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PubMed2006

A strategic view on the use of pharmacodynamic biomarkers in early clinical drug development.

Early-phase clinical trials have traditionally focused on the safety, tolerability and pharmacokinetic properties of a therapeutic candidate, while questions regarding efficacy have been left unanswered until phase II clinical development. Although an understanding of all of these parameters is unarguably essential to the successful development of a drug candidate, this information is insufficient. Biomarkers are increasingly being used in early drug development to allow for the exploration of pharmacodynamic effects of targeted therapeutics before clinical signs and symptoms are evaluated. The trend of using pharmacodynamic biomarkers will continue and, ultimately, may enable these biomarkers to be used routinely to demonstrate the impact of a compound on the treatment of a disease, and to aid in the selection of therapeutic doses and regimens based on accurate measures of human physiological responses. Biomarkers are also beginning to be used to determine those patients who are most likely to respond to a therapeutic, and thereby improve treatment outcomes while avoiding the administration of a drug to individuals who are unlikely to benefit. This article describes a strategy that is being used to achieve these aims for biomarkers, and discusses how biomarkers can be used to identify information that can be applied back into to the drug discovery process.

Biomarkers↗
PubMed2005

Using imaging biomarkers to accelerate drug development and clinical trials.

There is increasing evidence that human medical imaging can help answer key questions that arise during the drug development process. Imaging modalities such as magnetic resonance imaging, computed tomography and positron emission tomography can offer significant insights into the bioactivity, pharmacokinetics and dosing of drugs, in addition to supporting registration applications. In this review, examples from oncology, neurology, psychiatry, infectious diseases and inflammatory diseases are used to illustrate the role imaging can play. We conclude with some remarks concerning new developments that will be required to significantly advance the field of pharmaco-imaging.

Animals↗
PubMed2002

Overview of biomarkers and surrogate endpoints in drug development.

There are numerous factors that recommend the use of biomarkers in drug development including the ability to provide a rational basis for selection of lead compounds, as an aid in determining or refining mechanism of action or pathophysiology, and the ability to work towards qualification and use of a biomarker as a surrogate endpoint. Examples of biomarkers come from many different means of clinical and laboratory measurement. Total cholesterol is an example of a clinically useful biomarker that was successfully qualified for use as a surrogate endpoint. Biomarkers require validation in most circumstances. Validation of biomarker assays is a necessary component to delivery of high-quality research data necessary for effective use of biomarkers. Qualification is necessary for use of a biomarker as a surrogate endpoint. Putative biomarkers are typically identified because of a relationship to known or hypothetical steps in a pathophysiologic cascade. Biomarker discovery can also be effected by expression profiling experiment using a variety of array technologies and related methods. For example, expression profiling experiments enabled the discovery of adipocyte related complement protein of 30 kD (Acrp30 or adiponectin) as a biomarker for in vivo activation of peroxisome proliferator-activated receptors (PPAR) gamma activity.

Adiponectin↗
PubMed2006

Brachyury, a crucial regulator of notochordal development, is a novel biomarker for chordomas.

Chordomas are malignant tumours that occur along the spine and are thought to derive from notochordal remnants. There is significant morphological variability between and within chordomas, with some showing prominent areas of chondroid differentiation. Our microarray data from a broad range of connective tissue neoplasms indicate that, at the transcriptional level, chordomas resemble cartilaginous neoplasms. Here we show that chordomas express many genes known to be involved in cartilage development, but they also uniquely express genes distinguishing them from chondroid neoplasms. The brachyury transcription factor, known to be involved in notochordal development, is only expressed by chordomas. Using a polyclonal antibody, we show that brachyury is expressed in the embryonic notochord and in all 53 chordomas analysed, labelling both chondroid and chordoid areas of these tumours. In contrast, the protein was not detected in over 300 neoplasms, including 163 chondroid tumours. Brachyury was not detected in the nucleus pulposus, arguing against the hypothesis that this tissue derives directly from the notochord. These data provide compelling evidence that chordomas derive from notochord and demonstrate that brachyury is a specific marker for the notochord and notochord-derived tumours.

Biomarkers, Tumor↗
PubMed2001

Surrogate end-point biomarkers in chemopreventive drug development.

Relevant and feasible surrogate end-points are needed for the evaluation of intervention strategies against cancer and other chronic, life-threatening diseases. Carcinogenesis can be viewed as a process of progressive disorganization. This process is characterized by the accumulation of genotypic lesions and corresponding tissue and cellular abnormalities, including loss of proliferation and apoptosis controls. Potential surrogate end-points for cancer incidence include both phenotypic and genotypic biomarkers of this progression. In the US National Cancer Institute chemoprevention programme, histological modulation of a precancer (intraepithelial neoplasia) has so far been the primary phenotypic surrogate end-point in chemoprevention trials. Additionally, high priority has been given to biomarkers measuring specific and general genotypic changes correlated with the carcinogenesis progression model for the targeted cancer (e.g., progressive genomic instability as measured by loss of heterozygosity or amplification at specific microsatellite loci). Other potential surrogate end-points include proliferation and differentiation indices, specific gene and general chromosome damage, cell growth regulatory molecules, and biochemical activities (e.g., enzyme inhibition). Serum biomarkers thought to be associated with cancer progression (e.g., prostate-specific antigen) are particularly appealing surrogate end-points because of accessibility. Potentially chemopreventive effects of the test agent may also be measured (e.g., tissue and serum estrogen levels in studies of steroid aromatase inhibitors). To establish chemopreventive efficacy, prevention of virtually all biomarker lesions, or of those lesions with particular propensity for progression, may be required. Ideally, the phenotype and genotype of any new or remaining precancers in the target tissue of chemopreventive agent-treated subjects would show less, and certainly no greater, potential for progression than those of placebo-treated subjects.

Anticarcinogenic Agents↗
PubMed2004

Causal models of leukaemia and lymphoma.

In this chapter, we apply the molecular epidemiological paradigm of biomarkers of exposure, early effect and susceptibility to causal models of leukaemia and lymphoma. The aim is to enhance the development of biomarkers for use in studying the causes of these haematopoeitic cancers in the general population. Two causal models of acute myeloid leukaemia are discussed in detail: chemotherapy-induced and benzene-induced acute myeloid leukaemia. Specific chromosomal changes found in acute myeloid leukaemia may serve as useful biomarkers of early effect in these models, and genetic variants in glutathione S-transferases, NQO1 and DNA-repair enzymes may serve as useful biomarkers of susceptibility. Several causal models of lymphoma exist in which biomarkers could be developed and validated. These include human immunodeficiency virus (HIV) immunosuppression, families with inherited disorders and workers exposed to petroleum products, pesticides or organochlorines. Biomarkers of early effect could include markers of DNA double-strand breaks and aberrant V(D)J recombination, and susceptibility may be related to polymorphisms in genes controlling DNA repair and immunological status. We predict that biomarkers of susceptibility will continue to be studied in the case-control format, perhaps in large pooled studies, but that for biomarkers of early effect, there will be a move away from the study of diseased populations to the study of individuals 'at risk' in the causal models described above.

Autoimmunity↗
PubMed2006

A robust statistical procedure to discover expression biomarkers using microarray genomic expression data.

Microarray has become increasingly popular biotechnology in biological and medical researches, and has been widely applied in classification of treatment subtypes using expression patterns of biomarkers. We developed a statistical procedure to identify expression biomarkers for treatment subtype classification by constructing an F-statistic based on Henderson method III. Monte Carlo simulations were conducted to examine the robustness and efficiency of the proposed method. Simulation results showed that our method could provide satisfying power of identifying differentially expressed genes (DEGs) with false discovery rate (FDR) lower than the given type I error rate. In addition, we analyzed a leukemia dataset collected from 38 leukemia patients with 27 samples diagnosed as acute lymphoblastic leukemia (ALL) and 11 samples as acute myeloid leukemia (AML). We compared our results with those from the methods of significance analysis of microarray (SAM) and microarray analysis of variance (MAANOVA). Among these three methods, only expression biomarkers identified by our method can precisely identify the three human acute leukemia subtypes.

Biomarkers↗
PubMed2005

Internet-based Profiler system as integrative framework to support translational research.

BACKGROUND: Translational research requires taking basic science observations and developing them into clinically useful tests and therapeutics. We have developed a process to develop molecular biomarkers for diagnosis and prognosis by integrating tissue microarray (TMA) technology and an internet-database tool, Profiler. TMA technology allows investigators to study hundreds of patient samples on a single glass slide resulting in the conservation of tissue and the reduction in inter-experimental variability. The Profiler system allows investigator to reliably track, store, and evaluate TMA experiments. Here within we describe the process that has evolved through an empirical basis over the past 5 years at two academic institutions. RESULTS: The generic design of this system makes it compatible with multiple organ system (e.g., prostate, breast, lung, renal, and hematopoietic system,). Studies and folders are restricted to authorized users as required. Over the past 5 years, investigators at 2 academic institutions have scanned 656 TMA experiments and collected 63,311 digital images of these tissue samples. 68 pathologists from 12 major user groups have accessed the system. Two groups directly link clinical data from over 500 patients for immediate access and the remaining groups choose to maintain clinical and pathology data on separate systems. Profiler currently has 170 K data points such as staining intensity, tumor grade, and nuclear size. Due to the relational database structure, analysis can be easily performed on single or multiple TMA experimental results. The TMA module of Profiler can maintain images acquired from multiple systems. CONCLUSION: We have developed a robust process to develop molecular biomarkers using TMA technology and an internet-based database system to track all steps of this process. This system is extendable to other types of molecular data as separate modules and is freely available to academic institutions for licensing.

Automation↗
PubMed1991

Fetal drug therapy: principles and issues.

The 1990s may revolutionize the care of the fetus and create new options in gene control, immunotherapy, and drug therapy not only to identify susceptible populations but to treat selectively that population without increasing the risk to the mother. Fetal therapy is a notable goal, even now somewhat within our grasp. No longer is the womb an isolated, forbidding environment, but it is accessible with such tools as magnetic resonance imaging, ultrasonography, CVS, Doppler, and sound clinical judgement. Current limitations in our understanding of the pharmacokinetics associated with these chemical temper our enthusiasm. The development of biomarkers for appropriate fetal drug therapy is to be encouraged, but also the development of fetal and maternal biomarkers that will assist the physician in actively avoiding inappropriate fetal drug therapy is necessary, whether dose or chemical dependent.

Biomarkers↗
PubMed1990

Development and application of biomarkers exploitable for human exposure monitoring.

The objectives, applications and limitations of laboratory methods for assessing human exposure to carcinogens are concisely discussed. The available technologies include cytological, cytogenetic and molecular analyses, somatic cell mutation, carcinogen-DNA or carcinogen-protein adducts, metabolic markers, and chemical or biological analyses of expired air, body fluids, and excreta.

Biomarkers↗
PubMed2006

Variable number of tandem repeats of TNF receptor type 2 promoter as genetic biomarker of susceptibility to develop invasive pulmonary aspergillosis.

Tumor necrosis factor alpha (TNF-alpha) and lymphotoxin alpha (LT-alpha) are pivotal mediators of inflammatory responses in fungal infection diseases. We hypothesized that polymorphisms in genes of these cytokines or their receptors might increase the susceptibility of hematologic patients to develop invasive pulmonary aspergillosis (IPA). One hundred two hematologic patients and 124 age-matched controls were enrolled in the study, and the following standard single nucleotide polymorphisms were investigated: TNF-alpha -308 and +489, LT-alpha +252 and Tumor Necrosis Factor Receptor 2 (TNFR2) +676. Variable number of tandem repeats (VNTRs) at position -322 of the TNFR2 gene were also studied. Genotypic and allelic frequencies were similar between patients and controls. IPA was diagnosed in 54 of the 102 patients according to consensus criteria published by the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group. TNF-alpha and LT-alpha polymorphisms were not associated with presence of IPA. Susceptibility to IPA was strongly associated with VNTR at position -322 in the promoter region of the TNR2 gene (p = 0.029) but was not associated with the presence of TNFR2 +676 polymorphism. A genetic difference in TNFR2 promoter VNTR may play a major role in susceptibility to IPA infection.

Aspergillosis↗
PubMed2000

Development of a novel biomarker of free radical damage in reperfusion injury after cardiac arrest.

In a porcine model of cardiopulmonary resuscitation (CPR), we investigated changes in the plasma levels of 8-iso-PGF(2alpha), a marker for oxidative injury, and 15-keto-dihydro-PGF(2alpha), an inflammatory response indicator during the post-resuscitation period after cardiac arrest. Twelve piglets were subjected to either 2 or 5 min (VF2 and VF5 group) of ventricular fibrillation (VF) followed by 5 min of closed-chest CPR. Six piglets without cardiac arrest were used as controls. In VF5 group, 8-iso-PGF(2alpha) in the jugular bulb plasma (draining the brain) increased four-fold. Jugular bulb 8-iso-PGF(2alpha) in the control group remained unchanged. The 15-keto-dihydro-PGF(2alpha) also increased four-fold in the VF5 group. Thus, 8-iso-PGF(2alpha) and 15-keto-dihydro-PGF(2alpha) measurements in jugular bulb plasma may be used as biomarkers for quantification of free radical catalyzed oxidative brain injury and inflammatory response in reperfusion injury.

Animals↗
PubMed2005

Pathways of myocyte death: implications for development of clinical laboratory biomarkers.

The recognition that cardiac myocytes die by multiple mechanisms and thus substantially affect ventricular remodeling in diseased human hearts supports the concept of ongoing myocyte death in the progression of heart failure and constitutes the basis of this review. In addition, based on the pathophysiology of myocardial cell deaths, the present study emphasizes that currently methodologies, although with some inherent limitations, are available to recognize and measure quantitatively the contribution of myocyte cell death to the progression of the pathologic state of the heart. Our own studies show that application of such methodologies including modern microscopy techniques and the use of different molecular and immunohistochemical markers may generate the consensus that myocyte cell death is a quantifiable parameter in the normal and pathological human heart. The present study also demonstrates that myocyte cell death, apoptotic, oncotic or autophagic in nature, has to be regarded as an additional critical variable of the multifactorial events implicated in the alterations of cardiac anatomy and myocardial structure of the diseased human heart.

Biomarkers↗
PubMedDate not supplied

Development of a urinary biomarker for exposure to the organophosphate propetamphos: data from an oral and dermal human volunteer study.

Propetamphos is a member of the vinyl phosphate group of insecticides and is mainly used for sheep dipping. There have been no published metabolic studies on the effect of propetamphos in man to date, although the present authors have published the identification of a metabolite. The present paper presents data from a human volunteer study investigating the toxicokinetics of the organophosphorus pesticide propetamphos following oral and dermal exposure. Five volunteers ingested a propetamphos dose of 10 micrograms kg-1 (35 nmol kg-1) body weight. Following a washout of 4 weeks, a 100 mg (356 mumol) dermal dose of propetamphos was applied, occluded to 80 cm2 of the inner forearm, for 8 h to the same five volunteers. In a pilot study (several weeks before the main study), one volunteer also received an occluded dermal dose of 50 mg (178 mumol) propetamphos. Unabsorbed propetamphos on the skin was washed off after 8 h and collected. Blood and urine samples were collected over 30 and 54 h for the oral and dermal exposures respectively. Blood samples were analysed for plasma and erythrocyte cholinesterase. Urine samples were analysed for a urinary metabolite of propetamphos: methylethylphosphoramidothioate (MEPT). Following oral and dermal exposure, peak urinary MEPT levels occurred at 1 and 10-12 h respectively. The apparent urinary elimination half-lives of MEPT had means of 1.7 h (oral exposure) and 3.8 h (dermal exposure). Approximately 40% of the oral dose and 1% of the dermal dose were recovered as urinary MEPT or metabolites, which could be hydrolysed to MEPT. Approximately 90% of the dermal dose was recovered from the skin washings. Data from a volunteer showed that a doubling of the dermal dose resulted in approximately double the concentration of total MEPT. Alkaline hydrolysis of urine samples increased the level of MEPT detected after both oral and dermal doses. The increase was greater and statistically significant (p < 0.001, paired t-test) for the dermal dose. This increase in MEPT suggests the presence of other MEPT-containing metabolites or conjugates. The difference in the increase between oral and dermal doses raises the question of a difference in metabolism between the two routes. No individual showed a significant depression compared with their pre-exposure levels of erythrocyte acetyl cholinesterase or plasma cholinesterase activity for either dosing route. However, on a group basis, there was a statistically significant mean depression in plasma cholinesterase activity at 8 and 24 h for oral exposure, with a maximum mean depression of 7% from pre-exposure levels at 8 h. Hydrolysis of urine samples had the effect of reducing the interindividual coefficient of variation (CV) for total excretion of MEPT following both oral (CV reduced from 36 to 8%) and dermal (CV reduced from 40 to 17%) exposure. The ability to detect and follow the elimination of low doses of propetamphos by measurement of 'total' (after hydrolysis) urinary MEPT suggests it is a suitable biomarker of propetamphos exposure. The comparatively short elimination half-lives suggest a strategy for biological monitoring of occupational exposure based on samples collected at the end of the shift.

Administration, Cutaneous↗
PubMed2005

An in vivo tumor model exploiting metabolic response as a biomarker for targeted drug development.

In vivo models that recapitulate oncogene-dependent tumorigenesis will greatly facilitate development of molecularly targeted anticancer therapies. We have developed a model based on activating mutations in c-KIT in gastrointestinal stromal tumors (GISTs). This model comprises murine tumors of FDC-P1 cell lines expressing c-KIT mutations that render the tumors either responsive (V560G) or resistant (D816V) to the small-molecule c-KIT inhibitor, imatinib. Clinically, GIST response to imatinib is associated with rapid reduction in fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET), preceding changes in conventional response criteria by several weeks. Using the FDC-P1 model in small animal PET, FDG uptake into tumors expressing the c-KIT V560G mutation was significantly reduced as early as 4 hours after imatinib treatment. In contrast, no change in FDG uptake was observed in resistant c-KIT D816V-expressing tumors after 48 hours of imatinib treatment. Consistent with the PET results, expression of the glucose transporter, GLUT1, was significantly reduced in V560G tumors at 4 hours, preceding changes in markers of proliferation by several hours. In vitro, imatinib treatment of V560G cells resulted in a reduction of glucose transporter numbers at the cell surface and decreased glucose uptake well before changes in cell viability. Notably, decreased ambient glucose concentrations enhanced the cytotoxic effect of imatinib. Taken together, these data account for the rapidity and significance of the PET response to imatinib and suggest that metabolic effects may contribute to imatinib cytotoxicity. Further, the FDC-P1 model represents a very useful paradigm for molecularly targeted drug development.

Animals↗
PubMed2006

Use of nanotechnology for the development of novel cancer biomarkers.

Novel nanotechnologies can complement and augment existing genomic and proteomic techniques employed to analyze variations across different tumor types, thus offering the potential to distinguish between normal and malignant cells. Sensitive biosensors constructed out of nanoscale components (e.g., nanocantilevers, nanowires and nanochannels) can recognize genetic and molecular events and have reporting capabilities, thereby offering the potential to detect rare molecular signals associated with malignancy. Such signals may then be collected for analysis by nanoscale harvesters that selectively isolate cancer-related molecules from tissues. Another area with near-term potential for the early detection of cancer is the identification of mutations and genomic instability.

Animals↗