Epigenetic Memory Reset Therapies in Cancer

Oncology is moving beyond conventional treatments to target the underlying biological drivers of cancer, with a growing focus on therapies that reset epigenetic memory. It targets the heritable changes in gene expression occurring without any changes to the underlying DNA sequence, collectively called epigenetic memory. This memory compels the cells into a proliferative and drug-resistant state by stopping tumor-suppressing genes and activating oncogenes.

What is epigenetic memory?

Epigenetic memory is a stable pattern of gene regulation, like the cell’s learned identity passed down during division. In healthy cells, this memory is essential for proper function. In cancer, this system becomes corrupted, giving cells a “memory” that drives uncontrolled growth, spread, and resistance to treatment. This can be frightening for patients, as it makes the disease harder to treat. New therapies aim to reset this harmful memory, giving hope for restoring normal cell behavior and improving treatment outcomes.

Key drivers of epigenetic memory

Epigenetic memory is controlled by several interconnected mechanisms:

• DNA methylation: Adding a methyl group to DNA can turn genes off. In cancer, hypermethylation of tumor suppressor genes is common.
• Histone modification: Chemical tags on histone proteins, which package DNA, change how tightly DNA is wrapped. This can make genes active or silent.
• Non-coding RNAs (ncRNAs): MicroRNAs and other ncRNAs regulate gene activity after transcription, helping maintain the epigenetic system.

Reset therapies in cancer

Epigenetic reset therapies focus on chemically or physically reversing the pathological alterations, making way for non-chemotherapy intervention. There are two main strategies:

• DNA Methyltransferase (DNMT) inhibitors: Medications like azacitidine and decitabine reactivate the silenced tumor suppressor genes by eliminating methyl groups from the DNA.
• Histone Deacetylase (HDAC) inhibitors: These compounds increase histone acetylation and support a more open chromatin structure, thereby activating the silenced genes.

These therapies target the system of tumor memory maintenance and restore the cell’s natural tendency for differentiation or programmed cell death, resulting in tumor suppression. Trials are emerging to focus on combining these reset therapies with immunotherapy or precise inhibitors in solid tumors.

Advantages and challenges

Reset therapies in cancer could target tumors more precisely and cause fewer side effects than chemotherapy, which is a big advantage. However, there are challenges. Epigenetic drugs are not always specific to cancer cells and can affect healthy cells. Understanding a patient’s tumor and predicting how it will respond to these therapies is still difficult.

Personalized epigenetic therapies

Therapy for cancer in the future may involve treatments that address the defective signals that influence the turn-on and turn-off expression of genes. Special drugs would repair the regions of the cell that write, read, or erase these signals. This means that doctors could design therapies specific to each patient by analyzing the distinct gene patterns to reprogram the memory of the cell so the body responds more efficiently to treatment.