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PubMed2005

Method validation and measurement of biomarkers in nonclinical and clinical samples in drug development: a conference report.

Biomarkers are increasingly used in drug development to aid scientific and clinical decisions regarding the progress of candidate and marketed therapeutics. Biomarkers can improve the understanding of diseases as well as therapeutic and off-target effects of drugs. Early implementation of biomarker strategies thus promises to reduce costs and time-to-market as drugs proceed through increasingly costly and complex clinical development programs. The 2003 American Association of Pharmaceutical Sciences/Clinical Ligand Assay Society Biomarkers Workshop (Salt Lake City, UT, USA, October 24-25, 2003) addressed key issues in biomarker research, with an emphasis on the validation and implementation of biochemical biomarker assays, covering from preclinical discovery of efficacy and toxicity biomarkers through clinical and postmarketing implementation. This summary report of the workshop focuses on the major issues discussed during presentations and open forums and noted consensus achieved among the participants on topics from nomenclature to best practices. For example, it was agreed that because reliable and accurate data provide the basis for sound decision making, biomarker assays must be validated in a manner that enables the creation of such data. The nature of biomarker measurements often precludes direct application of regulatory guidelines established for clinical diagnostics or drug bioanalysis, and future guidance on biomarker assay validation should therefore be adaptable enough that validation criteria do not stifle creative biomarker solutions.

Biological Assay↗
PubMed1995

Opportunities for the development and use of biomarkers.

Limitations in understanding the relationship between occupational and environmental exposures and disease present opportunities for using biological markers to fill gaps in knowledge. Three situations can be identified that could foster the development and use of biomarkers, where epidemiological evidence is (1) definitive, (2) equivocal, and (3) lacking. When there is clear epidemiological evidence of disease risk given an exposure, biomarkers could be used to identify high- and low-risk subsets of a cohort that might benefit from differential practices such as counseling about job risks, varying frequency and intensity of medical surveillance, and using protective equipment. Biomarkers could also be used to test the effectiveness of environmental controls. Assessment of blood lead in bridge workers and purified protein derivative (PPD) testing in health care workers illustrates biomarkers that have been used to evaluate control efforts. When epidemiological evidence is equivocal, a broad and consistent database on intermediate biomarkers in the path between exposure and disease could provide a compelling case as to whether a substance should be treated as hazardous. The case of ethylene oxide illustrates this situation: the epidemiological evidence of risk of lymphohematopoietic cancer is equivocal but there is an informative database on genetic and cytogenetic changes in various species consistent with carcinogenicity. Biomarker data also can be used to assist in the interpretation of inconclusive epidemiological information as is illustrated in the case of styrene where markers provide a mechanistic rationale for the epidemiologic findings. When there is little or no epidemiological evidence of risk in an exposure situation, such as around hazardous waste operations or with new technologies, biological markers can serve as early warning indicators of exposure or risk. In such cases it is important to have an underlying biological theory and an appropriate epidemiological study design if the principal results are to be of value in indicating risk and preventing disease.

Biomarkers↗
PubMed2002

Functional foods and food supplements for athletes: from myths to benefit claims substantiation through the study of selected biomarkers.

The development of the sports food market and industrial involvement have led to numerous nutritional studies to define the type of nutrients that are most suited to support energy metabolism, fluid balance and muscle function. The key question in many of these studies was: 'Does the product lead to a significant product/consumer benefit that can be used as a claim on the package?' New methods and techniques have been developed, partly with sponsorship of the food industry, with the goal of measuring the effects of specific nutrients and supplements on athletic performance and metabolism. In line with this development, a wide variety of supplements and sports foods/drinks labelled with various performance or health benefit statements have been launched on the sports nutrition market. Although a variety of products have been tested clinically, there are also many products on the market with benefit claims that cannot be supported by sound nutritional and sports physiological science. The current short review highlights some of the methods and biomarkers that are used to substantiate product/consumer benefit claims for foods and drinks that are marketed as functional foods for athletes.

Biomarkers↗
PubMed1990

Can an index of aging be constructed for evaluating treatments to retard aging rates? A 2,462-person study.

Biomarkers of aging are needed to evaluate proposed treatments to retard aging rates. At present, the only validated biomarker of aging is maximum life span, which remains impractical for human use. Identification of other biomarkers awaits development of a method of biomarker validation. This paper outlines an approach for this purpose intended for selecting biomarkers usable in humans. Prospective biomarkers are validated and weighted according to their correlation with interventions that, in healthy individuals, influence life span, namely mortality risk factors. A general mathematical method is presented for combining biomarker scores into an index of aging rate. This method addresses problems encountered with the traditional (multiple regression) method of calculating biological age and develops an index termed standardized biological age, SBA. In applying the method to 2,462 office workers, SBA, based on 12 physiological tests under investigation as biomarkers of aging, was found to depend on most of 17 surveyed dietary, exercise, life style, and geographical risk factors for mortality or health, suggesting that many risk factors predict rates of common functional declines with age. The 12 candidate biomarkers of aging in this study differed widely in validity according to the criterion employed. The approach holds promise for assembling an experimentally useful battery of biomarkers of aging.

Adult↗
PubMed2003

Microbial community structure in biofilms and water of a drinking water distribution system determined by lipid biomarkers.

The development of microbial communities in biofilms of a drinking water distribution system was monitored, and compared to the microbial communities in water. The microbial communities were studied by phospholipid fatty acid (PLFA) profiles. In drinking water samples the most common PLFAs, with the proportion of 60.9%, were monoenoic fatty acids, such as 16:1omega7c and 18:1omega7c, indicating high abundance of gram-negative bacteria. Instead, in biofilm samples saturated fatty acids, such as 16:0 and 18:0, indicating general biomass, accounted for 54.9-78.4% of the total PLFAs. The proportions of monoenoic fatty acids in biofilm increased from 11.5% to 31.2% with water aging from 22 h to 62 h in the distribution system. In conclusion, water aging affected the structure of microbial communities in biofilms, and the microbes in water differed from those in biofilms. These differences might also reflect the differences in the physiological state of the microbes, which is influenced by water chemistry and by the growth environment, i.e. water or biofilm.

Bacteria↗
PubMed1995

Molecular biomarkers for aflatoxins and their application to human liver cancer.

The rationale for developing molecular biomarkers to monitor and assess risk from human exposure to aflatoxins have been justified by the association of these carcinogens with human liver cancer, a disease that causes at least 250000 deaths world-wide each year. The goal of our research has been the development of aflatoxin biomarkers based upon the knowledge of the biochemistry and toxicology of aflatoxins gleaned from both experimental and human studies. These biomarkers have been subsequently utilized in experimental chemoprotection models to provide data on the modulation of these markers under different situations of disease risk. Several of the aflatoxin specific biomarkers have been validated in epidemiologic studies and are now available to use as intermediate biomarkers in chemoprotection trials. This systematic approach provides encouragement for preventive interventions and should serve as a template for the development, validation and application of other chemical-specific biomarkers to cancer or other chronic diseases.

Aflatoxins↗
PubMed2026

Antibody-drug conjugates in selected solid tumours: a position statement update based on findings from the third workshop held by the ETOP IBCSG Partners Foundation.

The European Thoracic Oncology Platform (ETOP) International Breast Cancer Study Group (IBCSG) Partners Foundation initiated a series of workshops for experts to review current evidence and offer recommendations to guide future antibody-drug conjugate (ADC) research. Here, we summarise key findings from the third workshop, which included experts in various solid tumours, basic/translational research scientists and pharmaceutical industry representatives. Recent positive phase III trial data have further incorporated ADCs into the standard of care [e.g. lung: sacituzumab tirumotecan; breast: trastuzumab deruxtecan (T-DXd), sacituzumab govitecan, datopotamab deruxtecan; muscle-invasive bladder cancer: enfortumab vedotin; ovarian cancer: mirvetuximab soravastine; cervical cancer: tisotumab vedotin]. Thus, research priorities must be tailored according to tumour type, potentially focussing initially on settings where ADCs could replace chemotherapy. Many phase III ADC trials have been initiated based on positive phase I data and although these trials are larger than those conducted historically, prespecified criteria (e.g. patient numbers and magnitude of efficacy) should be met to justify proceeding directly to phase III. Importantly, although several ADCs have been successfully developed without mandatory biomarker selection, biomarker-driven ADC development enables rational patient selection, as illustrated by multiple ADCs (e.g. T-DXd, mirvetuximab soravtansine and telisotuzumab vedotin). The identification, development and validation of predictive biomarkers are therefore essential, particularly given several critical nuances, including the algorithms used to assess biomarker status and the type of specimen analysed, all of which may be influenced by temporal and spatial heterogeneity. Additional ADC research priorities include the optimisation of ADC constructs to enhance efficacy/tolerability and the identification of reliable ADC targets, including work to elucidate attributes of already-identified targets. Finally, considering the vast amount of ADC-related data being generated, artificial intelligence could be leveraged to analyse combined datasets and generate composite biomarkers, including tumour histology, optimal target expression thresholds, molecular alterations and activated pathways affecting payload activity and target function, to accelerate research.

Humans↗
PubMedDate not supplied

Development of a biomarker-based index for assessing the ecotoxic potential of aquatic sites.

The use of biochemical or physiological measurements as indicators of ecotoxicity is under constant development and has the advantage of delineating effects before the appearance of disease. However, these biomarkers are often part of a battery of tests, and it is difficult to integrate them together to gain an overall view of an organism's health. The aim of this study was to develop an index that could integrate the data derived from a battery of biomarkers for application to both spatial and temporal studies. Mya arenaria clams were collected at different sites along the Saguenay Fjord (Quebec, Canada). Six biomarkers were measured: metallothioneins, DNA strand breakage, lipid peroxidation, vitellin-like proteins, phagocytosis, and non-specific esterase activity in haemocytes. A biomarker index was obtained by summing the biomarker values expressed in term of classes. Classes were determined by a distribution-free approach derived from the theory of rough sets. The results of the spatial study show that the index values discriminated well between contaminated and uncontaminated sites. The highly polluted sites had the highest index values (18 compared with a reference value of 14). In the temporal study, the index was also able to highlight possible contamination-induced alterations, even though the interpretation of temporal variation is complicated by natural variations occurring throughout the year. A control chart approach is proposed for determining contaminated sites in both spatial and temporal surveys.

Animals↗
PubMed2005

In vivo measurement of bone aluminium: recent developments.

A biomarker of aluminium accumulation in the human body can play a valuable role in determining health effects of chronic aluminium exposure, complementing other human and environmental monitoring data. In vivo neutron activation provides such a non-invasive biomarker. To date, the best in vivo neutron activation system used thermalised neutrons from a nuclear reactor at Brookhaven National Laboratory, which suffered only slightly from interference from other elements, primarily phosphorus, and from the disadvantage of restricted accessibility. At McMaster, we use a nuclear reaction on an accelerator to select neutron energy, which eliminates the interferences. Spectral decomposition analysis improved sensitivity. A new 4pi detection system also enhanced sensitivity. Together these improvements yield a minimum detection limit of 0.24 mgAl in a hand, slightly better than at Brookhaven and equivalent to "normal" levels. Further improvements should result from a new irradiation cavity and from using a higher proton current on the accelerator to shorten irradiation times. The system is now ready for pilot human studies.

Aluminum↗
PubMed2002

Cancer biomarkers: easier said than done.

BACKGROUND: Biological and technical advances have led to greatly increased research and development of cancer biomarkers. This overview lists some of the challenges and barriers to developing novel effective cancer biomarkers and enablers to facilitate cancer biomarker development. METHODS: Current scientific literature regarding development of biomarkers for cancer and other diseases was reviewed. RESULTS: Challenges to developing cancer biomarkers include better understanding of biological heterogeneity, including host/tumor heterogeneity; analytical factors, such as interferences and analytical sensitivity; clinical pathologic factors, such as current histopathologic standards; and health service and market factors. More standardized biomarker definitions, standardization of cancer biology terminology, and high-quality reference materials (specimen and clinical data repositories) were identified as factors required to support advances in cancer biomarkers. CONCLUSIONS: With the above enablers, novel cancer biomarkers may be useful, both for assessing early and established neoplasia more precisely and for contributing data toward development of novel practical concepts regarding cancer biology.

Biomarkers, Tumor↗
PubMed2007

Comparison of pancreas juice proteins from cancer versus pancreatitis using quantitative proteomic analysis.

OBJECTIVES: Pancreatitis is an inflammatory condition of the pancreas. However, it often shares many molecular features with pancreatic cancer. Biomarkers present in pancreatic cancer frequently occur in the setting of pancreatitis. The efforts to develop diagnostic biomarkers for pancreatic cancer have thus been complicated by the false-positive involvement of pancreatitis. METHODS: In an attempt to develop protein biomarkers for pancreatic cancer, we previously use quantitative proteomics to identify and quantify the proteins from pancreatic cancer juice. Pancreatic juice is a rich source of proteins that are shed by the pancreatic ductal cells. In this study, we used a similar approach to identify and quantify proteins from pancreatitis juice. RESULTS: In total, 72 proteins were identified and quantified in the comparison of pancreatic juice from pancreatitis patients versus pooled normal control juice. Nineteen of the juice proteins were overexpressed, and 8 were underexpressed in pancreatitis juice by at least 2-fold compared with normal pancreatic juice. Of these 27 differentially expressed proteins in pancreatitis, 9 proteins were also differentially expressed in the pancreatic juice from pancreatic cancer patient. CONCLUSIONS: Identification of these differentially expressed proteins from pancreatitis juice provides useful information for future study of specific pancreatitis-associated proteins and to eliminate potential false-positive biomarkers for pancreatic cancer.

Biomarkers, Tumor↗
PubMed2003

Development of a urinary biomarker of human exposure to deoxynivalenol.

Deoxynivalenol (DON) is a mycotoxin frequently found as a contaminant of cereal crops and may be etiologically associated with adverse health effects in developing countries where considerable quantities of contaminated crops are consumed. We investigated the metabolism of DON in rats as a basis to establish methodology for a candidate biomarker of human exposure to this toxin and tested this methodology on urine samples from a potentially highly exposed population. Sprague-Dawley rats received a single dose of [14C]DON (5.0+/-0.1 mg/kg body weight, 5.5+/-0.1 microCi/kg) and the distribution of DON in body fluids was investigated over 72 h. DON and its metabolites were detectable in the plasma of rats with the highest levels at 8 h, at which time approximately 9% was bound to plasma protein. A total of 37% of the administered DON was excreted in the urine and DON-glucuronide was implicated as the major urinary metabolite based on reverse-phase HPLC analysis of beta-glucuronidase- and sulphatase-treated samples. An immunoaffinity column (IAC)-HPLC method was subsequently developed to measure urinary metabolites, with a view to establishing a urine-based human biomarker. Urine samples were collected from female inhabitants of Linxian County, China, a high risk region for oesophageal cancer (OC) and an area of potentially high DON exposure, and Gejiu, a low risk region in China. DON was detected in all 15 samples following beta-glucuronidase treatment and IAC enrichment with the identity of DON being confirmed by mass spectrometry. The mean levels of DON from the suspected high and low exposure regions of China were 37 ng/ml (range 14-94 ng/ml) and 12 ng/ml (range 4-18 ng/ml), respectively. This is estimated to correspond to daily exposures of 1.1-7.4 microg/kg/day and 0.3-1.4 microg/kg/day, respectively. This is the first reported measurement of a urinary biomarker for DON in both animals and humans and should facilitate epidemiological studies of disease associations with this mycotoxin.

Animals↗
PubMed2026

PRDX1 as a novel urinary biomarker for bladder cancer: Development of an integrated fiber optic sensing platform.

In this study, integrated proteomic and transcriptomic analyses identified peroxiredoxin 1 (PRDX1) as a novel urinary biomarker for bladder cancer (BC). PRDX1 was significantly upregulated in BC tissues and was associated with poorer overall survival. In vitro experiments further demonstrated that PRDX1 promotes malignant phenotypes of BC cells, including proliferation, migration, and invasion. Silencing PRDX1 in BC cells significantly reduced the invasiveness and proliferation ability.To address the clinical need for rapid and non-invasive detection, we developed an innovative optical fiber biosensor based on surface plasmon resonance (SPR) technology for the quantitative detection of urinary PRDX1. The biosensor exhibited excellent analytical performance, including high sensitivity (limit of detection: 0.06 ng/mL), a wide linear range (0-25 ng/mL), rapid response (∼14 s), as well as good stability and selectivity. In clinical validation involving 97 BC patients and 30 healthy controls, the biosensor demonstrated outstanding diagnostic performance, with an area under the receiver operating characteristic curve (AUC) of 0.91 and an overall diagnostic accuracy of 86.6%, outperforming conventional enzyme-linked immunosorbent assay (ELISA). Collectively, this study not only identifies PRDX1 as a promising biomarker for non-invasive diagnosis and prognostic evaluation of BC, but also establishes an efficient SPR-based optical fiber sensing platform, providing new insights into both clinical detection and the functional role of PRDX1 in BC progression.

Humans↗
PubMed1995

Evidence from cancer intervention and biomarker studies and the development of biochemical markers.

Evidence from intervention trials with vitamins E and C and beta-carotene are reviewed as well as evidence from trials that have used intermediate endpoints with a special emphasis on biomarkers of cancer of the colorectum. The methodologic issues that require resolution before a second generation of clinical trials are launched to assess the efficacy of these antioxidants in the prevention of cancer are identified. Specific concerns regarding the validation of pathologic biomarkers of cancer and biochemical markers of mechanism of action for the antioxidants are discussed. Cellular proliferation indexes in the colon are used as an example of pathologic biomarkers for cancer and the measurement of plasma and tissue malondialdehyde concentrations is used as an example of problems with the development of biochemical markers of oxidative stress that can be used in prevention trials. The use of DNA oxidation products as promising biomarkers is also discussed.

Antioxidants↗
PubMedDate not supplied

Molecular imaging in drug discovery and development: potential and limitations of nonnuclear methods.

Noninvasive conventional imaging methods are established technologies in modern drug discovery and development providing valuable morphological, physiological, and metabolic information to characterize disease phenotypes, to evaluate the efficacy of therapy and to identify and develop potential biomarkers for clinical drug evaluation. The development of target-specific or molecular imaging has added a new dimension: molecular events such as the target expression, the drug-target interaction, or the activation of signal transduction pathways can be studied in the intact organism with high spatial and temporal resolution. Molecular imaging is inherently a multimodality approach. In this article, we review the role of molecular imaging for drug discovery and development focusing on nonnuclear imaging methods, i.e., magnetic resonance imaging (MRI) and optical imaging techniques based on fluorescence and bioluminescence readouts. Examples discussed are direct visualization of target expression using target-specific ligands or reporter genes, pathway imaging, and cell-trafficking studies.

Animals↗
PubMedDate not supplied

Application of biomarkers in the clinical development of new drugs for chondroprotection in destructive joint diseases: a review.

Emerging evidence supports the concept that biochemical markers are clinically useful non-invasive diagnostic tools for the monitoring of changes in cartilage turnover in patients with destructive joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA). Epidemiological studies demonstrated that measurements of different degradation products of proteins in the extracellular matrix of hyaline cartilage in urine or serum samples are (1) increased in OA or RA patients compared with healthy individuals, (2) correlate with disease activity, and (3) are predictive for the rate of changes in radiographic measures of cartilage loss. The present review provides an updated list of available biomarkers and summarize the research data arguing for their clinical utility. In addition, it addresses the question whether or not the monitoring of biomarkers during different treatment modalities could be a useful approach to characterize the chondro-protective effects of approved and candidate drugs. Finally, it briefly reviews the in vitro/ex vivo experimental settings - isolated chondrocyte cultures and articular cartilage explants - that can assist in the verification of novel markers, but also studies assessing direct effects of drug candidates on chondrocytes. Collectively, biomarkers may acquire a function as established efficacy parameters in the clinical development of novel chondro-protective agents.

Arthritis, Rheumatoid↗
PubMed2003

Desmosterol: a biomarker for the efficient development of 20,25-diazacholesterol as a contraceptive for pest wildlife.

20,25-Diazacholesterol is being evaluated as a contraceptive for the nonlethal control of avian and mammalian wildlife pests. The identification of an analyte in blood which was highly correlated with absorbed dose and efficacy is valuable for determining effective formulations and dosing variables. Such an analyte or biomarker is also valuable for determining the percentage of pest populations that consume an effective dose of the active ingredient in the field. HPLC analyses of blood collected from dosed animals failed to detect 20,25-diazacholesterol but indicated that levels of free cholesterol and related compounds were affected by 20,25-diazacholesterol absorption. The greatest percent change in chromatographic peak area associated with 20,25-diazacholesterol administration was observed for desmosterol, a cholesterol precursor. 20,25-Diazacholesterol appeared to block the conversion of desmosterol to cholesterol, resulting in an elevated concentration of the precursor. The elevation of blood desmosterol levels is being used as an indicator of 20,25-diazacholesterol absorption and to facilitate the development of a 20,25-diazacholesterol-based contraceptive for pest wildlife.

Animals↗
PubMed2006

Pyrethroid insecticides: advances and challenges in biomonitoring.

Pyrethroid insecticides have a wide variety of applications throughout the world. They are structurally diverse chemicals that are synthetically derived from naturally occurring pyrethrin insecticides. Significant advances in analytical chemistry have led to the development of biomarkers of exposure to pyrethroids, and these methods are currently being applied to study exposure in the general population. This article reviews the chemistry and toxicology of pyrethroid insecticides, with an emphasis on the development of biomarkers to assess environmental exposure. Future challenges in the application of these biomarkers in epidemiological studies are explored, as is a need for improved understanding of the toxicokinetics of pyrethroids in humans.

Biomarkers↗