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Feb 1, 2010 (Vol. 30, No. 3)

Epigenetics Offers Strategies for New Drugs

Recent Elucidation of Role in a Myriad of Diseases Has Ignited Interest in Field

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    Mechanisms of action of different histone-modifying enzymes (CellCentric)

    Increasing numbers of scientists are focusing their studies on epigenetics to get a better handle on how internal and external factors lead to cellular malfunctioning and impact the progression of various human diseases.

    According to a recent report from Business Insights, “Innovations in Epigenetics: Advances in Technologies, Diagnostics & Therapeutics,” epigenetic medicine is already here.

    The company puts the epigentic market at over $560 million, derived from the sale of three anticancer products (Dacogen™ from Eisai, Vidaza® from Celgene, and Zolinza® from Merck), which target two epigenetic pathways—DNA methyltransferase (DNMT) and histone deacteylase (HDAC).

    Approximately 30 epigenetic drugs are under development by more than a dozen biotechnology companies, according to the Business Insights study. These drugs focus mainly on the treatment of cancer, and neurodegenerative and infectious diseases although research is under way to explore the role for epigenetics in cardiovascular, metabolic, ocular, and other diseases.

    The silver jubilee of groundbreaking discoveries in epigenetics by Azim Surani, Davor Solter, and Bruce Cattanach was commemorated at a meeting sponsored by CellCentric late last year. Epigenetics is the study of changes in phenotype and gene expression arising from mechanisms other than changes in a gene’s DNA sequence.

    Over 25 years ago, Surani et al. showed that certain regions of a cell’s genome carry markers over and above the actual gene sequence. This imprint conveys information on differential gene expression, and therefore, shapes the fate of the cell.  Epigenetic information is passed from one cell to another, but the epigenetic code can change through life by interacting with environmental factors. Moreover, unlike gene-sequence mutations, epigenetic changes may be reversible. 

    The initial focus in epigenetics was on its role in early development, but it has become apparent that epigenetic processes also play a role in many diseases, including cancer, neurodegenerative, inflammatory, and cardiopulmonary, opening up many potential opportunities for both big pharma and biotech. 

    “The epigenetic silencing of tumor suppressor genes is one of the most important findings in this area, it is found in almost all human cancers,” said Peter Jones, Ph.D., director of the University of Southern California/Norris Comprehensive Cancer Center.

    Presentations at the meeting ranged from detailed analyses of the epigenetics of individual genes to overviews of the entire genome. There was new information on the epigenome and the incidence of imprinting disorders in assisted reproduction, and on the role of epigenetic changes in cancer. 

    “Epigenetics bridges the gap between genes and the environment, and it is becoming clear that it is important in human disease,” explained Wolf Reik, Ph.D., the conference organizer whose group at The Babraham Institute is involved in imprinting and reprogramming. In fact, widespread loss of DNA methylation was observed in colorectal cancer as long ago as 1983. And now the tools and technologies, particularly in high-throughput format, are becoming available so this emerging field can start to open up to commercialization, he noted.

  • Therapeutics

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    Epigenomics' cancer diagnostic tests strive to find cancer in the early stages before symptoms occur.

    Therapeutic developments are focused in the two main areas of epigenetic modifications. The best understood is the covalent methylation of cytosine at the dinucleotide sequence CG in the genome. The pattern of methylation in the genome is tissue- and gene-specific, and DNA methylation is an effective method for gene silencing. 

    DNA methylation is catalyzed by DNA methyltransferases (DNMT), a process that is sometimes reversible. Cancer is associated with hypermethylation of tumor suppressor genes, abnormal expression of DNMTs, and hypomethylation of other cancer-related genes. The other key epigenetic modification area is chromatin variability, where there is still much to be understood. It involves post-translational modifications, including acetylation, ubiquitinylation, and phosphorylation of histone proteins. These histone variants alter the density and higher-order structure of chromatin which, in turn, influences gene expression. More than 100 specific chromatin modifications have been identified, some linked to actively transcribed genes, some to silenced genes.

    There is also a link between DNA methylation and chromatin modification in that inactive chromatin is hypomethylated and active chromatin is hypermethylated. In most cases, the epigenetic information is passed from one cell to another during cell division. It is when these processes go wrong that disease results; therapeutic applications in epigenetics involve blocking or reversing these aberrations.

    There are, potentially, many disease targets for therapies based upon DNA methylation. Several drugs targeting DNA methylation and histone deacetylation enzymes have already been approved and others are in clinical trials. The first DNA methylation inhibitor (Vidaza) and its deoxy analog (Dacogen) were approved by the FDA for myelodysplastic syndromes (the former was discovered by Dr. Jones in 1980, proving the link between DNA methylation and gene expression).

    Zebularine, another inhibitor, has been extensively studied in animal models and Dr. Jones is hoping that NCI might take this forward into clinical trials. Meanwhile, HDACs are an important target for cancer therapy. Examples of inhibitors include panabinostat, which is in Phase II/III for cutaneous T-cell lymphoma (CTCL), breast, prostate, and other cancers, and Zolinza, which is licensed by the FDA for CTCL. 

    CellCentric has a hub-and-spoke business model to drive its discovery engine. It has an exclusive agreement with around 30 epigenetic researchers, including Professor Surani, the company’s scientific founder, and Dr. Reik, where the company assesses, and has first refusal on, any developments that might potentially have commercial significance.  

    The company, which is semivirtual, has established a framework for ongoing and confidential dialogue and review of data and insights between CellCentric and its institutional collaborators. Any IP is protected in the name of the institution involved. IP can then be accessed by the company via a negotiated licence agreement within an exclusivity window. CellCentric then takes responsibility for translational research. 

    CellCentric will work in the preclinical area but will license out investigational drugs before clinical trials. It has already established collaborations with Pfizer and Takeda—the latter covering further validation of an epigenetic target that CellCentric has identified. The target is believed to play a key role in cancer, and inhibitors could be a new therapeutic approach.

    “Nine out of ten pharmas are interested in epigenetics and are formulating their long-term strategies,” Dr. West said. “We are a window into an emerging space.” From over 20 prioritized potential targets, CellCentric is taking eight forward—three protein methyltransferases, two protein demethylases, a ubiquitin ligase, a deubiquitinase, and a surface receptor antibody.

    There are a few other small biotechs in this space. For instance, Epigenomics specializes in DNA-methylation technologies and biomarkers and is developing a number of cancer diagnostics based on differences in DNA methylation between healthy and diseased tissue. Constellation Pharmaceuticals is focused on developing therapeutics based on epigenetics. It is currently establishing a preclinical pipeline and developing a technology platform for histone modification. Initial applications will be in oncology. Finally, Epizyme is looking at histone methyltransferases and is developing a pipeline of inhibitors for cancer.

    “There is collaboration between suppliers and academics, which is a clear sign of the importance of epigenetics,” Dr. Reik concluded. “Big pharma is interested in this space and is collaborating with the aim of taking hold of some of the smaller companies.”


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