST MANIFESTATIONS TO THE TERMINAL STAGES.

• THEY HAVE THE POTENTIAL ABILITY TO IDENTIFY NEUROLOGICAL DISEASE AT AN EARLY STAGE TO PROVIDE A METHOD FOR HOMOGENOUS CLASSIFICATION OF DISEASE AND TO EXTEND OUR KNOWLEDE BASE COVERING THE UNDERLYING DISESE PATHOGENISIS.

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• IN EPIDEMIOLOGICAL INVESTIGATIONS , BIOMARKERS INCREASE THE VALIDITY WHILE REDUCING ERRORS IN THE MEASUREMENT OF EXPOSURE FOR NEUROLOGICAL DISEASE

• MOLECULAR BIOMARKERS HAVE THE ADDITIONAL POTENTIAL TO IDENTIFY INDIVIDUALS SUCCEPTIBLE TO DISEASE (MOLECULAR GENETICS)

43BIOMARKERS FOR PERSONALIZED PREVENTION

STRATEGIES• Medicines that target the genetic signatures of diseases are making

inroads into modern medicine. Health experts see this therapeutic approach as the beginning of a new era in medicine.

• In the treatment of diseases especially cancer, there is a shift from the traditional clinical practices to novel approaches.

• Traditionally, cancer patients were treated with drugs of low toxicity or of high tolerance.

• novel approaches are intended to identify individualized patient benefits of therapies, minimize the risk of toxicity and reduce the cost of treatment.

• The chemotherapy drug irinotecan (Camptosar) is one example of personalized medicine,(used to treat advanced colorectal cancer)

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REFERENCES Ziad j.s, Suzan m. Semaan and Qing-a, Methodology and

Applications of Disease Biomarker Identifi cation in Human Serum Florida State University, Tallahassee.

Manoj .kand shiv .k s, Biomarkers of diseases in medicine, New Delhi, current trends in sciences, by Indian academy of sciences.

Abdel.bh, Biomarkers in Drug Development: A Useful Tool but Discrepant Results May Have a Major Impact, USA.

Dr. Austin.t, Application of Biomarkers in Early Phase Clinical Trials, Almac.

Dr Richard .k, biomarker and personalised medicine, Almac uk .

Ezzatollah.f, Seyed a.m and Raheleh.f Biomarkers in Medicine: An Overview, British Journal of Medicine & Medical Research, dec 2013.

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