Exploring Drug Mechanism of Action with CUT&RUN Services: Q&A with Foghorn Therapeutics
- Ellen Weinzapfel
Disruption of epigenetic mechanisms can lead to abnormal gene expression and is linked to many diseases, including cancer, inflammation, and neurological disorders. Epigenetic drugs, which target chromatin to restore normal cellular function, are a growing and promising class of therapeutics. A key part of developing these therapies is understanding their mechanism of action (MOA) to streamline development, reduce costs, and improve the chances of clinical approval. Chromatin mapping assays offer powerful insights into disease mechanisms and the molecular effects of these therapeutic interventions.
Foghorn Therapeutics is leveraging the profound impact of chromatin regulation on gene expression to drive next-generation drug discovery. At the heart of their efforts is the Gene Traffic Control® platform, a powerful tool to study and target the chromatin regulatory system. In this Q&A, Dave Lahr, PhD, Senior Director of Bioinformatics at Foghorn Therapeutics, explains how EpiCypher’s CUT&RUN Services have supported their work in epigenetic drug development.
Why is understanding drug mechanism of action so important?
Understanding a drug’s mechanism of action (MoA) can greatly increase the likelihood of successful clinical trials, for example by providing biomarkers of patient response and rationale for combination therapies.
Spending more time on studying the MOA in these preclinical research phases helps accelerate the entire drug development pipeline. This information is key to minimizing risk, particularly as you transition from cell lines and animal models to human trials – but it has not always been feasible with previously available tools and resources.
How can chromatin mapping assays impact this research?
For many drugs and disease states, defining MOA requires unraveling potential impacts on gene expression. As part of our research at Foghorn, we routinely examine gene expression changes in cell lines and mouse models treated with candidate compounds. However, we can’t rely solely on transcriptional profiling assays, as they are too indirect and lack the full context underlying drug activity – especially since our programs directly target chromatin regulators. Chromatin mapping can directly inform drug candidate MOA, revealing the “why” behind transcriptional changes following treatment.
What issues have you experienced with other chromatin mapping assays, such as chromatin immunoprecipitation sequencing (ChIP-seq)?
ChIP-seq has a whole host of problems: because of the labor-intensive nature of the assay the data are variable and hard to interpret. The antibodies are poorly validated, and it is difficult to optimize for drug-treated cells. Most chromatin mapping assays are not scalable, which becomes a huge issue when testing multiple compounds, cell lines, doses, and timepoints. The time and cost of doing an assay like ChIP-seq for many samples, combined with the other inherent inefficiencies, make it impractical for preclinical research.
How has EpiCypher CUT&RUN Services helped overcome these challenges?
Access to EpiCypher’s high-throughput workflows and expertise has been amazing. Through their platform, we were able to systematically test a variety of compound concentrations and time points that enabled us to understand both short- and long-term drug effects in cellular models. The throughput, cost, and reliability of their system also allowed us to scale up our experiments without compromising data integrity, thus enhancing the efficiency of our preclinical studies.
Watch this GEN Webinar, where Dave Lahr discusses how deeper insights into chromatin regulation and epigenetic mechanisms accelerate the progression of a drug candidate to successful clinical trials.
What features of the EpiCypher’s CUT&RUN Services were especially helpful?
The EpiCypher team’s deep knowledge of assay optimization was particularly helpful as we worked to refine protocols for drug-treated cell samples, which are notoriously tricky to work with. From start to finish, EpiCypher proved to be a reliable partner, making sure our chromatin mapping experiments delivered the high-quality data we needed to advance our drug development programs.
One standout feature of EpiCypher’s approach is the use of spike-ins and rigorous experimental controls, which helped us maintain consistency across plates and experiments. For example, one class of programs here at Foghorn Therapeutics uses degrader molecules to target proteins that apply chemical modifications to histones, which are part of the cell’s chromatin remodeling machinery. CUT&RUN can provide a direct (and invaluable) readout of where these proteins and their histone modifications are throughout the genome, revealing loss of the proteins – and importantly, loss of the histone modifications – that occur after drug treatment. An important additional piece of information comes from the use of spike-in controls – they can confirm protein degradation has occurred, and that the resulting changes are due to loss of protein, not just inhibition.
Why partner with EpiCypher? What has been the overall impact of this collaboration?
EpiCypher’s CUT&RUN services have been integral to our ability to explore the subtle effects of epigenetic-targeted inhibitors on chromatin landscapes, allowing us to gain deep insights into how these drugs function at a molecular level. In the rapidly evolving field of epigenetic drug development, having such reliable tools is invaluable for accelerating our research.
By partnering with EpiCypher, we have improved the efficiency, scalability, and reliability of our chromatin mapping experiments, which facilitates our Gene Traffic Control platform and the discovery of new drug targets and drug MOA. Their team’s expertise has been instrumental in advancing our drug development programs, and we look forward to continued collaboration as we push the boundaries of epigenetic drug research.
Ready to advance your drug development program?
EpiCypher’s CUTANA™ CUT&RUN Services provide unique access to our genomic expertise, enabling diverse applications across biomedical research and drug development. Fill out the form to get started.