Epigenetics: Asking cancer the right question



The “gene hunting” aspect of cancer research has for years been the stuff of headlines, thanks to discoveries like the mutations in several genes linked to a higher breast cancer risk.

After initially being able to sequence only one gene at a time, scientists can now test all 20,000. And these advances in sequencing a patient’s entire genome have made diagnosis and treatment cheaper and more available, inspiring hope that the rarest of mutations can be mapped out and matched to drugs currently in use or development.

But not all genetic mutations are alike. Some mutations are inherited, and others occur over a lifetime, influenced by environmental factors such as smoking, sun exposure and nutrition. And not all mutations go on to cause cancers.

Knowing the genetic changes responsible for a cancer is only part of the story. What is emerging as the next frontier in cancer research is the environment surrounding our genes that regulates their behaviour: epigenetics. In a new paper for the journal Science, the University of Melbourne’s Professor Mark Dawson evaluates where the research into the epigenetics of cancer is at.

“Epigenetics essentially refers to the study of chromatin biology,” says Professor Dawson, a leading researcher in the field, who is based at the Peter MacCallum Cancer Centre.

DNA is bundled into a structure known as chromatin, which acts a little like bubble wrap, in which proteins called histones enclose, compact and protect it, exerting a significant influence on genes’ behaviour.

“Every cell in our body has an identical copy of DNA, which is packaged in a way that regulates access so that it can repaired and replicated when needed, and the genes within our DNA can be expressed at the right place and time,” Professor Dawson explains.

“Histones, which are the proteins that help package DNA can be chemically modified and these chemical tags serve as instructive beacons. They mark genes as being ready to be turned on or off.”

Our DNA is the same throughout our bodies – but a skin cell expresses very different genes to a liver cell. If we think of our DNA as the words in a book, then epigenetics is the process of creating a table of contents so that the words can be read in the right order to tell a story.

For instance, how does a blood stem cell become a red blood cell or a white blood cell? Each of these cells have the same instruction manual (DNA code), however a different story is being read in the red blood cell compared to the white blood cell.

“I often use the example of how a caterpillar becomes a butterfly to illustrate the power of epigenetics,” says Professor Dawson. “Their DNA sequence is 100 per cent identical even though they look completely different. Different genes are being expressed.”

The power of epigenetics to tackle cancer-causing gene mutations is in using these processes to reverse a cell’s outcome.

“Cell differentiation is depicted in our textbooks as a one-directional path. The arrows go from embryogenesis to final state. But it’s not actually a one-way street – once a cell makes a cell fate decision, it is not stuck,” says Professor Dawson.

“Epigenetic proteins can be manipulated to take cells backwards and control their fate. If we know what genes have gone awry we can harness the epigenetic proteins to force that cell to make a different decision.”

Professor Dawson says researchers now see epigenetic drugs as central to any cancer treatment – by themselves unlikely to overcome a cancer ­– but powerful when used together with other therapies like chemotherapy and immunotherapy (where the body’s own immune system is turned on to attack cancer cells).

“Epigenetic therapies have been part of the suite of cancer therapies for at least 10 years”, he says. “Some of the drugs we use really change the chemical modifications of DNA or histones, and they are being used to treat certain malignancies, particularly some blood cancers.”

And while we may never reach a point where cancer patients are scanned, their particular barcode of mutations identified and a cocktail of therapies prescribed, we may reach a point that is not too far from that.

“Every time we put therapeutic pressure on a cancer we know it’s going to adapt to survive, so in any treatment program we will always need to monitor the patient,” says Professor Dawson. “We may get to a point where we identify the particular gene mutations for each patient, prescribe their initial treatment and then monitor them and change their drugs maybe as frequently as every single cycle of therapy to keep up with the cancer’s changes.”

The role of epigenetic drugs in this cocktail of treatment, says Professor Dawson, is to encourage cells to make a predictable decision that doctors can then exploit.

“I think the future of epigenetic therapies is in being able to use them intelligently to force cancer cells to make decisions that we want them to, and expose new vulnerabilities that we can attack to get more effective gains for our patients,” he explains.

Professor Dawson only sees leukaemia patients now, and within that group lies the perfect test case for epigenetic therapies.

“Acute myeloid leukaemia is primarily a disease of adulthood and it is devastating,” he says.

“Unlike melanoma or lung cancer it doesn’t have thousands of mutations – it can have as little as one. So rather than being driven by DNA mutations, it’s driven by the cancer cells hijacking the epigenetic system to give themselves a survival advantage. This makes it almost the perfect disease for finding applications for epigenetic therapies.”

Acute myeloid leukaemia is very malleable. If you challenge it with one set of therapies, it tends to adapt quickly and become resistant.

“This is a disease that simply hasn’t benefitted from the targeted therapies era. We’re not achieving a cure because we’re not eradicating the leukaemia stem cells. They tend to come back adapted to the pressures we’ve put on them.

“The opportunity for epigenetic therapies is to leverage the brut force of chemotherapy and then work on that minimal residual disease and reprogram the leukaemia stem cells to either die or differentiate.”

Professor Dawson’s team have already started several clinical trials for epigenetic therapies in acute myeloid leukaemia in the last five years, and drugs are being made and developed at a rapid rate.

“The medicinal chemistry has exceeded the scientific knowledge. We’re able to target these epigenetic proteins before we know how best to use the drug,” he says.

Professor Dawson is optimistic about discoveries to come.

“We live in this unbelievably fantastic era for science at the moment. We’re able to do things that even 5 or 10 years ago were absolutely fictional,” he says.

He says the genome editing technology CRISPR has “changed the game”.

“We can, in a very specific way – cut out selective parts of our genome and replace it with other parts,” he says. “We can take epigenetic proteins to very selective sites and ask ‘what happens if I tether this protein to this gene and turn the gene on or off?’”

Associated with CRISPR technology, says Professor Dawson, are rapid gains in medicinal chemistry. “We can develop drugs for things that were just un-druggable before.

“This is a fantastic time to be a scientist. It’s a real renaissance period. Because your toolbox has just become a toolshed, and what you’re constrained by now is no longer necessarily technology, but the question.

“We have to make sure we ask the right question.”





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