Chromatin's rising tide

To capitalize on the full range of possible chromatin targets in and beyond oncology, industry and academia will need to delve deeper into how chromatin regulation is altered in disease, create tools that can reliably validate new targets and develop biomarkers that can improve the chances of success in clinical trials.

A wave of compounds targeting chromatin regulators entered the clinic in 2013, enabled by a decade of progress in understanding how chromatin dysfunction drives cancer.1

The first DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors were approved to treat subtypes of lymphoma in 2004 and 2006, respectively. In the following decade, research linked genetic alterations in functionally diverse chromatin regulators to many additional types of cancer.

That fueled the discovery of a second generation of compounds against new targets to treat genetically defined cancers (see "Select clinical-stage compounds that target epigenetic regulators").

Development of this wave of compounds was aided by technical advances that allow chromatin to be biochemically characterized in detail. Despite the progress, there remains a huge opportunity in unexplored targets and much to discover about how chromatin-dependent cellular pathways are affected in different diseases.

Against this backdrop, SciBX organized a panel of thought leaders to discuss the possibilities and challenges in developing chromatin-targeted compounds and outline ways to accelerate the translation of this information into disease-modifying therapies.

The panel identified three areas of chromatin drug development that are most in need of innovation.

First, new chemical tools to functionally characterize chromatin will be critical to validate targets-including those currently deemed intractable. These tools will enable a deeper understanding of how mutations in chromatin regulators alter cell signaling pathways and cell fate.

Panel member Jim Audia, CSO at Constellation Pharmaceuticals Inc.,

said that the optimal way to generate new tool compounds would be through collaborations between industry and academia such as the Structural Genomics Consortium (SGC).

"We realize that, regardless of your company, the academic community from outside it is immense compared to the resources that you can muster from within," he said.

Second, identifying predictive biomarkers and developing new methods to measure target engagement in vivo will be needed to accelerate progress to the clinic. Information about how hitting chromatin targets provokes different cellular responses between individuals will help companies select appropriate patient populations.

Because little is known about how the cellular pathways involved in chromatin regulation differ cell by cell or tissue by tissue, that information will need to be integrated from multiple experimental approaches.

"The simplest readout, if you were to perform knockdowns or if you had an inhibitor, would just be to look at changes in gene expression," said Peter Tummino, who at the time of the panel was head of GlaxoSmithKline plc's Cancer Epigenetics Discovery Performance Unit (DPU). "But what we are finding is that it is entirely insufficient. You can look across a set of cell lines and there's no similarity, there is no common gene profile. And so the next step beyond that is to think about what are the changes in histone marks-which you might expect to change. You can perform transcription factor mapping, if possible. It's the integration of several different data sets that begins to lead toward an understanding of mechanism."

Tummino is now VP and global head of lead discovery at the Janssen unit of Johnson & Johnson.

Finally, the panel said that chromatin regulators should also be targeted outside of oncology. Human genetic studies and an increased understanding of how cell fate is determined in neurology and immunology suggest that these two fields are next in line.

"We're years behind the oncology field in terms of looking at target association

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