Changes to the complex of DNA and the proteins that form chromatin are important drivers in many cancers. We explore the challenges and progress in the development of new therapies targeting epigenetic regulators.
“Epigenetics was originally defined as the heritable changes that aren’t coded in the DNA sequence – but nowadays, people tend to use it more broadly to talk about anything to do with chromatin biology and changes in chromatin structure,” says Professor Jessica Downs, Team Leader of the Epigenetics and Genome Stability Group at The Institute of Cancer Research, London.
Every cell in our body contains about two meters of DNA that is tightly coiled around histone proteins – forming a complex called chromatin. But its compact structure can be reorganized in different ways – such as through post-translational modifications to the histones, or the activity of chromatin remodeling enzymes.
Over the last decade, the impact of epigenetic mechanisms in driving tumor development has become increasingly apparent.
“Large-scale cancer genome sequencing studies have shown that epigenetics is as important as genomic changes,” says Downs. “So, the more we understand it, the more we can use the vulnerabilities that we uncover to exploit it therapeutically.”
Chromatin is more than just packaging
Changes to chromatin structure can have profound consequences to many fundamental cellular processes – including gene expression, DNA repair, replication, gene silencing and chromosome segregation.
“All of the things that a chromosome does in the cell can be affected by changes in its epigenetic profile,” explains Jonathan D. Licht, MD, Director of the University of Florida Cancer Center.
One of the most well-studied is how epigenetic changes affect gene expression – as this has such a huge impact on cell identity and plasticity. For a long time, researchers have known that perturbations to gene expression patterns in cancer cells have consequences for their phenotype.
“You can shift something from a differentiated state to something that’s more stem-cell-like,” says Downs.
More recently, large-scale cancer genome and exome sequencing studies have shown that mutations in the enzymes and machinery that guide chromatin and DNA modifications are among the most highly mutated in human cancer.
“This highlights that the normal roles of these epigenetic proteins and then what happens to them in cancer is fundamental to the understanding of probably all cancers in all organisms,” says Licht.
Epigenetics: A wealth of therapeutic opportunities
One of the biggest challenges in targeting the epigenetic machinery with cancer therapies is that most are loss-of-function mutations.
“It’s hard to replace that function,” explains Licht. “But what does seem to occur in some cases is that it creates a vulnerability that you can potentially exploit.”
The SWI-SNF chromatin remodeling complex, which is a master regulator of gene expression and chromatin dynamics, is an example of this so-called ‘synthetic lethality’.
“There is a loss-of-function of SWI-SNF in about one in five of all human cancers – and what happens is this frequently creates a dependency on another epigenetic regulator,” explains Downs.
This has led to the development of multiple inhibitors that target an enzyme called EZH2, which are currently in early-phase clinical trials for treating different cancers.
Targeting cell differentiation using epigenetics
Another route for therapeutic intervention is through modifying the differentiation state of cancer cells. An example comes from acute myeloid leukemia (AML) patients with mutations in the genes encoding isocitrate dehydrogenases (IDHs).
“This leads to the build-up of a metabolite that poisons epigenetic enzymes and changes the normal gene expression pattern of the cell, effectively freezing them in mid-differentiation,” explains Licht.
Earlier this year, the US Food and Drug Administration (FDA) approved the drug ivosidenib for treating adults with relapsed or refractory AML and a mutation in IDH1 – the first drug in its class.
“The epigenetic regulators can now function and cells that were leukemic resume a program of cellular differentiation,” says Licht. “So, the cancer cells fully differentiate into mature white blood cells and then just die off.”
The drug can have dramatic effects, with some patients undergoing a complete remission along with experiencing fewer side effects.
“You don’t give large doses of chemotherapy that wipes out both the tumor and normal blood cells, meaning that patients could be in the hospital for weeks,” says Licht.
Drugs working through unknown mechanisms
One of the earliest success stories demonstrating the potential of targeting epigenetic regulators is the development of inhibitors that target histone deacetylases (HDACs). But, these drugs are notorious for their lack of specificity.
“When they tried to make them more specific, they were actually less effective – so in that case, it suggests that inhibiting more family members is actually what’s giving the effect,” says Downs.
Despite a number of HDAC inhibitors now approved for clinical use, it’s still unclear exactly how they work. “Epigenetic drugs have in fact been approved, without completely understanding if they’re really having an effect on gene expression,” says Licht.
The tip of the druggable iceberg
As many epigenetic regulators are in families with dozens of different members, there remains a myriad of potential therapeutic opportunities.
“We’ve only drugged a small percentage of what could be done,” says Downs.
For example, there are over 40 different human bromodomain proteins that act as molecular glue between different regulatory regions of a gene. A collaborative effort – the SGC (Structural Genetics Consortium) – aims to determine all of these protein structures and generate inhibitors that can target them.
However, some epigenetic regulators are huge multi-subunit complexes that are very difficult to target using small molecules.
“Inhibiting activity using one chemical binding to one face of a big molecular complex is actually quite a challenge,” says Downs.
One way of circumventing this will be using alternative approaches, such as PROTAC therapies that work by grabbing a protein and taking it to the proteasome for degradation.
Focus on understanding complex epigenetic mechanisms
Although researchers know that almost every facet of epigenetic regulation can be mutated in cancer, there is much more work to be done to understand the complex molecular mechanisms.
“We’re still in the phase of cataloging – we’re just about done with all of the genomic sequencing but we’re still trying to understand the functional consequences of these mutations under different contexts,” says Licht.
The next phase is searching for potential therapeutic workarounds that are exploitable, with many researchers carrying out large-scale functional screening platforms looking for synthetic lethality.
“We’re using CRISPR-Cas9 technologies to systematically knock out one epigenetic regulator and looking whether that cancer cell now has acquired a new susceptibility,” says Licht.
These screening platforms are becoming increasingly more sophisticated, with a shift towards using more physiologically-relevant systems – such as 3D cell cultures or patient-derived organoids.
Other technological advances are enabling researchers to get a clearer picture of 3D chromatin organization.
“We’re getting to the point where technology is allowing us to do whole genome mapping of the modifications and also detailed 3D mapping of where things are – and we can even do this at a single cell level,” says Downs.
Epigenetic drugs are tools for precision medicine
Researchers working within this fascinating, yet complex, field are hopeful about its potential to transform cancer medicine.
“What I’m hoping for is that we will get inhibitors that are more and more potent and more and more specific, so they can be used in a targeted way as part of precision medicine,” says Licht.
With the proof-of-principle already out there, indicating the potential of epigenetic therapies, there is much optimism for the future.
“There are many things to come – drugs to loads more targets, improvements in efficacy, combination therapies – we’re going to see a massive impact,” concludes Downs.