#BIOSPAIN2023Interview | 'Epigenetic therapies can complement existing cancer treatments'

Asebio

14 September 2023

Epigenetics is a regulatory system that controls gene expression without affecting the makeup of the genes themselves. Regulation of gene transcription and translation are key biological determinants for cellular differentiation and function, and transcriptional imbalances play a significant pathogenic role in a number of human diseases.

Epigenetics refers to functionally relevant changes to the genome that do not involve changes in DNA sequence. Epigenetic switches occur in normal biological or disease processes or as a consequence of diet and other external environmental factors. These switchesinduce changes in gene and protein expression. The form and function of every cell in the human body is determined by the genes and proteins it expresses and also by the signals it receives from the surrounding cells. Regulation of gene transcription and translation are therefore key biological determinants for cellular differentiation and function, and transcriptional imbalances play a significant role in a number of human diseases.

Every human cell contains about two meters of DNA organized into chromosomes. To allow for easy packing and unpacking, the DNA is wound around specialized proteins called histones to form nucleosomes. The nucleosomes in turn are organized into chromatin fibers that make up the chromosomes.

Many enzymes that modify or interpret histone modifications have been associated with human disease. Modulation of the activity of disease-associated histone-modifying enzymes offers a clear path for the development of small molecule drugsto act as personalized therapeutics in diseases such as cancer, CNS, inflammatory and metabolic diseases. Regarding the specific relationshipof epigenetics to cancer, we spoke with Douglas Faller, Chief Medical Officer of Oryzon, a biopharmaceutical company that develops innovative epigenetic personalized medicines for patients with cancer and nervous system diseases. Oryzon is also the Gold Sponsor of BIOSPAIN 2023, an international benchmark event in the biotechnological sector.

AseBio. How does epigenetics relate to cancer?

Douglas Faller. The diseases that comprise cancer have classically been thought to be the consequence of fixed mutations in the DNA genome, driving the cells to proliferate without checkpoints, escape normal constraints on cell lifespan, and metastasize. It has become increasingly clear, however, that epigenetic mechanisms play an intrinsic role in cellulartransformation, cancer initiation, and cancer progression and metastasis. Indeed, dysregulation of epigenetic processes alone can lead to malignancy.

This is particularlythe case in pediatric tumors. Epigenetic modifications are among the first aberrations to occur in cancer development. In 2022, the molecular "hallmarks of cancer" were expanded to include "non-mutational epigenetic reprogramming". Because epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression, it is not surprising that alterations in epigenetic controls can lead to wildly aberrant cell development and proliferation.

AseBio. What are the most common epigenetic changes observed in cancer cells?

Douglas Faller. The normal cellular "epigenome," which is distinct and characteristic for different types of cells, is generally progressively altered as a cell evolves to a malignant phenotype. The cancer epigenome is characterizedby widespread alterations in DNA methylation, histonemodifications (mostly methylation and acetylation) and non-coding RNA (ncRNA) mediated regulation of gene expression, which confers growth advantages to tumor cells and thereby promotes cancer development and progression. DNA methylation can silence critical regulatory genes. Histone methylation and acetylation affect the way DNA is packaged into chromatin, and thereby its accessibilityto transcriptional complexes. Non-coding RNAs control chromatin structure modulation, transcriptional regulationand post-transcriptional modification.

AseBio. How can epigenetic changes influence the development and progression of cancer?

Douglas Faller. Epigenetic changes contribute to each of the hallmarks of cancer. These hallmarks are growth signal self-sufficiency, anti-growth signal insensitivity, evasion of apoptosis, limitless replication, angiogenesis, tissue invasion, and metastasis. I will give some examples:

One is the inactivation of tumor suppressor genes by DNA methylation. Thecritical p53 gene is often inactivated in tumors by "two hits." The first is a genetic mutation in one p53 allele. Aberrant DNA methylation then silences the second allele.

Another example is common in certain tumors, notably lymphomas. Here epigenetic reprogramming leads to overexpression of the Bcl-2 gene. The resulting high levels of the Bcl-2 protein confer resistance to apoptosis and make these tumors refractory to a variety of cancer therapies.

Finally, Non-coding RNAs, particularly the subset known as microRNAs (miRNAs) have been shown to be oncogenic drivers and tumor suppressors in every major cancer type. Dysregulation of miRNA expression is particularly common and important in colorectal cancers and leukemias. Here they can also serve as potential diagnostic biomarker and therapeutic targets.

AseBio. How can histone modifications affect the function of cancer-related genes?

Douglas Faller. Gene expression in normal and malignant cells requires that the DNA be unwound from tightly packed chromatin. Unwinding can occur only when histones are modified by acetylation or methylation. This modificationtargetslysine residues on the histone tails. Acetylation of histone tails iscarried outby histone acetyltransferase (HAT) enzymes and reversed by histone deacetylases(HDACs). Acetylation of histonesopens chromatin and enhances gene transcription.

Methylation of histone residues is carried by histone methyltransferase (HMT) enzymes and reversed by demethylases(HDMs).In contrast to acetylation, histone methylation can either enhance or suppress transcription, depending upon the location of the methyl group.

Histones can also be modified by phosphorylation and ubiquitination, adding further levels of complexity and refinement to the process of epigenetic control.

Aberrant histone acetylation, methylation, phosphorylation and ubiquitination are commonly found in cancer genomes, and cause activation or suppression of genes critical to the cancer process.

AseBio. Currently, what epigenetic therapies are being investigated for cancer treatment?

Douglas Faller. Because epigenetic modifications to the genome are readily reversible, as opposed to fixed genetic mutations, modification of the cancer epigenomeis an attractive option for cancer therapeutic intervention.

Many epigenetic therapies being explored target the epigenetic "writer" molecules -the enzymes that control methylation and acetylation of histones. Small molecule inhibitors of HMTs and HDMs are in advanced clinical trials for a variety of cancers and non-malignant conditions. Similarly, inhibitors of HATs and HDACs have also been explored, with certain HDACs reaching global approval as new drugs for lymphomas and other diseases. DNA methyltransferase (DNMT) enzymeinhibitors are a main stay of therapy for myeloid malignancies.

Oryzon Genomics has developed potent and selective inhibitors of HDMand HDAC. In preclinical studies and in clinical trials, Oryzon's drugsare being used to reverseresistance to other cancer therapies, to enhance the activity of targeted therapies and conventional chemotherapy, and to augment theability of immune checkpoint inhibitors to recognize and destroy tumor cells.

AseBio. What are the main advantages that epigenetic medicine offers compared to conventional cancer therapies?

Douglas Faller. Even with the evolution towards targeted therapies, most current conventionalanti-cancer agents are cytotoxicfor the cancer cell, but also have cytotoxic activity on certain normal celltypes, giving rise to adverse events and safety issues.

In contrast, epigenetic therapies are generally not cytotoxic-at least cytotoxicity is not their primary mode of anti-tumor action.

Epigenetic therapies can be complementary to existing cancer therapies, with non-overlapping safety profiles.

The evolution of cancer drug resistance is frequently due to compensatory epigenetic modifications, which can be reversed by the appropriate epigenetic agents, thus resensitizing the tumor cells. Epigenetic therapies can reactivate silenced tumor suppressor genes, to facilitate the activity of other anti-cancer drugs. Conversely, they can silenceaberrantly activatedtumor-promoting genes. Epigenetic agentscan enhance expression of the protein products that are targets of available targeted therapies, making these therapies more effective.

Oryzon and others have also demonstrated that epigenetic approaches can re-program tumor-specific T lymphocytes to extend their life and enhance their activity.

At present, seven epigenetic agents in three target classes (DNMT, HDAC and EZH2 inhibitors) have been approved by the US FDA for the treatment of diverse malignancies and a wide range of epigenetic-based drugs are in advancedclinical trials. Epigenetic approaches hold great promise for patients afflicted with cancer.

AseBio. What does Oryzon expect from BIOSPAIN 2023?

Douglas Faller. BIOSPAIN is one of the fastest-growing BioConferences in the European calendar. It brings the opportunity to showcase the science and technology developed in Spain, and attracts in every edition more and more industry partners and investors from abroad.

For Oryzon, with our late-stage pipeline in CNS and oncology, this event is a must in our partnering strategy with big pharma companies and to present the company to new investors.We are glad to contribute to this event with our presence and with our support.

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