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Perspective: The Epigenetic Keys to Unlocking the Full Potential of Immunotherapy

By VolitionRx

Epigenetics is the key to unlocking the full potential of cancer therapy, including immunotherapies, by revealing deep insights into how the body reacts and responds to medication. The rise of novel immunotherapies has created bulging pipelines with thousands of products progressing through R&D and into clinical trials, strengthening their position as a potent weapon to combat cancers that resist conventional treatment. The Cancer Research Institute recorded that the number of immuno-oncology drugs either approved or in development had risen by 233 percent from 2017 to 2020, with the climb likely to continue as nations emerge from the pandemic burdened with backlogs in cancer treatment.

But, despite their promise, only 20 percent to 40 percent of patients respond positively, because tumors can evolve, downregulating immune recognition and activation, increasing immune checkpoint activation, and creating an immunosuppressive tumor microenvironment.

In effect, the immunotherapy is neutralized, or its efficacy is vastly reduced so that tumors can progress while patients suffer a range of side effects from ineffective treatment. Having markers that can predict their treatment response or ineffectiveness would improve patient outcomes and save millions of dollars.

This is more than a scientific and medical inflection point.

Understanding how patients will respond to immunotherapy is critical to targeting therapies to the right patient at the right time while also accelerating diagnostics by revealing biomarkers that enable clinicians to tackle tumors earlier and with more precision. Immunotherapy drugs are potentially transformative, but they can activate a broad range of immune cells and trigger severe auto-immune reactions. Predicting who will be a non-responder will sharpen clinical research focus, save treatment costs, and spare patients from unnecessary side effects.

Improved identification of biomarkers needs to be twinned with immunotherapy’s potential, which is where epigenetics plays a crucial role. Research has demonstrated that epigenetic alterations are present at the early stage of disease and that these alterations increase cancer cell proliferation and allow cancer cells to evade chemotherapy and host immune surveillance. Epigenetics is a core component of biology, and alterations can be found across all forms of cancer, providing a route for identifying biomarkers associated with cellular dysregulation, disease progression, and the ability to resist and evade therapy. The composition and location of nucleosomes — the repeating structural units of chromosomes — can be altered by treatments and trigger disease progression and immune response.

The Role of Nucleosomes

Cancer cell death results in chromatin fragmentation and the release of nucleosomes into the blood. This activity can be measured and monitored as a clear indicator of disease progression and response to treatment, making nucleosomes a rich source of biomarkers across all cancers. With epigenetic alterations present at all stages of tumor development, studies have demonstrated that modifications on histone proteins from the nucleosome can indicate the presence of cancer, enabling early detection and targeted treatment.

This image is an informative illustration depicting the process of chromatin modification and its relationship to disease. At the top, a chromosome unravels into a strand of chromatin, which further unwinds to show nucleosomes. These nucleosomes are illustrated as green spheres wrapped by a strand of DNA. A magnified view of a nucleosome shows the types of post-translational modifications (PTMs) that can occur on the histone proteins, such as methylation, acetylation, phosphorylation, and citrullination.  Below the nucleosome, there are three labeled entities: "Writer," "Eraser," and "Reader." The "Writer" is described as an enzyme that adds PTMs, with EZH2, DOT1L, and PRMT listed as targets. The "Eraser" is an enzyme that removes PTMs, with LSD1 and HDAC as examples. The "Reader" proteins recognize PTMs, with BET given as an example.  On the left side, it is indicated that cancer and cell death cause chromatin fragmentation, and nucleosomes can be released into the blood. This is linked to a list of diseases such as cancer, inflammatory disease, autoimmune disease, and neurodegenerative disease, suggesting that errors in this process lead to these conditions.  At the bottom, the references for the information are provided: Li X and Li XD. "Integrative Chemical Biology Approaches to Deciphering the Histone Code: A Problem-Driven Journey." Analytical Chemistry 2018 Jan 2;90(1):361-373; Regnier FE, Kim J. "Proteins and Proteoforms: New Separation Challenges." Analytical Chemistry 2018 Jan 2;90(1):374-397.


Deciphering how to measure nucleosomes and their modifications both swiftly and sensitively has been the driving ethos of Volition, the multinational epigenetics company whose proprietary Nu.Q nucleosome quantification platform and its range of state-of-the-art assays is generating epigenetic intelligence for developers and scientists across disease model development, pre-clinical testing, and clinical studies.

Nucleosomes contain more than 200 possible modifications that are fundamental to every cellular process. Measuring nucleosome levels and modifications in circulating blood has the potential to aid the diagnosis, prognosis, and monitoring of many human diseases, and there are already applications in oncology, inflammation, auto-immune diseases, and neurodegenerative diseases.

Dysregulation of histone modifications has been associated with the complex origins of colorectal cancer and pancreatic cancer, for example, suggesting that changes in histone modification patterns detected on circulating nucleosomes could therefore be a source of powerful blood-based biomarkers for early cancer detection. A 2019 report in Pathology and Oncology Research into histone modifications in colorectal cancer, stated: “It is evident that epigenetics that affects gene activity and expression has been recognized as a critical role in the carcinogenesis.”

Further scientific studies and data continue to confirm the pivotal role epigenetics and nucleosome testing can play in advancing treatments across human biology and answering the hardest scientific questions.

Introducing Nucleosomics

Volition’s patented Nucleosomics technology detects characteristic changes in nucleosomes that occur from the earliest stages of disease, enabling early detection and a better way to monitor disease progression and the patient’s response to treatment. In many cases, epigenetic changes can be detected before genomic changes, before the diseased cells are detected in traditional biopsies, and before the first symptoms are felt, sparing patients from invasive and uncomfortable tests.

Volition’s Nu.Q Discover program enables drug developers and scientists access to a range of state-of-the-art assays for rapid epigenetic profiling in disease model development, preclinical testing, and clinical studies — from discovery to market.

“A lot of standard testing focuses on part of the nucleosome, either the DNA or protein, and does not examine them holistically,” said Terry Kelly, chief innovation officer at Volition. “Our assays look at modifications in both the DNA and protein, giving a deeper insight and a more complete picture of what is happening at the genomic and cellular level. The Nu.Q approach is sensitive and rapid and, because it requires small volumes for testing, we can look for more markers and ask a lot more questions, resulting in greater understanding and value for clinical researchers and drug developers. Epigenetics generates an understanding that allows us to get better results and interrogate the questions in a different and more complete manner.”

Rapid, sensitive tests can save R&D budgets and schedules, liberating clinical research time and defraying financial constraints. They also allow researchers to explore further upstream into the potential causes of disease and triggers for its progression.

Epigenetic Intelligence

Two papers published in Epigenomics have emphasized the importance of epigenetics in determining both the presence of cancer and its prognosis with levels of circulating nucleosomes providing a treatment response biomarker for advanced hepatocellular carcinoma.

The first paper, published online in September 2020, illustrated that the histone modifier enhancer of zeste 2 (EZH2) downregulated immune recognition and activation, and upregulated immune checkpoints to create an immunosuppressive tumor microenvironment. Critical observations have proposed that surviving epithelial cancer cells may acquire immune-suppressive qualities that enable the cancer cells to communicate with immune cells and have an immuno-editing influence through the sequential phases of elimination, equilibrium, and escape (the Three Es) leading to reduced antigenicity and an immunosuppressive tumor microenvironment. EZH2’s ability to suppress innate and adaptive immune responses indicates the potential value of deploying EZH2 inhibitors in combination with immunotherapies to achieve better responses.

The second paper, published by the Open University, took these findings a step further by analyzing the role of EZH2 as a driver of sorafenib resistance in patients with advanced hepatocellular carcinoma (HCC). It noted that EZH2 drives this through the epigenetic modification H3K27me3 but that it is counteracted by the enzyme SETD2, and that a higher EZH2/SETD2 ratio predicts a worse prognosis.

This image is a set of two box plots comparing the expression of EZH2 and SETD2 genes in normal tissue and primary tumor samples from hepatocellular carcinoma (HCC) patients. The left plot shows SETD2 expression levels, with the y-axis indicating expression and the x-axis indicating the sample type. Normal tissue samples (n=50) show lower SETD2 expression compared to primary tumor samples (n=371), with a statistically significant difference denoted by three asterisks (p<0.05). The right plot shows EZH2 expression levels, also displaying significantly higher expression in primary tumor samples compared to normal tissues, indicated by the same statistical significance marker. The data is sourced from TCGA (The Cancer Genome Atlas) samples. The abbreviation 'HCC' stands for hepatocellular carcinoma, and 'PTMs' for post-translational modifications. The reference provided is "Salani F et al. Predictive significance of circulating histones in hepatocellular carcinoma patients treated with sorafenib. Epigenomics 2022 14:9, 507-517". The red color theme and the simplicity of the plots suggest it's designed for a clear presentation of the comparative expression data.

These findings were enabled by the ability to test sensitively for circulating nucleosomes, and they underscore the opportunities for clinical research to gain deep insights into how drug actions are impacted by epigenetic alterations and how, potentially, to counter and reverse any immunoediting that occurs.

This is particularly pressing in HCC — a disease driven by the interaction between genetic and epigenetic alterations — and the most common type of primary liver cancer. Liver cancer accounts for around 8.3 percent of cancer deaths worldwide and is a leading cause of cancer deaths in 46 countries, according to figures published in the Journal of Hepatology in October 2022. The number of new cases and deaths of primary liver cancer is predicted to rise by more than 55 percent by 2040. The report concluded: “Liver cancer is a major cause of death in many countries, and the number of people diagnosed with liver cancer is predicted to rise. Efforts to reduce the incidence of preventable liver cancer should be prioritized.”

The Nu.Q platform and Volition’s assays, which were used in the sorafenib study, offer routes to scientific knowledge that can help direct and strategize research projects. The Open University paper reported that the histone H3K27me3/H3K36me3 ratio is a potentially non-invasive predictive biomarker for HCC patients treated with sorafenib, which will allow clinicians to test accurately which patients will respond well to treatment and those who will fail.

SETD2 has been described as an oncosuppressor, while EZH2 overexpression is associated with poor outcomes in liver cancer. The levels of both EZH2 and SETD2 are elevated in liver cancer, reflected by the plasma levels of H3K27Me3 and H3k36Me3 nucleosomes respectively. The ratio of the two Nu.Q scores was predictive of poor outcomes.

“We are at the cutting edge of epigenetic research, and Volition is constantly developing its assays and platforms to create understanding that can positively influence drug development and clinical research programs,” said Kelly. “Our assays are high quality and are developed with the clinic and the customer in mind, and we are continuing to innovate to enable them to look deeply into epigenetics. Epigenetic biomarkers are a valuable tool from target identification to validation in clinical studies, and being able to access rapidly and sensitive testing generates transformative results.”

About Volition

Volition is a multinational epigenetics company, powered by Nu.Q, its proprietary nucleosome

quantification platform. The Nu.Q Discover program enables drug developers and scientists

access to a range of state-of-the-art assays for rapid epigenetic profiling in disease model development, preclinical testing, and clinical studies.

For details go to:

For research use only. Not for use in diagnostic procedures.

This sponsored content is provided by an advertiser and published in collaboration with the GW Custom Solutions Group, a division of GenomeWeb. The content was not produced by the editors or reporters of GenomeWeb, 360Dx, or Precision Oncology News, and does not represent the views of these publications or GenomeWeb's parent company, Crain Communications Inc.