Cancer Epigenetics: New Therapies and New Challenges

Cancer is nowadays considered to be both a genetic and an epigenetic disease. The most well studied epigenetic modification in humans is DNA methylation; however it becomes increasingly acknowledged that DNA methylation does not work alone, but rather is linked to other modifications, such as histone modifications. Epigenetic abnormalities are reversible and as a result novel therapies that work by reversing epigenetic effects are being increasingly explored. The biggest clinical impact of epigenetic modifying agents in neoplastic disorders thus far has been in haematological malignancies, and the efficacy of DNMT inhibitors and HDAC inhibitors in blood cancers clearly attests to the principle that therapeutic modification of the cancer cell epigenome can produce clinical benefit. This paper will discuss the most well studied epigenetic modifications and how these are linked to cancer, will give a brief overview of the clinical use of epigenetics as biomarkers, and will focus in more detail on epigenetic drugs and their use in solid and blood cancers. 1. Introduction It has been thirty years since the “war on cancer” was declared, yet in 2008, the most recent year for which incidence and mortality rates are available, almost 12.7 million people were diagnosed with cancer and more than 7.5 million died of the disease [1]. Enormous progress has been made in the understanding of the molecular basis of carcinogenesis and the complete sequencing of the human genome represents a milestone in this quest [2]. The situation though is far more complex than a simple catalogue of genes and despite this progress the discovery of anticancer drugs remains a highly challenging endeavor and cancer a hard-to-cure disease. Traditionally, the development of cancer is thought to be largely due to the accumulation of genetic defects such as mutations, amplifications, deletions, and translocations affecting the cancer cell machinery and providing the cancer cell with the advantage to survive and metastasize. In addition, interactions between cancer cells and their microenvironment further support these processes [3]. Of equal importance is a second system that cells use to determine when and where a particular gene will be expressed during development. This system is overlaid on DNA in the form of epigenetic marks that are heritable during cell division but do not alter the DNA sequence [4]. The pattern of these chemical tags is called the epigenome of the cell, whereas epigenetics is the study of these marks that lead to changes in gene expression in the absence of