The 2nd World Epigenetic Summit was held December 7-8th 2011, and our friend Gregor Gilfillan from the University of Oslo was there to take in the action. Apparently, the setting in Munich was a winner. Or as Gregor described it…”Fantastic city with Christmas markets in full swing, and gluhwein on tap!”
The summit was aimed primarily at the Biotech / Pharma industries and their suppliers – and attendees from these categories were very enthusiastic about the talk contents and networking opportunities. I found the scientific content to be based more on previously published work than I’m used to seeing at some more academic events, but it provided an interesting look inside the industry. The unusual “speed networking“ session (yes, akin to speed dating -just for scientists and with less nerves and anticipation) is a very smart idea that was employed to great effect – the opportunities at the meeting for informal networking were impressive. Moments of frantic business card swapping abounded, but there was ample time to chat with the forty or so other attendees, practically all of whom you could expect to meet within the space of 2 days. Below are my selected digests from the 15 oral presentations:
Histone Methylation Targets
Robert Copeland, Epizyme
Robert opened the meeting with a brief overview of all 96 known & predicted HMTs, from which Epiyzme has drilled down to a list of 20 that they will focus on as prioritised targets for inhibition, based on target disease, availability of patient groups, and biochemical “assayability”. Two examples were given: First, the HMTase DOT1L, which is aberrantly recruited by cancerous MLL fusion protein (itself an HMT in the wt form, but not in the cancerous fusion form), resulting in inappropriate H3K79 methylation. Epizyme have, through mechanism-guided inhibitor design, produced a small molecule inhibitor that specifically inhibits DOT1L (EPZ004777 – which exhibits impressive 1000-fold greater specificity for DOT1L over the next interacting HMTase). EPZ00477 drives MLL tumour cells into apoptosis. This particular inhibitor apparently holds little promise for therapeutic use, but we are assured that Epizyme has more promising molecules up their sleeves. Secondly, EZH2, which in the case of Non-Hodgkin’s lymphoma appears in mutant forms that exhibit altered substrate specificity. These mutant forms interact with the wild-type enzyme (i.e. In heterozygous state) resulting in abundant aberrant methylation. Epiyzme have again produced a specific inhibitor.
Global Protein Modification Assays
Nathalie Rouleau, Perkin Elmer
Nathalie gave an overview of Perkin Elmer’s LANCE Ultra and AlphaLISA epigenetic assays for global protein modification levels (validated for the moment for a handful of histone H3 acetyl and methyl modifications). Based on antibody targeting combined with FRET or singlet oxygen (which allows longer range interactions to be assayed), these bead-based assays offer a scalable alternative to ELISA assays and Westerns – and the possibilities to take epigenetic analysis to high throughput levels. The impressive bit is the ability to seed, lyse and assay your cells all in the same well – from as few as 100 cells in some cases.
Transgenerational Effects of Epigenetic Drugs
Nessa Carey, Pfizer
Nessa raised a spectre: we worry about epigenetic drug toxicity, but largely ignore the potential minefield of transgenerational effects. Demonstration of transgenerational effects would effectively class epigenetic modifiers as teratogens. Nessa argued that the Pharma industry ought to anticipate some hurdles here and invest now in high throughput model systems that can test transgenerational effects – agouti mice just aren’t going to cut it. That said – how many existing drugs prescribed for non-epigenetic effects are going to end up in this category – and should existing drugs also be screened?
Epigenetics in Cognitive Disorders
Roberto Carlos Agis-Balbo, University of Göttingen
Roberto (speaking on behalf of André Fischer) covered epigenetic modulation of cognitive disorders. Examining histone acetylation in murine hippocampus, the team observed transient histone acetylation following stress (for example, fear response). However, this acetylation – in particular at H3K12 – was lost in older mice, which may resemble in this aspect cognitive loss of function in Alzheimer’s disease. ChIPseq confirmed this, and the effects could be rescued in older mice when treated with the pan-HDAC inhibitor SAHA. Similarly, in a mouse model of post-traumatic stress disorder (formin-2 gene knockout mice, which have problems with extinction of fear memories), have deregulated H3K12ac in hippocampal CA3 pyramidal neurons – which can be rescued by SAHA. Alzheimer’s disease and PTSD are therefore promising targets for drugs that can reconstitute H4K12 acetylation.
Esterase Sensitive Motifs for Delivering Epigenetic Regulators
Alan Drummond, Chroma Therapeutics
Alan addressed the problematic issue of delivering epigenetic regulators, on which Chroma have a unique position with their esterase sensitive motif (ESM) technology. Intracellular esterases, with cell type specific expression patterns, can be exploited to modify esterified drugs – effectively imprisoning them within the cell and driving cellular accumulation. Although currently limited to use in macrophages, current targets of ESM technology include inflammation and anti-cancer treatments. Of note, an ester-conjugate directed towards AML has completed phase I clinical trials.
HDAC Protein Degradation
Oliver Krämer, Friedrich-Schiller-Universität, Jena
Oliver detailed how HDAC inhibition leads to proteosomal HDAC protein degradation. Focusing on the most common mutation found in AML, FLT3-ITD (which becomes constitutively active and leads to cellular proliferation), his group noted that HDAC inhibition led to preferential degradation of mutant over wild type protein. Notably, they discovered HDAC inhibition led to phosphorylation of FLT3-ITD by UBCH8, resulting in ubiqutylation of FLT3-ITD by the SIAH-1 and -2 ubiquitin ligases, and ultimately leading to its destruction. Therefore, by combining HDAC inhibitors with a tyrosine kinase inhibitor, they were able to synergistically induce apoptosis in an AML model cell line – opening possibilities for combination therapy in AML.
**EpiGenie would like to thank Gregor Gilfillan, Ph.D., who is from the Department of Medical Genetics, Oslo University Hospital and University of Oslo, in Norway for providing this conference coverage.