Epigenetic Therapy of Cancer [recurso electrónico] Preclinical Models and Treatment Approaches

The growing knowledge about disturbances of epigenetic gene regulation in hematopoietic stem cell disorders such as myeloid leukemias and preleukemias (myelodysplasias) is now being translated into treatment approaches that target the epigenetic defects pharmacologically. Such approaches include reactivation of tumor suppressor genes and other antiproliferative genes by reversal of DNA hypermethylation through azanucleosides, and use of HDAC inhibitors to reverse gene silencing mediated by chimeric, leukemia-specific transcription factors. This book first presents the latest evidence derived from preclinical models regarding the epigenetic regulation of hematopoietic stem cell differentiation and hemoglobin production. The significance of DNA methylation abnormalities in hematopoietic disorders and of epigenetic disturbances in lung cancer and other solid tumors is then discussed. A major part of the book, however, relates specifically to the translation of basic research and drug development to clinical applications, and in this context both present and future clinical strategies are considered. Individual chapters are devoted to the use of DNA hypomethylating agents and chromatin-modifying agents, and the treatment of hematologic malignancies and solid tumors by means of epigenetic agents is discussed in detail Front Matter....Pages i-x The Fundamental Role of Epigenetic Regulation in Normal and Disturbed Cell Growth, Differentiation, and Stemness....Pages 1-41 Mouse Models to Study DNA Methylation in Cancer Research....Pages 43-66 Epigenetic Regulation of Normal Hematopoietic Development....Pages 67-87 Epigenetic Regulation of Globin Genes and Disturbances in Hemoglobinopathies....Pages 89-106 DNA Methylation Abnormalities in Hematopoietic Disorders: Biological Significance and Methodological Approaches....Pages 107-120 Epigenetic Modifications Mediated by the AML1/ETO and MLL Leukemia Fusion Proteins....Pages 121-144 Treatment of Hematologic Malignancies with DNA Hypomethylating Agents....Pages 145-170 Pharmacodynamic Responses to DNA Methyltransferase Inhibition....Pages 171-188 Histone Methyltransferases: Opportunities in Cancer Drug Discovery....Pages 189-226 Histone Deacetylase (HDAC) Inhibitors in Recent Clinical Trials for Cancer Therapy....Pages 227-255 Clinical Implications of Epigenetic Alterations in Lung Cancer....Pages 257-282 Epigenetic Disturbances in Colorectal Cancer....Pages 283-298 Epigenetic Therapies in Solid Tumours: From Preclinical Models to Clinical Trial Results....Pages 299-317 Back Matter....Pages 319-325