Summary of Keystone Symposium: Epigenetic Marks and Cancer Drugs
In order for each of the cells of our bodies to stay healthy, gene expression must be controlled in a tightly regulated fashion. DNA is packaged around histone proteins, and a diverse set of enzymes are responsible for adding or removing specific post-translational modifications, or epigenetic marks, to histone tails. The precise timing and degree to which those marks are added ensures proper gene expression and genome stability, allowing our cells to thrive. However, it is now clear that mutations occur in many genes that code for histone modifying enzymes thereby disrupting their carefully coordinated action and thus contributing to many human diseases, including cancer. In order to help blaze new and innovative paths geared toward developing therapeutic strategies combating those aberrant histone modifications, a recent keystone symposium relating the connection between epigenetic marks and cancer drugs just concluded in Santa Fe, New Mexico, from March 20-25. In an interview broadcast on YouTube, conference scientific organizer and investigator at the Stowers Institute for Medical Research in Kansas City, MO, Ali Shilatifard, Ph.D., said “bringing together experts from both academia and the pharmaceutical industries is a very unique aspect of this symposium”. The hope is that leaders from diverse fields will be given an arena to discuss the molecular properties governing cancer-associated epigenetic enzymes and find new agents that can be used as treatments for cancer or other diseases.
The conference got off to a strong start with the plenary presentation given by Howard Hughes Medical Institute Investigator and member of the Broad Institute, Stuart Schreiber. Dr. Schreiber is a distinguished chemist with a long track record of developing effective small molecule inhibitors using his Diversity Oriented Synthesis (DOS) approach to drug discovery. As an epigenetic therapeutic, Schreiber’s lab developed the HDAC inhibitor Vorinostat, a drug with FDA approval for the treatment of cutaneous T-cell lymphoma. Numerous diseases could be treated through the use of HDAC inhibitors and Schreiber’s presentation mainly focused on recent advances in the areas of HDAC inhibition compound development using his DOS methods.
Other emerging themes from the conference included the connections between transcription, especially Myc-driven transcription, and the epigenetic contributions made by histone “writers”, such as lysine methyltranserases like EZH2 or Suv39h1, “readers”, such as the bromodomain-containing proteins like Brd4, and “erasers”, such as the JMJD family of histone demethylases. By targeting individual members from each of these enzyme classes, treatments for genetically defined and otherwise difficult to treat tumors may be possible in the future. Scientists giving presentations relating chromatin modification and transcriptional control included Franklin Pugh (Penn State), Patrick Cramer (University of Munich), Richard Young (Whitehead Institute), Shilatifard, Peter Verrijzer (Erasmus University, Netherlands), Charles Lin (Whitehead Institute), Tony Kouzarides (Cambridge, UK), Michael Cole (Dartmouth), Bruno Amati (IIT, Italy) James Bradner (Dana-Farber), Francois Fuks (University of Brussels, Belgium) and Junwei Shi (Cold Spring Harbor).
Epigenetic control is not limited to histone modifications, of course. Peter Jones (USC) and Jean-Pierre Issa (Temple University) gave presentations updating the use of DNA methyltransferase inhibitors to treat various types of cancers and provided the most recent theories as to the molecular mechanisms making them effective therapies. Ramin Shiekhattar (Wistar Institute), Jeannie Lee (Massachusetts General Hospital), and Robert Martienssen (Cold Spring Harbor) all gave presentations describing some of the ways that aberrant non-coding RNA expression contributes to cancer development. In another area garnering much attention, presenters including Shiv Grewal (NIH), Thomas Jenuwein (Max Planck Institute, Germany), Yi Zhang (Harvard), and Laurie Boyer (MIT) described how some of the shared epigenetic processes seen during development are inappropriately activated in committed cell lineages, thereby contributing to tumorigenesis. On a related topic, Anne Brunet (Stanford) and Shelley Berger (UPENN) described epigenetic changes that occur during aging and showed that their reversal mimics the lifespan extension seen for animals fed calorie restricted diets. Together most of the talks elucidated numerous novel pathways to be exploited for the development of therapeutics to help treat cancers.
During the conference’s final session, scientists from major pharmaceutical companies, including Robert Gould (Epizyme, Inc.), Patrick Trojer (Constellation Pharmaceuticals), and Marie Classon (Genetech, Inc.), described the latest advances in the development of drugs targeting aberrant epigenetic pathways in cancers. In the leading talk of the session, Dr. Gould explained how Epizyme developed a class of SAM/SAH (the essential cofactors for histone methylation reactions) derived competitive inhibitors to the lysine methyltransferases MLL and EZH2 for the treatments of mixed lineage leukemias and non-Hodgkins lymphoma, respectively. The key kinetic features of the most successful inhibitors involved their potency (effective concentrations in the low nanomolar ranges), high specificity, and especially their very large koff rate. Gould emphasized that the slow koff rate was essential for allowing the compound to see its beneficial epigenetic effects. Both compounds are in advanced pre-clinical stages with patient trials set to begin soon.
The overall feelings coming out of the conference was that there are a lot of new data describing the ways that epigenetic modifications contribute to cancer on the molecular level. And with every new revelation comes a new therapeutic target to potentially treat cancers that are defined by their altered epigenetics. Given the recent industry advancements with inhibitor development, there is hope that the newly defined targets will be translated to clinical success. As Dr. Shilatifard stated, the recently completed Keystone Symposium will surely prove to be “an important setting for the future course of the field”.