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PubMed2000

Biomarkers as surrogates for cancer development.

Biomarkers are routinely applied in the management of chronic diseases to reduce morbidity and mortality through early diagnosis, as well as to assess the necessity for, and responsiveness to, applied interventions. Biomarkers yield mechanistic insights into layers of biologic organization from molecule to organelle, to cell, and finally to cellular organization and tissue. A step-wise approach to the development of tissue-based biomarkers is presented. These biomarkers may serve as molecular targets for scientific inquiry and intervention, as well as approvable endpoints for clinical trials.

Biomarkers, Tumor↗
PubMed2007

Using exposure-response and biomarkers to streamline early drug development.

Biomarkers (BMs) are biological measures of PD drug effects or disease markers that may represent clinically significant patient outcomes, either efficacy or toxicity. Their use in drug development, especially as an integral part of PK/PD modeling, has become a popular strategy for optimizing development time and resources. This approach supports quantitative integration of information across different species and throughout the clinical phases I-III. If the BM is based on the mechanism of action (MOA) of the drug, it is expected to follow an exposure-response relationship (E-R). If it is also involved in causal pathways in the pathophysiology of the disease (POD), it may become a surrogate marker (SM). SMs allow prediction of clinical outcomes for different dosing regimens of drug candidates and patient individualization of treatment in clinical practice. Appropriate evaluation of BMs by mechanistic, epidemiological, and clinical pharmacology studies as part of the drug development process allow scientists to establish clinically relevant ER. In early drug development, known ERs for BMs facilitate translation of in vitro findings to in vivo consequences, interspecies PK/PD comparisons, and streamlining of dose-finding phase I and II studies, as well as assessment of new dosing regimen candidates for their likely clinical efficacy and safety, extrapolation of clinical study results to special populations (e.g., pediatrics), and interpretation of exposure differences found in food, drug interaction and special populations studies. Recently, two novel BMs, namely, P50, a measure of ex vivo/in vitro whole blood oxygen affinity and S(pO2), i.e., in vivo pulse oximetry, were used in the development of an allosteric synthetic hemoglobin modifier (SAM), efaproxiral, as PD endpoints; these BMs are based on the MOA of SAMs. Early use of these BMs established excellent in vitro/in vivo PK/PD correlations, appropriate interspecies PK and PD scaling as well as PD-guided phase I and II dose-finding studies. This approach allowed appropriate translation of in vitro and preclinical information along with early identification of sources of PK/PD variability. Frontloading drug development with the identification and use of mechanism-based (MOA/POD) BMs constitutes a rational strategy to quantitatively integrate PK/PD information and optimize dose finding.

Allosteric Site↗
PubMed2003

Clinical biomarkers in drug discovery and development.

Biomarkers enable the characterization of patient populations and quantitation of the extent to which new drugs reach intended targets, alter proposed pathophysiological mechanisms and achieve clinical outcomes. In genomics, the biomarker challenge is to identify unique molecular signatures in complex biological mixtures that can be unambiguously correlated to biological events in order to validate novel drug targets and predict drug response. Biomarkers can stratify patient populations or quantify drug benefit in primary prevention or disease-modification studies in poorly served areas such as neurodegeneration and cancer. Clinically useful biomarkers are required to inform regulatory and therapeutic decision making regarding candidate drugs and their indications in order to help bring new medicines to the right patients faster than they are today.

Alzheimer Disease↗
PubMed2000

Optimizing the use of biomarkers, surrogate endpoints, and clinical endpoints for more efficient drug development.

Biomarkers and surrogate endpoints are critical to the future of efficient drug development. Definitions, a conceptual model, and a conceptual framework for validating and bridging biomarkers to clinical endpoints are provided in this presentation. In addition, a few examples are provided to support the development concept. Poor correlation between a biomarker and its clinical endpoint may result from (1) poor measurement of one or both, (2) selection of an inappropriate biomarker, or, more important, (3) use of an inappropriate clinical endpoint. Pharmacokinetic/pharmacodynamic (PK/PD) modeling output can be no better than biomarkers or surrogate endpoints used for the modeling. As we increase our understanding of biomarkers, surrogate markers, and the mechanistic basis for the processes of interest, biomarker and surrogate endpoint predictive power will no longer be an issue and PK/PD modeling inputs and outputs will improve.

Biomarkers↗
PubMedDate not supplied

The Agency for Toxic Substances and Disease Registry's role in development and application of biomarkers in public health practice.

An overview of the Agency for Toxic Substances and Disease Registry's (ATSDR) biomarker program is presented in the context of the paradigm for biomarkers developed by the National Research Council (NRC, 1987, 1991). The status and projected utility of four biomarker studies conducted by NRC and sponsored by ATSDR, the Environmental Protection Agency (EPA), and the National Institute of Environmental Health Sciences (NIEHS) are discussed. These studies include a review of relevant research on biomarkers for specific toxicologic end points, including reproductive toxicology, pulmonary toxicology, neurotoxicology, and immunotoxicology. Also, the scope of related research on exposure characterization being conducted by the ATSDR-sponsored research program at Rutgers University is reviewed. The potential impact of biomarkers on public health assessments and on the range of ATSDR programs is described. Specifically, the role of biomarkers in dose reconstruction, in ATSDR's health studies program, and in the emerging field of molecular epidemiology is reviewed. In addition, future directions and research needs are addressed.

Animals↗
PubMed2004

Development of biomarkers based on diet-dependent metabolic serotypes: practical issues in development of expert system-based classification models in metabolomic studies.

Dietary restriction (DR)-induced changes in the serum metabolome may be biomarkers for physiological status (e.g., relative risk of developing age-related diseases such as cancer). Megavariate analysis (unsupervised hierarchical cluster analysis [HCA]; principal components analysis [PCA]) of serum metabolites reproducibly distinguish DR from ad libitum fed rats. Component-based approaches (i.e., PCA) consistently perform as well as or better than distance-based metrics (i.e., HCA). We therefore tested the following: (A) Do identified subsets of serum metabolites contain sufficient information to construct mathematical models of class membership (i.e., expert systems)? (B) Do component-based metrics out-perform distance-based metrics? Testing was conducted using KNN (k-nearest neighbors, supervised HCA) and SIMCA (soft independent modeling of class analogy, supervised PCA). Models were built with single cohorts, combined cohorts or mixed samples from previously studied cohorts as training sets. Both algorithms over-fit models based on single cohort training sets. KNN models had >85% accuracy within training/test sets, but were unstable (i.e., values of k could not be accurately set in advance). SIMCA models had 100% accuracy within all training sets, 89 % accuracy in test sets, did not appear to over-fit mixed cohort training sets, and did not require post-hoc modeling adjustments. These data indicate that (i) previously defined metabolites are robust enough to construct classification models (expert systems) with SIMCA that can predict unknowns by dietary category; (ii) component-based analyses outperformed distance-based metrics; (iii) use of over-fitting controls is essential; and (iv) subtle inter-cohort variability may be a critical issue for high data density biomarker studies that lack state markers.

Algorithms↗
PubMedDate not supplied

Development and use of biomarkers in oncology drug development.

Successful development and use of biomarkers will improve the productivity of oncology drug development. Recognition of the importance of biomarkers for speeding drug development is reflected in the precise definitions and concepts proposed by an NIH Working Group to standardize terminology and promote a more coherent and systematic approach to the development and use of biomarkers. Potential clinical biomarkers of drug efficacy are often identified through pre-clinical studies or basic research. Identification of potential biomarkers for use in oncology is moving rapidly forward through continuing advances in clinical imaging technologies, especially molecular and functional imaging. Other rapid advances are a product of the growing availability of new scientific reagents for established technologies and of high-throughput genomic and proteomic technologies that can generate hundreds of potential biomarkers for further evaluation. In certain cases, conventional clinical diagnostic techniques or assays can be adapted for use in pre-clinical models to evaluate their ability to serve as biomarkers for predicting clinical responses to new drug candidates. Evaluation (pre-clinical and clinical) of a potential biomarker is often the longest stage of biomarker development, and standards for evaluation or validation depend on the intended use and stage of clinical development. Biomarkers verified for use in preclinical studies can be used to help select appropriate animal models and lead compounds. Biomarkers verified for use in clinical trials can confirm a drug's pharmacological or biological mechanism of action, guide protocol design, aid patient and dose selection, and help to minimize safety risks. Oncology drug development can be optimized by using a tiered set of clinical biomarkers that predict compound efficacy and safety with increasing confidence at each rise in tier thereby aiding corporate decision-making about advancing compounds. In oncology, a special class of extensively evaluated biomarkers of efficacy (surrogate endpoints) that generally correlate with desired clinical outcomes can be used as a basis for corporate decisions as well as for gaining accelerated provisional regulatory approval of a drug.

Animals↗
PubMed1994

Validity of lead exposure markers in diagnosis and surveillance.

Extensive research has been devoted to the development of biomarkers of environmental and occupational exposure to lead (Pb). This body of work can serve as a paradigm for biomarker development for other chemical exposures. Early efforts focused on indirect measurements of exposure by analyzing precursors and enzymes of a biosynthetic pathway (heme) in blood and urine. However, the direct measurement of Pb in blood has become increasingly simple and reliable and is now widely accepted for pediatric surveillance programs, in part because of known associations of Pb with adverse health outcomes. Other markers of exposure include measurements of Pb in important compartments: bone Pb, tooth Pb, and chelatable Pb. In addition, the technique of stable isotope dilution is available, since Pb exists in numerous nonradioactive isotopic forms. The strengths and weaknesses of all Pb biomarkers for confirming a diagnosis or for epidemiologic research vary widely depending upon the hypothesis under investigation.

Biomarkers↗
PubMed1995

A phase II chemoprevention trial design to identify surrogate endpoint biomarkers in breast cancer.

Surrogate biomarkers for risk assessment and efficacy of potential chemopreventive agents are needed to improve the efficiency and reduce the cost of conducting chemoprevention trials. In addition to criteria of sensitivity, specificity, quantifiability, and reproducibility applicable to most potential biomarkers, there are additional specific constraints in developing biomarkers for specific organ sites. In the case of breast tissue, these difficulties include lack of a consensus on the nature of premalignant lesions and the histologic criteria used to define them; even when such a consensus can be evolved, there are limitations in visualizing such lesions without invasive biopsies. Also, knowledge of specific genetic and biochemical changes in premalignant lesions is limited. In addition, the physiology of breast tissue is cyclic, no proven, relevant markers can be studied in a randomly obtained needle aspirate. The earliest determinate lesion that can be recognized in breast tissue is ductal carcinoma in situ (DCIS). At the University of Texas M.D. Anderson Cancer Center, we have initiated a study to develop biomarkers for tamoxifen and 4-hydroxyphenylretinamide by administering one or both of these drugs to women with DCIS or small invasive lesions in the interval between the initial diagnostic core biopsy and definitive surgery. The treatment is to be administered for 2-4 weeks. Proposed biomarkers to be studied include: (a) markers associated with neoplastic phenotypes, e.g., excessive proliferation, alternations of nuclear morphology and angiogenesis; (b) proteins likely to be required for response to the putative chemopreventive agents, e.g., estrogen receptor, nuclear retinoid receptors; (c) markers indicative of intact downstream response pathways, e.g., progesterone receptors; (d) oncogenes and tumor suppressor genes regulated by the proposed chemopreventive agents, e.g., neu, TGF-beta; and (e) potential novel markers of genetic instability that could be studied in randomly obtained needle aspirates, i.e., random chromosomal gains and losses in high risk mammary epithelium. The experience gained in designing and conducting this trial is expected to facilitate development of future chemoprevention trials of breast, as well as other organ site cancers.

Anticarcinogenic Agents↗
PubMed1999

Fumonisin contamination of food: progress in development of biomarkers to better assess human health risks.

Fumonisins, fungal toxins produced by Fusarium moniliforme, contaminate maize based foods and feeds throughout the world. They cause liver and kidney toxicity in animals in addition to leukoencephalomalacia in horses and pulmonary edema in pigs. Fumonisin B(1) is carcinogenic in rats and mice. Ecological studies have linked consumption of fumonisin contaminated maize with oesophageal cancer in human populations in South Africa and China. This review discusses the potential health risks for people exposed to the fumonisins, and describes how mechanistic studies of toxicity in animal models have allowed the development of putative biomarkers of fumonisin exposure at the individual level. The requirements for an applicable biomarker include sample availability as well as a high specificity and sensitivity for the exposure of interest. Most environmental toxic insults involve complex exposures both to other toxins and to infections; these confounding factors need to be considered in assessing both the validity of the biomarker and the exposure-disease associations. Fumonisins can be detected in the urine of animals in feeding studies but the sensitivity of the current methodology means only highly exposed people could be monitored. Mechanistic studies indicate that ceramide synthase, an enzyme involved in sphingolipid synthesis, is one cellular target for fumonisin toxicity and carcinogenicity, and this disruption to sphingolipid metabolism increases the ratio of two sphingoid precursors, sphinganine and sphingosine. The altered ratio has been observed in tissues, serum and urine for a number of animal models suggesting it as a good candidate marker of fumonisin exposure. Despite development of analytical methods to measure this biomarker there have been no studies to date correlating it to fumonisin intake in people. Given the toxic effects of fumonisins in animals and the widespread human exposure, which has been calculated to reach 440 micrograms kg(-1) body weight day(-1) in a population consuming high quantities (460 g day(-1)) of contaminated maize, then the development of biomarkers and their application in epidemiological studies should be a priority for research on these toxins.

Animals↗
PubMed2005

Developing drugs for cognitive impairment in schizophrenia.

There are strong data suggesting that improvement in the cognitive impairment associated with schizophrenia will contribute to enhanced functional outcomes for patients with this illness. Measurement and Treatment Research to Improve Cognition in Schizophrenia was established to provide a pathway for developing and registering potential cognitive-enhancing agents for this condition by addressing issues related to the content of the cognitive assessment battery and the clinical design features to be used in registration studies. This article examines key challenges related to the actual clinical development of cognitive-enhancing agents. These challenges include improving the probability of technical success and attrition rates of candidate molecules, establishing better animal models of human cognition, and developing biomarkers to decrease development costs and increase the speed of the clinical discovery process. Biomarkers are important for molecular target validation, dose selection, surrogate end points, and population segmentation. Examples of approaches for the development of agents for cognitive impairment associated with schizophrenia are discussed. It is concluded that close collaboration among academia, the National Institutes of Health, regulatory bodies, and industry will be important to advance the goal of developing drugs for this important condition.

Animals↗
PubMed1995

Development of biomarkers of human exposure to carcinogens: the example of DNA-protein cross-links.

Biomarkers are considered to be more biologically informative than traditional methods and less prone to misclassification bias. However, new biomarkers are conceived in experimental laboratories and normally undergo extensive experimental in vitro and in vivo testing, usually without regard as to their potential use in humans. Whereas the epidemiologist had no role in the original development of the basic research idea leading to the initial formulation of a biomarker, the new biomarker or technical modification of an existing one are the product of observations in humans. The results of our field studies on DNA-protein cross-links (DPX) among chromate workers illustrates inherent difficulties in the process of development and validation of biomarkers.

Biomarkers↗
PubMedDate not supplied

[New effect biomarkers].

The major research goals for researchers developing biomarkers of effect are the development and validation of biomarkers that permit the prediction of the risk of disease in individuals and groups. One important objective is to prevent human cancer. This article reviews the most recent analytical methodologies, validation studies and field trials together with auditing and quality assessment of the necessary data based on scientific grounds. Consideration is given to new developments in the relatively young field of toxicogenomics, possibly leading to the identification of early changes that may lead to both cancer and non-cancer end points. Although the creation and development of reliable databases integrating information from genomic and proteomic research programmes should offer a contribution to the prediction of risks and prevention of diseases related to chemical exposure, the most promising future application of these technologies lies in the molecular diagnosis of diseases whose nosography will probably be redefined.

Biomarkers↗
PubMed2002

Effects of long-term nonylphenol exposure on gonadal development and biomarkers of estrogenicity in juvenile rainbow trout Oncorhynchus mykiss.

Environmental pollutants with estrogenic activity including nonylphenol (NP) have the potential to alter gonadal development and reproduction of wild fish. To investigate the estrogenic action of environmentally relevant concentrations of NP, rainbow trout (Oncorhynchus mykiss) were continuously exposed during the embryonic, larval and juvenile life stage to 1.05 and 10.17 microg/l NP for 1 year, and sexual differentiation, vitellogenin (VG), VG mRNA, and zona radiata protein (ZRP) expression were examined after that period. The applied NP concentrations did not affect mortality and hatching rates, and did not have an influence on the body weight of 1-year-old fish. No occurrence of testis-ova was observed and sex-ratios of NP exposed groups of fish were unchanged when compared with control groups. The induction of VG and ZRP expression was a more sensitive reaction to the presence of NP than the formation of testis-ova and the reversal of sex. Increased VG expression in trout liver occurred already at 1.05 microg/l NP, whereas VG mRNA levels, quantified by competitive RT-PCR, were not significantly elevated in NP exposed fish. ZRP contents were significantly higher at 10.17 microg/l NP. Since induction of VG did not occur in all fish exposed to 1 or 10 microg/l NP and ZRP induction did not occur in all fish exposed to 10 microg/l, some individuals may be more affected by exposure to NP than others. This study demonstrates that NP concentrations typically found in sewage treatment effluents and some rivers do not affect sexual differentiation in rainbow trout, but induce VG and ZRP expression in the liver of exposed fish.

Animals↗
PubMed2004

Development of biomarkers in multiple sclerosis.

Multiple sclerosis is a complex disease, as several pathophysiological processes (including inflammation, demyelination, axonal damage and repair mechanisms) participate in the disease process. Furthermore, as new pathological evidence reveals, these processes are not uniformly represented across patient populations but can selectively predominate in individual patients, thus contributing to the heterogeneity in phenotypic expression of the disease, its prognosis and response to therapies. While the armamentarium of available therapies for multiple sclerosis broadens, little is known about factors that predict treatment response in individual patients to a specific drug. More importantly, we are beginning to understand that, analogous to cancer therapy, the successful therapeutic strategy in multiple sclerosis might ultimately involve the combination of different therapeutics targeting several dominant pathophysiological processes. The development of these process-specific therapies will be impossible without the use of biomarkers that reflect the targeted process, can select patient population in which the targeted process is prevailing and can aid during the more rapid screening of therapeutic agents in the early phase of their development. This review summarizes the general concepts of biomarkers and their potential use as surrogate endpoints and tailors these concepts to specific applications in multiple sclerosis research.

Biomarkers↗
PubMed2004

Using molecular markers to predict outcome.

PURPOSE: Developing molecular tests to predict prostate cancer progression requires first defining meaningful clinical end points and defining strategies to take advantage of emerging technology. MATERIALS AND METHODS: The select relevant literature was reviewed concerning clinical trials, clinical prostate cancer nomograms, molecular biomarker development and molecular prostate cancer imaging. RESULTS: There is controversy regarding the use of prostate specific antigen or biochemical failure following prostatectomy or radiation therapy for clinically localized prostate cancer as a marker of progression. As a consequence, advances in prostate cancer biomarker development may require using population based cohorts or cases from clinical trials to identify meaningful associations. Whereas the discovery of novel candidate biomarkers was slow 5 to 10 years ago and often resulted from serendipity, advances in high throughput technologies have led to the identification of a large number of candidate genes. Strategies to identify candidate genes include the use of expression array analysis, single nucleotide polymorphism arrays (single nucleotide polymorphism chips), proteomics and bioinformatics. Monitoring the progression of prostate cancer has been limited to standard approaches such as computerized tomography or magnetic resonance imaging, which in general do not delineate the extent of disease. By carefully selecting novel prostate cancer biomarkers future work should allow in vivo monitoring of prostate cancer. This will represent a revolutionary advance in our ability to monitor prostate cancer progression and ultimately it may be one of the most important applications of cancer biomarkers. CONCLUSIONS: Emerging technology should allow us to analyze clinical prostate cancer trials with sufficient followup to help develop meaningful markers of prostate cancer progression.

Biomarkers, Tumor↗
PubMed2006

Proteomic analysis of individual human embryos to identify novel biomarkers of development and viability.

OBJECTIVE: To develop a method to analyze the proteome of individual human blastocysts and identify differentially expressed proteins prior to implantation. DESIGN: Experimental study. SETTING: Research environment. PATIENT(S): Couples undergoing infertility treatment donated with consent cryopreserved human cleavage-stage embryos for research. INTERVENTION(S): Individual embryos were extracted and analyzed by time-of-flight mass spectrometry. MAIN OUTCOME MEASURE(S): The protein expression profiles of individual embryos. RESULT(S): Differential protein expression profiles were observed between early and expanded blastocysts, as well as between developing blastocysts and degenerate embryos. Significantly, several up-regulated and down-regulated proteins were detected in degenerating embryos. A search in the protein databases highlighted several candidates, including an inhibitor of Tcf-4 (transcription factor mediating Wnt signaling) and an apoptotic protease-activating factor. CONCLUSION(S): This is the first study to successfully analyze the proteome of individual human embryos. This study has shown that protein expression profiles relate to morphology, with degenerating embryos exhibiting significant up-regulation of several potential biomarkers that might be involved in apoptotic and growth-inhibiting pathways.

Biomarkers↗