Drug Discovery In Cancer Epigenetics

Drug Discovery in Cancer Epigenetics is a practical resource for scientists involved in the discovery, testing, and development of epigenetic cancer drugs. Epigenetic modifications can have significant implications for translational science as biomarkers for diagnosis, prognosis or therapy prediction. Most importantly, epigenetic modifications are reversible and epigenetic players are found mutated in different cancers; therefore, they provide attractive therapeutic targets. There has been great interest in developing and testing epigenetic drugs, which inhibit DNA methyltransferases, histone modifying enzymes or chromatin reader proteins. The first few drugs are already FDA approved and have made their way into clinical settings. This book provides a comprehensive summary of the epigenetic drugs currently available and aims to increase awareness in this area to foster more rapid translation of epigenetic drugs into the clinic. Highlights the potential of epigenetic alterations in cancer for drug development Covers the tools and methods for epigenetic drug discovery, preclinical and clinical testing, and clinical implications of epigenetic therapy Provides important information regarding putative epigenetic targets, epigenetic technologies, networks and consortia for epigenetic drug discovery and routes for translation

This book will provide an invaluable guide to epigenetics, one of the fastest moving fields in drug discovery, for medicinal chemists working in academia and in the pharmaceutical industry.

This broad view of epigenetic approaches in drug discovery combines methods and strategies with individual targets, including new and largely unexplored ones such as sirtuins and methyl-lysine reader proteins. Presented in three parts - Introduction to Epigenetics, General Aspects and Methodologies, and Epigenetic Target Classes - it covers everything any drug researcher would need in order to know about targeting epigenetic mechanisms of disease. Epigenetic Drug Discovery is an important resource for medicinal chemists, pharmaceutical researchers, biochemists, molecular biologists, and molecular geneticists.

Establishment of a normal phenotype involves dynamic epigenetic regulation of gene expression that when affected contributes to human diseases. On a molecular level, epigenetic regulation is marked by specific covalent modifications (acetylation, methylation, phosphorylation, sumoylation, PARylation and ubiquitylation) of DNA and its associated histones. Studies also suggest the influence of such epigenetic modifications on non-coding RNA expression implicated in normal and diseased phenotypes. Epigenetic control of genetic expression is a reversible process essential for normal development and function of an organism. Alteration of epigenetic regulation leads to various disease forms such as cancer, diabetes, inflammation and neuropsychiatric disorders. Assessing these alterations provides a deeper insight into the changes induced in the genome, which is often informative for identifying disease subtypes or developing suitable treatments. Therefore, epigenetics proves to be a key area of clinical investigation in diagnosis, prognosis, and treatment of complex diseases. Genetic mutations, environmental stress, pathogens and drugs of abuse are some of the predominant factors that induce and impact changes on chromatin, which directly dictate a diseased phenotype. It is essential to consider the interaction between genetic and epigenetic factors to understand the molecular mechanisms of complex human diseases for safer and efficient drug development. Furthermore, genetic variation in absorption, distribution, metabolism, and excretion (ADME) genes is insufficient to account for interindividual variability of drug response. Therefore, current efforts aim to identify epigenetic components of ADME gene regulation, which include phase-I and phase-II enzymes, uptake transporters, efflux transporters and nuclear receptors involved in regulation of ADME genes. Monitoring circulatory epigenetic biomarkers in liquid biopsies (blood, saliva, urine, cerebrospinal fluid) of disease-associated and drug-associated epigenetic alterations may prove useful for decision support for routine clinical treatment and drug discovery. Hence, recent drug discovery efforts on targeting the epigenome, has emerged an area of interest with several new drugs being developed, tested and some already approved by the US Food and Drug Administration (FDA). These new insights into the complexities of epigenetic regulation are key contributors to our basic understanding of this process in human health and disease, which will provide scope for innovative drug therapies. It is of urgency to aid the present understanding of epigenomics driven diseased outcomes, with the expectation that further studies will identify early markers of disease and targets for therapeutics.

Epigenetic Cancer Therapy, Second Edition provides a comprehensive discussion of healthy and aberrant epigenetic biology, along with new discoveries to improve our understanding of cancer epigenetics and therapeutics. The book encompasses large-scale intergovernmental initiatives, as well as recent findings across cancer stem cells, rational drug design, clinical trials, and chemopreventative strategies. As a whole, the work articulates and raises the profile of epigenetics as a therapeutic option in the future management of cancer. Since the publication of the first edition of this book, the field of epigenetics has undergone significant change. New epigenetic therapies have been designed and approved for clinical use. Our knowledge of the plasticity of the epigenome in cancer and disease has expanded dramatically, with increasing evidence linking pollution to epigenetic changes in cancer development. This second edition has been fully updated to address these changes, along with promising therapeutic programs such as CRISPR/Cas9 mediated approaches, CAR-T based therapies, epigenetic priming, histone modifications, and similar, transformative advances across synthetic biology and cellular engineering. Concisely summarizes the therapeutic implications of recent, large-scale epigenome studies Covers new findings in the interplay between cancer stem cells (CSCs) and drug resistance, thus demonstrating that epigenetic machinery is a candidate target for the eradication of these CSCs Provides a fully updated resource on new topics, including the epitranscriptome, oncohistones, single cell analysis, epigenetic priming, CRISPR therapy, CAR-T therapy, and epigenetics and pollution Features chapter contributions from leading experts in the field

In recent years, knowledge of epigenetic mechanisms underlying disease onset and progression has proven crucial for the development of novel early diagnosis and prognosis biomarkers for patient stratification and precision medicine. Epigenetics in Precision Medicine, a new volume in the Translational Epigenetics series, provides a thorough discussion and overview of current developments in clinical epigenetics with special emphasis on epigenetic biomarkers that can be used for clinical diagnosis, prognosis, patient stratification, and treatment monitoring. Disease types discussed include cancer, metabolic disorders, neurodegenerative diseases, bone disease, and immune-related disorders. The book examines the challenges of advancing epigenetics research and translating findings to the clinic and drug discovery in each of these areas, as well as current solutions; chapter authors discuss how to leverage epigenomic technologies, applications, and tools, such as next-generation sequencing, to discover new epigenetic biomarkers in disease and drug studies. Epigenetics in Precision Medicine focuses on complex epigenetic mechanisms in several pathologies, and explores how epigenetics can power the advance of precision medicine, not only by improving in vitro diagnostic and prognostic tools, but by providing new therapeutic approaches to treat human disease. Provides a thorough grounding in epigenetics-driven precision medicine, with emphasis on developing and implementing early diagnosis and prognosis biomarkers, and supporting patient stratification Empowers researchers and clinicians to incorporate epigenetics in new disease research, drug discovery, and clinical practice Features chapter contributions from international leaders in the field

Epigenetics has emerged recently as an important area of molecular biological studies. Epigenetic modifications lead to potentially heritable but reversible alterations in the expression of genes that determine cell fate. Epigenetic misregulation is thus often linked to degenerative diseases, cancer and neuronal disorders. Recent biomedical interest in this regulatory system stems from the fact that epigenetic, in contrast to genetic, alterations are in principle amenable to pharmacological intervention. A few epigenetically active drugs, for example histone deacetylase inhibitors (HDACi) and DNA methyltransferase (DNMT) inhibitors, have been approved by FDA for treatment of cancers such as CTCL, MDS, and AML. This volume explores the scientific background for clinical applications of epigenetically active drugs. Included are descriptions of epigenetic controls over gene expression, the post-transcriptional silencing of genes by RNA interference (RNAi) and microRNAs, as well as new findings from stem cell research which are relevant to pharmacological applications.