MethylGene and Pharmion Expand Collaboration on Epigenetic Therapies

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MethylGene Inc. (TSX:MYG) and Pharmion Corporation (NASDAQ:PHRM) today announced a “research collaboration for the development of novel small molecule inhibitors targeting sirtuins, a separate and distinct class of histone deacetylase enzymes (Class 3 HDACs) implicated in cell survival and death.”

MethylGene and Pharmion’s Class I specific HDAC inhibitor, MGCD0103, has demonstrated efficacy in a number of tumor types, and the sirtuins represent potentially attractive novel cancer targets within a related family of enzymes. Sirtuins (including SIRT1) have been shown to deacetylate histone proteins and numerous transcription factors, leading to promotion of normal cell survival and aberrant gene silencing in cancer cells. Inhibition of sirtuins allows reexpression of silenced tumor suppressor genes, leading to reduced growth of cancer cells, and anti-cancer effects have been observed with SIRT1 inhibitors in vitro and in vivo. As yet, no sirtuin inhibitors have entered the clinic. Synergies in gene reexpression have been demonstrated by combining SIRT1 inhibition with either standard cytotoxics or other epigenetic modifying drugs, including inhibitors of DNA methylation and histone deacetylation. Two epigenetic therapy combinations are already under active investigation in Phase II studies combining Pharmion’s Vidaza, a DNA hypomethylating agent, with MethylGene and Pharmion’s HDAC inhibitor, MGCD0103. The parties intend to explore combinations with resulting anti-sirtuins as well.


Epigenomics AG Delivers Clinical Proof-of-Concept for Lung Cancer Detection

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Epigenomics AG (Frankfurt:ECX) today announced that it has procured positive results from a clinical trial investigating the feasibility of a test to detect patients with non-small cell lung cancer (NSCLC).

The program aims at developing a blood based test for the reliable and convenient early detection of lung cancer. In an initial study last year Epigenomics identified numerous candidate DNA methylation biomarkers that appear in lung tumors, but not in normal lung tissue. The objective of this most recent study, run in cooperation with the Department of Pneumology at the Charite in Berlin headed by Prof. Dr. Christian Witt, was to show that the most promising candidate biomarker identified previously can also be detected in blood plasma of lung cancer patients. This is an important prerequisite for developing a convenient blood based early detection test for this cancer. The study was carried out on a group of patients with either lung cancer or benign lung disease. The study came to the result that the most promising candidate biomarker detects patients with lung cancer, and differentiates them from individuals with positive computer tomography (CT) due to non-cancerous lung diseases. Based on this proprietary novel DNA methylation biomarker and the encouraging results, Epigenomics will continue the development of its lung cancer screening test. With these results in lung cancer, Epigenomics has achieved clinical proof-of-concept in the third major cancer indication, after successful clinical studies in colorectal cancer and prostate cancer screening programs.

Lung cancer is responsible for approximately 1.3 million deaths worldwide annually, and accounts for the most deaths of any cancer. Epigenomics notes that most lung cancer patients are currently diagnosed when their disease is advanced, and nealy 90 percent die within two years. An effective blood-based screening test for lung cancer would be a tremendous advance for aiding in the early detection and improved treatment options for lung cancer patients. Link

Role of the Polycomb Repressive Complex 2 in Acute Promyelocytic Leukemia

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New research published today in the journal Cancer Cell by Villa et al. sheds new light on the interaction between two gene regulation mechanisms: DNA methylation and the Polycomb protein complex.

Epigenetic changes are common alterations in cancer cells. Here, we have investigated the role of Polycomb group proteins in the establishment and maintenance of the aberrant silencing of tumor suppressor genes during transformation induced by the leukemia-associated PML-RAR fusion protein. We show that in leukemic cells knockdown of SUZ12, a key component of Polycomb repressive complex 2 (PRC2), reverts not only histone modification but also induces DNA demethylation of PML-RAR target genes. This results in promoter reactivation and granulocytic differentiation. Importantly, the epigenetic alterations caused by PML-RAR can be reverted by retinoic acid treatment of primary blasts from leukemic patients. Our results demonstrate that the direct targeting of Polycomb group proteins by an oncogene plays a key role during carcinogenesis.

innovations-report has a nice summary of previous work done in this area and the significance of the current paper.

The featured article in the June issue is available for free. Link

AACR 2007: SuperGen Showcases Selective Degradation of DNMT1

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At the 2007 annual meeting of the American Association for Cancer Research (AACR), pharmaceutical company SuperGen (NASDAQ:SUPG) presented data on a class of quinilone-based compounds that are not incorporated into DNA, selectively induce the degradation of DNA Methyltransferase I (DNMT1) in human cancer cells and re-express silenced tumor supressor genes.

Researchers have discovered a novel class of quinoline-based compounds that are not incorporated into DNA and cause selective degradation of DNMT1 in human cancer cells with minimal or no effects on DNMT3A and DNMT3B that have been discovered. This addresses an issue with re-activation of silenced tumor suppressor genes by 5-Azacytidine (5-AzaC or Vidaza) and its congener 5-aza- deoxycydinite (5-aza-CdR or Decitabine or Dacogen). These compounds provide a different mechanistic approach to the creation of cancer therapies because they selectively and rapidly induce degradation of maintenance DNA methyltransferase, DMNT1. However, they show some toxicity due to their incorporation into the cell DNA. One compound in particular, S1027, resulted in complete degradation of DNMT1 within 24 hours of treatments and also blocked degradation as a pre-treatment of cells with proteasomal inhibitors.

SuperGen also showcased their work showing that zebrafish provide an excellent screening model for small molecule inhibitors of DNMT1. Link

AACR 2007: Epigenomics Improving Colorectal Cancer Detection Success Rate

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Berlin- and Seattle-based Epigenomics AG has announced at the Annual Meeting 2007 of the American Association for Cancer Research (AACR) that it has significantly improved its success rate at detecting colorectal cancer by analyzing DNA methylation in blood serum. The increased success of detection was mediated by altering the assay procedure and rules for test result interpretation.

The poster presentation by Cathy Lofton-Day, Ph. D., Vice President Molecular Biology of Epigenomics, focused on the benefits of modifications of the assay procedure and rules for test result interpretation on the performance of Septin 9 for the early detection of colorectal cancer in blood plasma. Using these modifications Septin 9 detected 70% (91 out of 130) of the colorectal cancers in the study and was falsely positive in only 10% (19 out of 183) of the cancer-free controls. When specificity was set at 97% (3% false positive rate in the non-cancerous controls) 63% of cancers were reliably detected. More importantly, the 70% cancer detection rate was also achieved in individuals found to have earlier stage disease (stage I-III, 75 out of 107).

Epigenomics is now focusing on further streamlining and simplification of the assay procedure to decrease test costs, improve ease-of-use and thus facilitate transfer into clinical routine use.

The PDF of the poster presented by Dr. Lofton-Day is available at the Epigenomics web site.

In July 2006 Epigenomics announced that it had improved its colorectal cancer detection rate by using a Septin9 methylation assay in conjunction with a previously unidentified marker, ALX4. This new data seems to suggest that Epigenomics is now trying to improve detection through analysis of Septin9 alone, possibly to streamline the development of the assay for clinical use. Link

Epigenetics in Focus at Nature Reviews Genetics

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Following closely on the heels of the special issue of Cell on epigenetics, Nature Reviews Genetics today published its own focus issue on epigenetics (April 2007), with reviews from some of the most prominent experts in several sub-disciplines within epigenetics, including stem cell research, cancer epigenomics, and environmental epigenetics. The editors of the journal open the issue with a brief introduction:

The explosion of interest in epigenetics over the past few years has had an impact on many branches of genetic and genomic research. One of the hottest topics in the field of gene regulation relates to the role of epigenetic modifications in dictating the expression output of the genome. In genomics, the advent of technologies for the large-scale profiling of these marks has made the characterization of epigenomes a coveted goal. And chromosome biologists are increasingly learning how epigenetic modifications contribute to the structural packaging of the genetic material at various levels.

The cover of the issue, pictured below, is a cartoon sketchboard by the journal’s art editor, Patrick Morgan.

The issue is packed with five reviews on epigenetics topics of interest:

  • Environmental epigenomics and disease susceptibility by Jirtle RL and Skinner MK. Epigenetic modifications provide a possible link between the environment and disease-causing alterations in gene expression. Evidence from animal studies increasingly supports this theory, including recent findings of epigenetically mediated transgenerational alterations in phenotype that are caused by environmental exposure. Link
  • Epigenetic signatures of stem-cell identity by Spivakov M and Fisher AG. How do stem cells keep the genes that drive differentiation in a repressed state, while maintaining the ability to express them in the future? Increasing evidence indicates that distinctive epigenetic traits underlie this unique aspect of stem-cell biology. Link
  • Transposable elements and the epigenetic regulation of the genome by Slotkin RK and Martienssen R. Cells use a range of increasingly well understood epigenetic mechanisms to keep transposable elements under control. These silencing mechanisms have been co-opted during the course of evolution to contribute to key aspects of chromosome biology and gene regulation. Link
  • Cancer epigenomics: DNA methylomes and histone-modification maps by Esteller M. Recent technological advances allow epigenetic alterations in cancer to be studied across the whole genome. These approaches are being used to answer key outstanding questions about cancer biology, and to provide new avenues for diagnostics, prognostics and therapy. Link
  • The epigenetic regulation of mammalian telomeres by Blasco MA. Epigenetic modifications are key players in the regulation of fly and yeast telomeres, and recent studies indicate that the same applies in mammalian cells. These findings have implications for our understanding of the roles of telomeres in ageing and cancer. Link

The recent surge of coverage by high impact journals in the area of epigenetics likely reflects the major advances and discoveries made in recent years, and will hopefully provide renewed interest among scientists, funding bodies, and most importantly, the general public.

Cell Reviews Epigenetics and Chromatin Organization

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The journal Cell has released a special review issue, “Epigenetics and Chromatin Organization.” The issue contains 11 review articles, beginning with a review of one of the most exciting aspects of epigenetics: its effect on evolution.

According to classical evolutionary theory, phenotypic variation originates from random mutations that are independent of selective pressure. However, recent findings suggest that organisms have evolved mechanisms to influence the timing or genomic location of heritable variability. Hypervariable contingency loci and epigenetic switches increase the variability of specific phenotypes; error-prone DNA replicases produce bursts of variability in times of stress. Interestingly, these mechanisms seem to tune the variability of a given phenotype to match the variability of the acting selective pressure. Although these observations do not undermine Darwin’s theory, they suggest that selection and variability are less independent than once thought. Link

A nice summary of this review article is available at Gene Expression.


The other review articles include:

This special review issue from Cell is a clear indication of the role that epigenetics is playing in changing the scope and direction of scientific research in many different areas. My hope is that epigenetics will continue to inspire more articles in the press and will become well known among both those in science and the general public. Link

How I Found the Greally Lab

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The Greally lab was really easy to find. They linked to me. I have access to a nice stats package through my Web host that shows every referrer to Epigenetics News. So if any Web site links to any page of this site, I’ll eventually see it. Eventually, because there are now hundreds (if not thousands) of sites that link to Epigenetics News. And Dr. Greally, or presumably the person that updates their lab’s web page, decided to add a nice link to “Trevor Covert’s Epigenetics News site, a really valuable blog of all things current in the world of epigenetics.”

So, why should anyone care about the Greally lab? Well, as it turns out, they’re doing some fantastic epigenetics research. Based at the Albert Einstein College of Medicine in Bronx, New York, Dr. John M. Greally “has a long-standing interest in gene regulatory processes that extend over large regions of the genome and give rise to human diseases.”

Our major projects are centred on the discovery of DNA sequence characteristics that discriminate genes undergoing genomic imprinting, using these to find new imprinted genes that are candidates for causing human disease.

The technologies required for this research include innovative molecular assays and bioinformatics techniques. This combination provided the foundation for our recent new avenue of study into cytosine methylation patterns in large regions of the genome.

We use these techniques to learn the rules of normal epigenetic gene regulation through cytosine methylation, creating the foundation for understanding how it is disrupted in disease.

The disease-relevance of epigenetics is now being appreciated. The core dogma of medical genetics is that genes cause disease through mutations. However, this assumes that the gene is switched on appropriately to start with. In the field of cancer research in particular, it is now appreciated that inappropriate silencing of tumour-suppressor genes or activation of oncogenes through epigenetic dysregulation is a major contributor to neoplasia.

We study how the epigenome is altered in cancer, type 2 diabetes mellitus, aging, and as a response to diet and other influences. It is our belief that epigenetic dysregulation will prove to be a much more common cause of complex human diseases than DNA mutations.

I’d like to thank the Greally lab for their ongoing research because, without it, epigenetics would not be where it is today. Greally research articles Link

Cause For Concern in Microarray-Based Studies

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New research published in the Journal of the National Cancer Institute shows that many microarray-based cancer studies have critical flaws in their analyses or conclusions.

In the study, Simon and his NCI colleague Dr. Alain Dupuy looked at 90 studies published through the end of 2004 that compared microarray profiling with medical results. The most frequently studied cancers were blood malignancies (24 studies), lung tumors (12 studies), and breast cancer (12 studies).

Simon and Dupuy then specifically looked at the statistical methods and reporting in 42 studies published in 2004. Half of these efforts had at least one basic error. In the 23 studies with an outcome-related gene finding, nine involved inadequate, confusing, or unstated methods to account for false-positive results, Simon and Dupuy found.

In 13 studies, there were unsupported claims of meaningful classifications of results, where the authors did not do adequate analyses to reach their conclusions. In addition, in the 28 studies that predicted outcomes, 12 used biased estimates of the accuracy of their predictions, according to Simon and Dupuy.


Tumor-Free Breast Tissue Can Have Increased Methylation

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New research from a team at the Ohio State University Comprehensive Cancer Center shows that normal breast tissue as much as 4 cm away from a cancerous breast tissue can have increased methylation in the RASSF1A gene promoter.

During this study, the researchers measured the degrees of methylation in tissue removed from 47 patients who had undergone mastectomies for a form of breast cancer called invasive ductal carcinoma. This tissue was compared with 69 samples of normal tissue taken up to four centimeters (almost two inches) from the tumor’s visible edge and with control tissues removed during breast-reduction surgery.

The study also included two double-mastectomy cases in which both breasts had been removed to prevent cancer recurrence. For these, the researchers also tested tissue from four locations on the breast that had no visible tumor.

The researchers used microdissection techniques to isolate tiny milk ducts in each sample. They then measured methylation levels in the RASSF1A gene in epithelial cells that lined the ducts. These cells were the sources of the initial tumor.

As expected, tumor cells showed the highest methylation levels. But the researchers found significant methylation levels in normal tissue adjacent to the tumors in 29 patients. The degree of methylation was lower than in the tumor cells, but it was 1.75 times higher than in control cells.

“In both double-mastectomy cases, we were surprised to find high methylation levels in the tumor-free breast,” says Yan.

In addition, the researchers identified three other genes (called CYP26A1, KCNAB1 and SNCA) that were highly methylated in about one-third to nearly one-half of the breast tumors.

“Again to our surprise, we found that in 70 percent of cases, when these genes were highly methylated in tumor cells, they were also highly methylated in the adjacent normal tissue,” says Yan.

“This suggests that the presence of DNA methylation in normal tissue adjacent to tumors is more prevalent that previously thought.”


Late Fall Issue of Journal of Epigenetics Available

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The October/November/December 2006 issue of the journal Epigenetics is now available and contains four research papers covering topics related to breast cancer, autism, and prostate cancer.


Results of Clinical Trial in Blood-Based Cancer Detection

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BioCangen Inc. has announced the initial results of its clinical validation study of early cancer detection.

    Among the blood samples from 102 patients with solid tumors including lung cancer, colon cancer, breast cancer and stomach cancer, 73 samples were correctly identified as the cancer, showing a 71.6% detection sensitivity. Among the 82 health individuals, only 3 samples were identified as the cancer, indicating a 96.3% specificity.

These results will be further validated with multi-center trials for submission to the FDA. Link

Illumina Introduces High Throughput DNA Methylation Profiling

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Illumina Inc. (NASDAQ:ILMN) has announced that it has introduced a high-throughput DNA methylation profiling technology capable of surveying up to 1,536 methylation sites across 96 samples simultaneously. From Business Wire:

    By pairing Illumina’s proven BeadArray platform with the GoldenGate(R) assay approach, researchers have the ability to perform genome-wide methylation profiling across multiple areas such as cancer and human embryonic stem cell research. The GoldenGate Methylation Cancer Panel I, the first standard panel, covers 1,505 methylation sites over 800 cancer genes. Custom-content methylation panels will soon be available to meet individual research needs.

    Recently, the NCI and the National Human Genome Research Institute (NHGRI) announced two more components of The Cancer Genome Atlas (TCGA) Pilot Project, a three-year, $100 million collaboration established to test the feasibility of using large-scale genome analysis technologies to identify important genetic changes involved in cancer. As part of this project, the Sidney Kimmel Comprehensive Cancer Center of the Johns Hopkins University and the Norris Comprehensive Cancer Center of the University of Southern California were awarded funds to establish Cancer Genome Characterization Centers (CGCC). At these centers, researchers will utilize Illumina’s GoldenGate methylation technology to detect changes in methylation profiles associated with transcribed genes in cancer samples.


Epigenetics Garners Fifth Spot in Discover’s Top Science Stories of 2006

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Discover Magazine has recognized several related discoveries in the field of epigenetics as the fifth top science story of 2006. The article details the research of Dr. Minoo Rassoulzadegan at the University of Nice:

    Minoo Rassoulzadegan’s mice are unruly. In blatant violation of the laws of genetics—described a century ago by famed monk-scientist Gregor Mendel—they inherit their parents’ coloring without inheriting the genes that cause it.
    Rassoulzadegan stumbled upon her rodent scofflaws after altering a gene in gray mice so that their feet and the tips of their tails turned white. The big surprise came in the next generation. Some offspring also had white spots, even though they didn’t inherit the mutated gene and so should have been all gray. When she looked for the cause, Rassoulzadegan found unusual amounts of RNA in the sperm of the mutant parents. She then injected RNA from the brains and sperm of those mice into ordinary gray mouse embryos. Many of the RNA-injected embryos likewise grew into white-tailed adults, regardless of the coloration written in their DNA.

The article also highlights the research of Dr. Vicki Chandler of the University of Arizona at Tucson and Dr. Michael Skinner of Washington State University. Link

Epigenetic Stem Cell Signature in Cancer

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Nature Genetics has published a brief communication from Marth et. al on the epigenetic stem cell signature in cancer:

    Embryonic stem cells rely on Polycomb group proteins to reversibly repress genes required for differentiation. We report that stem cell Polycomb group targets are up to 12-fold more likely to have cancer-specific promoter DNA hypermethylation than non-targets, supporting a stem cell origin of cancer in which reversible gene repression is replaced by permanent silencing, locking the cell into a perpetual state of self-renewal and thereby predisposing to subsequent malignant transformation.


Update: There are great summaries and reactions to this letter available at Migrations and Pure Pedantry.