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The most powerful approaches toward discovery of molecular biomarkers are derived from recent advances in the fields of proteomics and genomics. Molecular biomarkers can be used to refer to nonimaging biomarkers that have biophysical properties, which allow them to be measured in biological samples, and include nucleic acid–based biomarkers such as gene mutations or polymorphisms and quantitative gene expression analysis, peptides, proteins, lipids metabolites, and other small molecules. Biomarkers can also be classified based on their application, such as diagnostic biomarkers, staging of disease biomarkers, disease prognosis biomarkers such as cancer biomarkers, and biomarkers for monitoring the clinical response to an intervention.
Biomarkers have many potential applications in oncology including risk assessment, screening, differential diagnosis, determination of prognosis, prediction of response to treatment, and monitoring of progression of disease. Because of the critical role that biomarkers play at all stages of disease it is important that they undergo rigorous evaluation, including analytical validation, clinical validation, and assessment of clinical utility, prior to incorporation into routine clinical care. Oncology biomarkers discusses and addresses key steps in the development of biomarkers, including ways to avoid introducing bias and guidelines to follow when reporting results of biomarker studies. With the tremendous increase in knowledge about the biology of cancer and the rapid changes in molecular technology that have occurred in the past decade, studies of biomarkers in cancer have increased multifold.
Biomarkers provide a dynamic and powerful approach to understanding the spectrum of neurological diseases with applications in observational and analytic epidemiology, randomized clinical trials, screening and diagnosis and prognosis. Defined as alterations in the constituents of tissues or body fluids, these markers offer the means for homogeneous classification of a disease and risk factors, and can extend our base information about the underlying pathogenesis of disease. Molecular biomarkers in the hands of clinical investigators provide a dynamic and powerful approach to understanding the spectrum of neurological disease with obvious applications in analytic epidemiology, clinical trials and disease prevention, diagnosis, and disease management. Biomarkers can also reflect the entire spectrum of disease from the earliest manifestations to the terminal stages.
The potential clinical benefits for disease-specific biomarkers include a more rapid and accurate disease diagnosis, and potential reduction in size and duration of clinical drug trials, which would speed up drug development. The application of biomarkers into the clinical arena of motor neuron disease should both determine if a drug hits its proposed target and whether the drug alters the course of disease. The study and research addresses the issues concerning the discovery of suitable biomarker candidates from a variety of sources including imaging, neurophysiology and proteomics. For biomarkers to have clinical utility, specific criteria must be satisfied. While there has been tremendous effort to discover biomarkers very few have been translated to the clinic.
The discovery of new biomarkers for a given pathway or drug class is an integral component of successful methods for measuring pharmacological and biological consequences. As new proteins continue to be surveyed as potential drug targets, the need for markers that are tightly linked to their functions or downstream consequences continues to increase. The need is particularly high for novel targets where the associated biochemical pathways are not well characterized, but many validated targets could also benefit from expanded portfolios of biomarker endpoints to track during drug discovery and development efforts. Biomarkers used in drug development may be categorized into general classes of qualification, each one with increasing evidentiary requirements such as exploration biomarkers are research and development tools applied to the preclinical setting without evidence necessarily linking the biomarker to clinical outcomes in humans.
Biomarker discovery efforts utilize numerous platforms including genomics, proteomics, metabolomics, imaging modalities and neurophysiology, and often search for the diagnostic utility of biomarkers. Diagnostic biomarkers would permit diagnosis at an earlier stage of disease at potentially preclinical as well being informative with regards to underlying pathological causative pathways. Diagnostic biomarkers may not change during disease progression and therefore may be informative regarding the initiation of disease but have little merits for monitoring disease progression. For instance, a specific protein or metabolite may exhibit alterations during disease initiation and remain at the same altered level throughout the course of disease. However, it is possible that diagnostic biomarkers function within a biochemical pathway targeted by a specific drug therapy. In this case, the diagnostic biomarker may also be useful to monitor the ability of the drug to hit its target in the nervous system.
The use of biomarkers and diagnostic tests continues to evolve with expanded uses, new targets for assessment, and the introduction of newer and higher-sensitivity assays. These tests are powerful adjuncts to standardized clinical care in various different therapeutic areas including cardiology, infectious disease, oncology, immunology, hematology, and endocrinology. The study and research includes important information on the latest advances in the clinical application and appropriate integration of biomarkers and diagnostic tests into clinical care. Tremendous technological advances and ample venture capital are combining to produce new medical diagnostics. New biomarkers are being identified to predict or detect a wide range of diseases; new devices are being developed to continuously monitor biologic parameters.
Biomarkers are often measured and evaluated to examine normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Knowledge about the molecular pathology of these lesions is still limited; and there are few clinically useful diagnostic and prognostic biomarkers. However, recent discoveries of certain key genomic alterations such as chromosome translocations, copy number alterations, and mutations, provide new insights into the molecular pathogenesis of these lesions and may help to better define them. It is also hoped that this new knowledge can help to guide therapy but this translation has been somewhat slow to develop perhaps due to the rarity of these tumors and the lack of large randomized studies.
The science of molecular profiling has expanded our knowledge of cancer at the cellular and molecular level such that numerous subtypes are being described based on biomarker expression and genetic mutations rather than traditional classifications of the disease. Drug development has experienced a concomitant revolution in response to this knowledge with many new targeted therapeutic agents becoming available and this has necessitated an evolution in clinical trial design. These trials need to be more efficient and adaptive in order to quickly assess the efficacy of new agents and develop new companion diagnostics. We are now seeing a substantial shift from the traditional multiphase trial model to an increase in phase II adjuvant and neoadjuvant trials in earlier-stage disease incorporating surrogate endpoints for long-term survival to assess efficacy of therapeutic agents in shorter time frames.
New trial designs have emerged with capabilities to assess more efficiently multiple disease types, multiple molecular subtypes, and multiple agents simultaneously, and regulatory agencies have responded by outlining new pathways for accelerated drug approval that can help bring effective targeted therapeutic agents to the clinic more quickly for patients in need. Some initial studies were followed by separate reports of longer subject follow-up; both are included here. For some studies, large samples were acquired over prolonged periods of time. Interpretation of results from many of these studies is limited by small samples, lack of internal or historical controls, limited use of quantitative measures. Solutions to these barriers will require multicenter collaboration, partnership with patient organizations, training a new generation of researchers interested in rare diseases, and leveraging existing resources.
Increasingly use of animals in the scientific procedures has drawn more attention to the primary ethics of these valuable creatures. There are international guidelines for use and care of animals in scientific procedures. Growing usage of animals in the research projects has drawn more attention to their welfare and ethics surrounding this practice. Dissemination of information about the existing ethical consideration and alternatives in animal experiments has two important functions. First it increases the researcher's awareness of the possible methods of using animals in the experiment; and second it ensures that potential users are aware of the established alternatives. For example, legislations enacted in many countries during the 1980s state that laboratory animal applications should be Reduced, Refined and Replaced wherever possible according to principles of the 3Rs. Thus, scientists around the world tried to apply the 3Rs in their biomedical researches regarding welfare of the laboratory animals.
Functional genomics is a field of molecular biology that attempts to make use of the vast wealth of data given by genomic and transcriptomic projects such as genome sequencing projects and RNA sequencing to describe gene and protein functions and interactions. Functional genomics focuses on the dynamic aspects such as gene transcription, translation, regulation of gene expression and protein–protein interactions, as opposed to the static aspects of the genomic information such as DNA sequence or structures. Cytogenetic biomarkers have long been applied in surveillance of human genotoxic exposure and early effects of genotoxic carcinogens. Due to their wide use it has been possible to evaluate in international collaborative studies if a high level of these biomarkers in peripheral lymphocytes is predictive of cancer risk. Thus far, such an association has been observed for chromosomal aberrations (CAs), but not for sister chromatid exchanges (SCEs) or micronuclei (MN).
Imaging can assess therapeutic efficacy for cancers and may be a part of the solution to reduce costs and improve timeliness of clinical trials. Imaging was identified as one of the components that could play an important role in reducing the cost of clinical trials, which is a major component of drug approval costs. Imaging has traditionally played three roles that relate to clinical trials. They are detection, characterization and monitoring/assessment. Developing imaging modalities that can better detect and characterize lesions also receives wide attention with relatively little funding going to the evaluation and validation of imaging-based assessment. Advances in medical imaging have resulted in substantially improved detection and diagnosis of tumors over the past twenty five years.