Lorenzo de la Rica from IDIBELL in Spain gave the inside scoop on the European EpiCongress held on November 19th, 2013 in London. See his full report below:
This conference was held at the Strand Palace Hotel, in London city center , near Covent Garden. The organizers (Hanson Wade) pulled together attendees mostly from big or medium pharma companies (Glaxo, Novartis, Pfizer, Epizyme, Genentech, etc.) , as well as small spin-offs, specialized companies providing services to pharma, and some academics coming from Imperial College and Oxford.
The Field of Epigenetic Drug Development
Bob Copeland, Epizyme
Bob Copeland described the advances that Epizyme has shown in the treatment of acute leukemia patients with epigenetic drugs. One example, EPZ-5676 seems to be a potent and selective inhibitor of the DOT1L histone methyltransferase (HMT). This drug is being developed for the treatment of acute leukemia with alterations in the MLL gene, and has succeeded so far in an ongoing phase 1 dose escalation study. They observed a)No dose-limiting toxicities; maximum tolerated dose (MTD) not reached; b)Treatment effects, consistent with genetically defined therapeutic mechanism of action, observed in 4 of 8 acute leukemia patients with MLL-rearrangement (MLL-r); no effects observed in non-MLL-r patients. c)Dose-proportional exposure. d)Dose- and time-dependent methyl mark inhibition. Moreover some MLL-r patients experienced resolution of leukemia-related symptoms and manifestations, including fevers, cachexia, and leukemia cutis.
Copeland also showed results from other potential epigenetic drugs that targets the EZH2 histone methyltransferase. EZH2 is a histone 3 K27 methyltransferase (HMT) that can become oncogenic and cause non-Hodgkin lymphoma and solid tumors. EPZ-6438 is a SAM-competitive inhibitor that showed strong antitumoral activity in several xenografts models. This drugs also inhibited H3K27 methylation in non-tumour tissues such as PBMCs and Bone marrow. It is currently in Phase 1/2 Clinical Trials.
More info available at the Epizyme website.
Chemical Biology Interrogation of Chromatin Signalling
Steve Bellon, Constellation Pharmaceuticals and Andrea Cochran, Genentech
This talk shared between Steve Bellon and Andrea Cochran, showed the results from an ongoing collaboration between their two companies focused on the development of inhibitors of the BET chromatin reader. BET proteins have bromodomains, that bind to histones. Teams from both companies have taken advantage of their knowledge on chemical biology to develop small molecules for bromodomain inhibition.Focusing on Bromodomains, Constellation Pharmaceuticals showed the workflow for bromodomains inhibitors development. Bromodomains have several features that makes them ideal for chemical inhibition:
- great sequence homology in the binding site =>Great potency for inhibition
- low sequence homology on the surroundings =>Allows specific inhibition of the different families
Once the best hits are found for each of the different families, Genentech would enter into action. Genentech also talked about the importance of the newly discovered histone marks. Those are not well understood yet, and so they wonder if there are readers for such modifications. As an example, Dr. Cochran cited the different binding preference of the bromodomains for the Histones modified with acetyl, crotonyl and butyril groups. Of course, she also shed light into the non-histone protein acetylations, that could be key for off-target effects.
Beyond First Generation BET-Protein Inhibitors
Norman Wong, Zenith Epigenetics
Dr. Wong nicely explained general features of BET chromatine readers. BET proteins play a critical role in the epigenetic regulation of transcription of particular gene and contain highly conserved bromodomains that play a key role in their epigenetic control of gene expression. BET proteins are often called “readers” of the histone/chromatin structure because they recognize a particular modification of proteins, associated with the DNA where they can bind and recruit other proteins essential to the regulation of gene transcription. Wong also explained about future plans of the company, that will mainly focus on oncology and autoimmune research.
4SC-202 molecule inhibits Wnt and Hh Pathways by Epigenetic Regulation
Daniel Vitt, CSO, 4SC AG
4SC has already twoe pigenetic compounds in clinical development. One is 4SC-202, classified as a selective deacetylase (DAC) inhibitor, which specifically inhibits the HDAC 1, 2 and 3 enzymes. It is an oral anti-cancer compound that targets Wnt signalling pathway, thus leading to an inhibition of cellular signal transduction. It is widely known that Wnt pathway plays an important role in the origination and metastasis of cancer diseases, and this molecule is able to inhibit it, even in cancer stem cells.
This molecule also targets Hedgehog signalling pathway, thus showing a promising potential for the treatment of haematological cancers, as well as cancers whose growth depends substantially on the Hedgehog and Wnt signalling pathways. More info available at the 4sc website.
Novel Epigenetic Targets to Prevent and Treat Women Specific Cancers
Martin Widschwendter, Professor, UCL
Professor Widschwendter is world famous for its contributions on Epigenetic stem cell signatures in cancer [Nature Genetics 39, 157 – 158 (2006)]. He is Professor in Women’s Cancer, Head of the Department of Women’s Cancer at University College London (UCL) and a Consultant Gynecological Oncology Surgeon at University College London Hospital (UCLH). During this talk, among several other interesting topics, Martin focused on one of his latest published projects. His team investigated the Role of DNA Methylation and Epigenetic Silencing of HAND2 during Endometrial Cancer Development. In these patients, HAND2 methylation is a common molecular alteration. The DNA methylation status could potentially be employed as a biomarker for early detection of endometrial cancer and as a predictor of treatment response. Moreover, mice harboring a Hand2 knock-out specifically in their endometrium developed precancerous endometrial lesions with increasing age, and these lesions also demonstrated a lack of PTEN expression.
Epigenetic Speed Networking
One of the most interesting moments of this event, was the “Speed Networking” time. During this time, people stood at different tables, in groups of 6, allowing you to get a brief idea of what your table-mates were working on. If it turned out that you had similar interests, then those introductions would make it easy to identify and network further with potential clients, suppliers, or collaborators. After 5 minutes, a bell would ring, and half of the table would then move clockwise. When it was over, you had the chance to meet all the other attendees and collect lots of business cards!
Moving from Academia to Industry
As an attendee with nothing to sell and nothing to buy (I work in “Academia”), I realized that indeed, for many EpiGenie readers, it might be really interesting to know some of the most valuable skills needed to make the jump from academia to industry. So, I fired these three simple questions to the people I met:
-Is it worth it to do a postdoc after a PhD if you want to change into Industry?
The consensus answer was that if that postdoc is going to add value, skills or techniques, then go for it. Otherwise, there is no sense on spending 3 or 4 extra years just doing the same of what you did during your PhD.
-What are the most valuable skills that a PhD should learn in order to work in Industry?
You should feel comfortable in decision-making scenarios, as you would be making decision in many different topics, that you will never be sure if is the right choice. Moreover, you should be quite a good sales person, and also have very good presentation skills.
-What positions are more likely to be held by newly awarded PhDs?
This depends on how much you want to invest in your future in industry. There is not a magic formula nor a position designed for PhDs. If someone is good, then the kind of degree isn’t all that critical to enter in the business and grow.
During this meeting many of the big pharma, and also some other smaller pharma or biotechnological companies, disclosed the areas that they are working in. This meeting was geared for those working in Industry to get an idea of what other companies were doing, network a lot, and of course, learn a lot about this promising “new” pharmacologic era of Epigenetic Therapy.
***EpiGenie would like to thank Lorenzo de la Rica, who is a PhD candidate in the Cancer Epigenetics and Biology Programme (PEBC) at the Bellvitge Biomedical Research Institute (IDIBELL), Spain for providing this conference coverage.