Snuggled next to the looming giant of Boston’s World Trade Center is Waterfront Mariott hotel – which became the venue for CHI Discovery on Target 2013, Histone Demethylases meeting (Held on September 25th). This rapidly developing and “up-and-coming” neighborhood of Boston, called Fort Point Channel, provided a perfect backdrop for a meeting that is devoted to the equally dynamic field of targeted therapies. Academia and industry professionals alike gathered to exchange expertise and talk about their findings that some day (perhaps soon) will end up in a clinic, helping patients to fight cancer, heart disease, obesity and a number of other devastating conditions.
The breadth of the information presented at this meeting made it exceedingly difficult to choose a few talks to highlight – so here are the three studies that I believe provided the widest appeal for those gathered to listen.
Using Epigenetics to Develop Better Targeted Therapies
Stuart Schrieber, Broad Institute of Harvard and MIT
The first talk I would like to mention here is the work by Dr. Schrieber’s group at that focused on developing a better way for finding successful targeted therapies. Current approaches all fall short in one way or the other: animal based studies fail to accurately recapitulate the human disease, bioinformatics studies often use observed correlations which are not causations and cannot be utilized as potential targets. Evidently, there is an unmet need for a more robust approach. To this end the Schrieber group created a new massive library of chemical compounds all of which illicit various biological and biochemical phenotypes, using gene expression and morphology as a read-out. Through this approach the scientists found a complementary, non-competing drug for malaria that would augment the existing treatment.
Additionally, as Dr. Schrieber had reported his group produced a system to address cancer genetic dependencies – a work published in this year’s issue of Cell. Briefly, the group has created a resource that allows one to identify a cancer vulnerability based on a given genetic alteration of that particular cancer type. For example, high levels of RIPK1 predict sensitivity of cancer cells to XIAP inhibitor or NSD2 mutant cells are dependent on HDAC1,2 for its survival and thus are acutely sensitive to HDAC inhibitors.
Treating Type II Diabetes
Paul Feldman, GlaxoSmithKline
Following this strong lead came a talk by Paul Feldman of GlaxoSmithKline, whose focus and approach were dramatically different, but no less impressive. The focus of his group’s study was treatment of type II diabetes and the approach was to biochemically mimic bariatric surgery in patients. The idea came from the original observation that 84% of obese patients who receive Roux-en-Y gastric bypass have complete remission of their type II diabetes. They found specific peptides in the gut that assist insulin in telling the brain to uptake glucose – and went on to synthesize those peptides. This beautiful in its simplicity approach is also a great example of the “cross-pollination” between the disciplines, where a mere side effect in case of a weight loss surgery turned into a major benefit for a large number of diabetic patients.
JQ1 Inhibition of BRD4 in Cancer Therapies
James Bradner, Dana Farber Cancer Institute
Finally, a talk by Dr. Bradner, I believe warrants a special attention in this report. As it is well known, Dr. Brander and his group were the first ones to synthesize a potent inhibitor of bromodomain protein BRD4 – which they previously identified as a critical dependency of all MYC driven tumors. BRD4, as they showed, turns out to be a bridge between chromatin and transcriptional signaling. It is asymmetrically loaded at gene promoters and enhancers, strongly preferring so-called super-enhancers. Inhibition of BRD4 using JQ1 (aforementioned inhibitor of BRD4) has a potent cytostatic and in some cases cytotoxic effect on virtually all transformed cell types.
In his talk Dr. Bradner has addressed a growing skepticism on the part of academic community as to the specificity of JQ1 in that its effect on cancer seems to be unbelievably strong and ubiquitous. The idea, he explained, is that BRD4 maintains dominant transcriptional signature of a given cell and JQ1 inhibits it, whatever that signature is in a given cell. In other words BRD4 does not have a specific and limited downstream effectors, its targets change from cell to cell, from cancer to cancer. As such it appears to be a common vulnerability of all malignancies since there always is a dominant signaling network that a cell relies on.
More recently, this amazing effect of JQ1 has been extended into the field of cardiovascular disease. One of the most detrimental and so far incurable heart conditions is hypertrophy that results from aberrantly elevated signaling within cardiomyocytes that result in overgrowth and ultimately heart failure and death. Bearing the same idea in mind that JQ1 should inhibit a dominant signaling network within a cell, scientists have administered the drug to the animals designed to model human hypertrophy. Astonishingly, all the animals that received JQ1 have been able to bypass hypertrophy and heart failure, unlike those ones that received vehicle treatment.
This drug, that could very well be a panacea, might still turn out to have its limitations in clinic, but its unprecedented pluripotency has already encouraged a whole new field of research.
***EpiGenie would like to thank Miriam Enos who is a Post doctoral fellow, at the Brigham and Women’s Hospital for supplying this excellent conference coverage***