- Cancer Biology & Biomarkers
- Chromatography & Mass Spectrometry
- Contract Research, Clinical Trials and Outsourcing
- Drug Discovery
- Drug Targets
- Flow Cytometry
- Informatics & Lab Automation
- Ingredients, Excipients and Dosages
- Microbiology & RMMs
- NIR, PAT & QbD
- Raman Spectroscopy
- Screening, Assays & High-Content Analysis
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Cancer Biology & Biomarkers
A selection of articles from European Pharmaceutical Review covering Cancer Biology and Biomarkers:
6 January 2016 • Irmgard Riedmaier, Melanie Spornraft, Benedikt Kirchner and Michael W. Pfaffl, Technical University of Munich
Molecular diagnostics and biomarker discovery are gaining increasing attraction in clinical research. This includes all fields of diagnostics, such as risk assessment, disease prognosis, treatment prediction and drug application success control. The detection of molecular clinical biomarkers is very widespread and can be developed on various molecular levels, like the genome, the epi-genome, the transcriptome, the proteome or the metabolome. Today, numerous high-throughput laboratory methods allow rapid and holistic screening for such marker candidates. Regardless of which molecular level is analysed, in order to detect biomarker candidates, high sample quality and a standardised and highly reproducible quantification workflow are prerequisites. This article describes an optimal and approved development strategy to discover and validate ‘transcriptional biomarkers’ in clinical diagnostics, which are in compliance with the recently developed MIQE guidelines. We focus on the importance of sample quality, RNA integrity, available screening and quantification methods, and biostatistical tools for data interpretation...
19 February 2014 • Shi-Yong Sun, Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute
The mammalian target of rapamycin (mTOR) has emerged as a promising cancer therapeutic target. Some rapamycin analogues (rapalogues) as mTOR allosteric inhibitors are FDA-approved drugs for treatment of certain types of cancers. However, the modest clinical anticancer activity of rapalogues, which preferentially inhibit mTOR complex 1, in most types of cancer, has spurred the development of ATP competitive mTOR kinase inhibitors (TORKinibs) that inhibit both mTOR complex 1 and complex 2, in the hope of developing a novel generation of mTOR inhibitors with better therapeutic efficacy than rapalogues. So far, several TORKinibs have been developed and some are under clinical testing. With a strong rationale, we expect great success in the treatment of cancer with TORKinibs.
22 October 2013 • Amancio Carnero, Instituto de Biomedicina de Sevilla, Consejo Superior de Investigaciones Científicas
There is an urgent need to predict which treatment will report the most benefit to a patient with cancer. To that end, scientists are exploring any possible biomolecule in the organism that can mark each individual for its adequate treatment. If achieved, it will open a personalised medicine era.
10 July 2012 • Péter Horvatovich & Rainer Bischoff, Analytical Biochemistry, Department of Pharmacy, University of Groningen
Biomarkers are biological characteristics that are objectively measured and evaluated as indicators of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention. Biomarkers can be used to determine disease onset, progression, efficacy of drug treatment, patient susceptibility to develop a certain type of disease or predict efficacy of treatment at a particular disease stage. Protein molecular biomarkers are particularly popular due to the availability of a large range of analytical instrumentation, which can identify and quantify proteins in complex biological samples. Proteins are key compounds in biosynthesis, cell, tissue and organ signalling and provide cell and tissue structural stability in living organisms. The primary protein sequences are encoded in the genome; however, their complex posttranslational modifications (PTMs) and three dimensional structures are fairly unpredictable from genomic information. In this mini-review, we will provide an overview of the current state, challenge and important aspects of protein biomarker discovery and validation...
28 February 2012 • Janina Staub and Jochen Utikal, Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, University of Heidelberg & Skin Cancer Unit, German Cancer Research Center
During the last few years, significant improvements in the treatment of metastatic melanoma were reported, targeting molecules involved in the pathogenesis of melanoma. Different clinical trials were able to prove a prolonged overall survival by introducing new therapeutic agents. Hereby an imunomodulating therapy with the anti-CTLA-4 antibody ipilimumab has been established. Other promising treatment possibilities include targeted therapies for melanoma patients showing certain activating mutations in their tumour cells, e.g. BRAF V600 mutations and their selective inhibition by vemurafenib or the inhibition of the c-Kit receptor by drugs such as imatinib mesylate. This review will provide a brief overview of the latest therapeutic strategies and recent achievements in treating metastatic melanoma, as well as discuss the arising problems with resistance mechanisms to selective therapies. It will also highlight future approaches to combine specific treatments in an attempt to individualise melanoma treatment for every patient with the best possible efficacy and outcome...
19 October 2011 • Richard Morgan, Postgraduate Medical School, Faculty of Health and Medical Sciences, University of Surrey
The HOX genes are a family of closely related transcription factors that help to define the identity of cells and tissues during embryonic development and which are also frequently deregulated in cancer, where they have been shown to promote cell survival and proliferation. The high level of cancer-associated HOX expression and the pro-oncogenic functions of these genes make them strong candidates for biomarkers in multiple roles including diagnosis, prognosis, drug sensitivity and drug resistance. The HOX genes are a family of homeodomaincontaining transcription factors that were first identified as determinates of cell and tissue identity in early development, although they are now also known to function in adult stem cell renewal and differentiation. A series of duplication events is thought to have given rise to the four separate clusters of HOX genes found in vertebrates, with each cluster consisting of a group of closely linked members that often share enhancer regions. These clusters are named A, B, C and D, and together they contain the 39 HOX genes found in mammals. Each gene within a cluster is labelled with a number according to their relative position in the chromosome, so for example HOXB1 is the 3’ most member of the B cluster, and HOXB13 is the 5’ most member. The linkage of genes within each cluster is closely reflected in both their temporal and spatial order of expression in the embryo, with the 3’ genes being expressed more anteriorly and earlier than their 5’ neighbours. The relative position within the cluster is also reflected in the co-factor interactions, DNA binding specificity and regulation of each member.
20 June 2011 • Sheraz Gul, Vice President & Head of Biology, European ScreeningPort GmbH
The development of most diseases is often attributed to the dysfunction of the activities of key proteins involved in biological processes and their modulation by a therapeutic agent is considered to offer the potential to alleviate the disease state.
19 April 2011 • Magnus Ivarsson, Head of Physiological Biomarkers, Pfizer and Mark Fidock, Head of Quantitative Biomarkers, Research Enabling Group, Pfizer
The current high rate of attrition during drug development is unsustainable. An increasing amount of the cost of developing a new drug is made up of the investment in molecules that fail at some point during the process and the later that failure occurs, the more costly it will be. Recent surveys suggest that the attrition rate in the pharmaceutical industry is now more than 90 per cent from the first in human study to launch. Reducing attrition is now one of the key challenges for the pharmaceutical industry, but before exploring potential ways forward, it is necessary to understand what drives the attrition and causes drug candidates to fail during the development process.
16 February 2011 • Ross Sibson, Director of Research, Applied Cancer Biology Group, University of Liverpool
The rate of progress in molecular cell biological sciences has become dramatic. This is fuelled in part by developments in technology, none more so than in the field of nucleic acid sequencing. So-called Next Generation Sequencing Platforms promise to revolutionise our understanding of the importance of genetic differences on an individual basis. According to the modern personalised or stratified medicine paradigms, this will revolutionise current practices in terms of early detection, treatment, diagnosis, prognosis and even prevention. Revolutions are apt to disappoint and drug pipelines have yet to justify such optimism yet molecular geneticists can point already to notable successes like the completion of their flagship project, the human genome in 2001, within time and within budget. What are the current realities? The field of cancer serves as an excellent test and would suggest that advances are being made incrementally but rapidly.
16 December 2010 • Wolfgang M. Brueckl & Joachim Ficker, Department of Internal Medicine 3, Lung Cancer Center and Thomas M. Mundel, Roche Parma AG
Despite innumerable clinical studies in the past three decades with lots of traditional chemotherapeutical drugs and drug combinations, survival in lung cancer has increased by far less than other entities. Research now focuses on inhibitors of tyrosine kinases which have been shown to have a central role in the development of lung cancer. However, as recent developments show, unselected use of those ‘targeted therapies’ is not always effective and may even be harmful to lung cancer patients if given at the wrong time or to the wrong patient. Biomarkers with predictive value will, in future, be of utmost importance for an individualised tumour tailored therapy. In this perspective, we describe the latest developments in EGF-R directed tyrosine kinase inhibitors and other targeted therapies. Additionally, the actual (limited) predictive role of biomarkers is discussed in this context and further directions are pinpointed.
1 November 2010 • Attila A. Seyhan.Translational Immunology, Inflammation and Immunology, Pfizer
Robust and validated biomarkers are needed to improve diagnosis, monitor drug activity and therapeutic response and guide the development of safer and targeted therapies for various chronic diseases. While different types of biomarkers have been impactful in the field of drug discovery and development, the process of identifying and validating disease specific biomarkers has been quite challenging. Recent advances in multiple ‘omics’ (multi-omics) approaches (e.g., genomics, transcriptomics, proteomics, metabolomics, cytometry and imaging) in combination with bioinformatics and biostatistics have made it possible to accelerate the discovery and development of specific biomarkers for complex chronic diseases. Although many challenges still need to be addressed, current efforts for the discovery and development of disease-related biomarkers will assist in optimal decision-making throughout the course of drug development and improve our understanding of the disease processes. Furthermore, effective translation of the preclinical biomarkers into the clinic will pave the way towards effective execution of personalised therapies across complex disease areas for the benefit of patients, healthcare providers and the bio-pharmaceutical industry.
29 October 2010 • Brian Flatley Dept of Chemistry, University of Reading, Reading and Harold Hopkins Dept of Urology, Royal Berkshire NHS Foundation Trust Hospital, Reading and Peter Malone Harold Hopkins Dept of Urology, Royal Berkshire NHS Foundation Trust Hospital, Reading and Rainer Cramer Dept of Chemistry, University of Reading, Reading
Each year, approximately 10,000 men in the UK die as a result of prostate cancer (PCa) making it the third most common cancer behind lung and breast cancer. Worldwide, more than 670,000 men are diagnosed every year with the disease. Current methods of diagnosis of PCa mainly rely on the detection of elevated prostate-specific antigen (PSA) levels in serum and/or physical examination by a doctor for the detection of an abnormal prostate. PSA is a glycoprotein produced almost exclusively by the epithelial cells of the prostate gland. Its role is not fully understood, although it is known that it forms part of the ejaculate and its function is to solubilise the sperm to give them the mobility to swim. Raised PSA levels in serum are thought to be due to both an increased production of PSA from the proliferated prostate cells, and a diminished architecture of affected cells, allowing an easier distribution of PSA into the wider circulatory system...
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