For Actionable Drug Information, Consider Dynamic Epigenetics Data

In the early days following the Human Genome Project, there was tremendous hope that DNA data would drive novel drug discovery and development efforts. While genomic information has indeed been helpful, DNA alone does not allow biopharmaceutical scientists to spot many of the important biological changes associated with disease over time. For that, researchers need a truly dynamic data source – and more and more labs in both academia and biopharma are incorporating epigenomic information via liquid biopsy to fill that gap.

The epigenetic marks that sit on top of DNA are highly reactive to environment, stressors, chemical exposures, disease and more. Epigenomics can reveal specific signatures of gene regulation and activation to offer a more dynamic view of the onset and progression of disease; in some cases, epigenetic changes may be the first detectable signs of these events. From a practical standpoint, epigenetic data also offers the appeal of an easily accessible biomarker especially since it is retained in cell-free DNA and circulating cells, making it possible to generate useful intel from simple blood tests instead of relying only on tissue.

Epigenomic data is increasingly important for a variety of applications in biopharma, from biomarker discovery to clinical trial testing including patient selection. By adding this information on top of DNA sequence data, scientists can gain new insights into disease biology, response to treatment, resistance pathways and more.

Epigenomic analysis

In 2017, Steve Quake’s team published a key article in the journal Cell Research reporting the ability to track the stable epigenetic marker 5-hydroxymethylcytosine (5hmC) in circulating cell-free DNA. The 5hmC modification was chosen because it is involved in gene regulation and had previously been linked to the onset of cancer. In this study, Quake’s lab analyzed 5hmC patterns in samples collected from patients with a variety of cancer types, identifying specific epigenetic patterns associated with each type and the stage of those cancers. This proof-of-concept research effort laid the foundations for using epigenetic profiles as potential prognostic and diagnostic tools, as well as tools for early cancer detection.

The focus on 5hmC, when most epigenetic investigations typically focus on 5-methylcytosine (5mC), was a critical choice. 5mC methylation is associated with transcriptionally repressed regions of the genome, while 5hmC is found near active genes and gene regulatory regions. Genome-wide, there is far less 5hmC compared to 5mC, making the former a more precise signal while the latter is associated with high levels of noise. There’s a nice workflow advantage to 5hmC as well: while traditional methylation analysis for 5mC involves a bisulfite conversion process that damages DNA, and therefore requires higher volumes of DNA for analysis, 5hmC profiling can be performed on any DNA sample (including cell-free DNA) with far less sample volume or mass and a lower sequencing depth needed to generate comprehensive data. Overall, this makes 5hmC a stronger biomarker of active disease, such as the onset of cancer – and one that’s more efficient and less costly to query for drug discovery and development efforts.

Applications in biopharma

As more scientists recognize the value of 5hmC epigenetic data, they are using it for a range of applications throughout the process of discovering, validating and clinically testing new therapies – all based on easily accessible blood samples. In the early stages of drug discovery, unbiased, genome-wide readouts of 5hmC patterns can provide insights into disease biology, offering new clues about disease targets and how progression occurs. Later, 5hmC profiling can be used to select patients for whom a therapy is most likely to be effective, stratifying populations into responders and non-responders based upon an understanding of different gene pathways associated with their tumor and therapeutic effect. As candidate therapies enter clinical trials, 5hmC can help scientists monitor response to treatment over time with the development of epigenetic biomarkers associated with drug benefit or, alternatively, the risk of adverse events. Finally, scientists can identify 5hmC signals associated with the emergence of resistance to treatment, creating a better biological definition of resistance and ultimately a tool that would allow physicians to shift patients to a new therapy quickly when needed.

In the Journal for ImmunoTherapy of Cancer, scientists reported using 5hmC profiles to predict which patients would be more likely to respond to treatment with an immune checkpoint inhibitor. In more than 150 blood samples collected serially from 31 patients with non-small cell lung cancer, they found that the treatment induced detectable changes in 5hmC profiles in patients who responded to therapy that were different from changes found in non-responder patients as early as the first cycle of treatment. For example, higher levels of 5hmC were found around genes responsible for immune activation in responder samples, consistent with current understanding of disease biology of immunotherapy. Differences were also found in samples collected prior to treatment, indicating that distinct 5hmC profiles could be useful in selecting patients for this type of therapy as well as in monitoring response to treatment over time.

This approach has also been used to map immune cells by chromatin accessibility and transcription levels, identify cancer signaling activity and cancer cell subtypes, analyze biological processes involved in human hematopoiesis with important implications for characterizing preleukemia, as well as a number of other disease-related studies. In addition, epigenomic analysis can be paired with next-generation sequencing data for a more comprehensive biological view.

What’s next

Unlike rare DNA mutation events, epigenetic profiles are highly responsive to biological changes, offering a dynamic view of active health or disease in a patient. With ready access via blood samples and the potential for easy serial testing of epigenetic changes over time, these biomarkers are an important tool across the drug discovery, development and treatment spectrum.