Hanson Wade’s EpiCongress events have become a mainstay in the field, and offer a unique blend of academic and industrial research. Sophia Kim from the Albany College of Pharmacy took the trip to Boston to fill us in on everything that happened. Check out her report:
EpiCongress Meeting Summary
This year’s EpiCongress was held at the Hyatt Regency in Cambridge, MA in the President’s Ballroom from July 23rd to July 24th 2014. As a student attending a professional conference for the first time, EpiCongress 2014 was a great meeting for someone new to the growing field of epigenetics research. The meeting was low key and on the cozy side in terms of attendance, giving attendees a chance to chat with each other rather than feeling lost in the crowd.
Despite being a student with limited research experience, I’ve had the pleasure to talk to some of the key presenters and event organizers over some coffee on the first day and during the speed networking sessions without feeling intimidated by my lack of experience with conferences. In general, everyone was excited to talk about their research and share their own experiences.
The focus of EpiCongress was mainly covering the latest data in drug development utilizing epigenetic research such as Resverlogix Corp’s RVX-208, a BET inhibitor with usage in atherosclerotic diseases or Zenith Epigenetic’s ZEN-3365.
In general, most of the conference focused on the oncologic applications of current drugs in development. However, there was some discussion about developing bromodomain inhibitors and epigenetics eventually to help treat chronic conditions as Resverlogix Corp is attempting, and the future discussions that will be needed about the effects for long term therapy.
RVX-208 a BET Inhibitor that Raises ApoA-I in Human Clinical Trials
Norman Wong, Resverlogix Corp
Dr. Wong presented Resverlogix Corp’s compound RVX-208, a small molecule BET inhibitor selective for the second bromodomains (BD2s). Its mechanism of action is to increase the production of apolipoprotein A-I (apoA-I), key in the structure of high-density lipoprotein (HDL). HDL is important for managing cholesterol levels and important for cardiovascular diseases.
In preclinical studies with ApoE knockout mice on high fat diets showed increased HDL levels and decreased atherosclerotic lesions while African green monkeys showed increased HDL and apoA-I levels.
Wong also talked about two major clinical trials, ASSURE and SUSTAIN. SUSTAIN results showed RVX-208 significantly increased HDL levels. While the results of the ASSURE trial failed to meet its primary endpoint of change in percent atheroma volume, RVX-208 did show significant relative risk reduction of major cardiovascular events (MACE), even more so in patients with c-reactive protein (CRP) > 2.0mg/dL.
Overall, the main take home points Dr. Norman Wong wanted the audience to take home were:
- RVX-208 is an orally active BET inhibitor that increases production of apoA-I
- RVX-208 showed reduction in MACE
- RVX-208 may have some CRP benefits
Inhibition of Methyl-Lysine Readers by Small Molecule Chemical Probes
Lindsey Ingerman James, University of North Carolina
Dr. James opened her presentation covering methyl-lysine readers, which stood out since most presentations covered bromodomains, the current hot topic in epigenetics. She particularly focused on malignant brain tumor (MBT) domains, which recognize mono and di-methylated lysines.
Currently in development is the lethal(3) malignant brain tumor-like protein 3 (L3MBTL3) small molecule inhibitor, UNC1215, the first probe known for methyl-lysine binding proteins. Using AlphaScreen assays, this small molecule inhibitor showed selectivity for L3MBTL3 when compared to over 200 similar readers. Cell assays showed that UNC1215 was effective at reducing MBT foci in cells.
L3MBTL3 also localizes with UNC1215 in the nucleus, and a pulldown assay showed that the compound interacts with endogenous L3MBTL3. L3MBTL3 forms a dimer in order to accommodate binding. Future studies for understanding L3MBTL3 involve modifying L3MBTL3 in order to look at protein-protein interactions and localization.
Dr. James also covered the p53-binding protein 1 (53BP1), which also binds mono and di-methylated lysines to show how these readers can recognize the same epigenetic mark. Of particular importance is that 53BP1 is found to be underexpressed in triple-negative breast cancer and is known to promote DNA double strand break repair.
While she did not present much data, Dr. James talked about a fragment-like 53BP1 ligand is under development for improving potency. The last reader presented is chromobox homolog 7 (CBX7), which has been found to bind tri-methylated lysine 27 and 9 of histone H3 (H3k27me3; H3k9me3). As of now, there are peptide ligands in development for CBX7 looking at peptide length, backbone methylation, tri-methylated lysine mimetic, and structural design. There is still a lot of research left for CBX7 inhibition, but future applications look towards effecting cell proliferation on several cancer lines. Dr. James’s summary points were:
- There is progress on developing inhibitors for methyl-lysine readers
- Further development on these readers may open up more opportunities
- Small molecule inhibitors are key to understanding the chemical biology of methyl-lysine readers
Safety Considerations in Developing Epigenetic Drugs
Jatinder Singh, AstraZeneca
Rather than talking about research data, Dr. Singh discussed the implications of chronic treatment with drugs that affect patients’ epigenomes. While most of the drugs in development are for use in oncology, as more indications and trials are completed, he discusses the importance of looking at the long term side effects that can occur when considering chronic conditions.
First, Singh points out that these drugs can have long term effects in the patients that may not manifest in preclinical trials, which tend to be a snapshot of side effects that can occur. As these drugs affect genetic expression, side effects may not be as acute. This may mean a much longer follow up time.
Second, epigenetic therapy can have transgenerational effects that will greatly impact the risk/benefits of therapy. He cites data showing epigenetic changes carried through several generations such as height reduction in progeny whose ancestors lived through the Great Famine in Ireland. Preclinical studies may have to cover several generations of animal studies prior to moving onto clinical trials.
Another aspect that Singh covers is that xenografts may also not be ideal for studying these drugs as epigenetic drugs are not selective to just the xenograft, but also the entire system and environment.
Some of the summary points from Dr. Singh’s talk were:
- Differences in requirements for cancer therapy versus chronic conditions such as outcomes and long term side effects may affect trials
- Effects may be long term in patients, transgenerational, and later in onset
- Using xenografts for monitoring efficacy may not encompass all the systemic effects of epigenetic drugs
- Preclinical trials may need to cover multiple generations of animals
**EpiGenie thanks Sophia Kim, who is a Pharm D. candidate at the Albany College of Pharmacy and Health Sciences, for kindly providing this conference report.**