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Preventing different forms of resistance to AML would “make a massive difference”

Professor Mark Dawson thinks a patient’s interest in research is not in understanding the detail of how experiments are done or what methods are being used, but “the big picture”.

Mark Dawson in the lab with a colleague
Professor Mark Dawson, Group Leader and consultant haematologist at
Peter MacCallum Cancer Centre (Melbourne)

They want to know “what is the big question that you are trying to answer?” and “why will that be important to me or my friends or family who suffer from cancer?” said Prof. Dawson, a Leukaemia Foundation Research Fellowship recipient.

Researchers are engaging consumers – patients or other people who understand the patient journey – early in the research process, “to understand what we are going to do and how this will be of benefit to those with these diseases”.

“These are people with a clear understanding of what this journey is, the highs and lows. Being told you are in remission, or that you have relapsed and what happens next.

“Trying to understand why it came back and was there something they could have done to prevent it coming back,” said Prof. Dawson, Group Leader and consultant haematologist at Peter MacCallum Cancer Centre (Melbourne).

“All these questions are critical.

“We currently give the same two treatments [for AML] as we have done for the last 40 years,” said Prof. Dawson.

“It cures about 25% of patients overall – less in older adults, more in younger adults.

“You could say, ‘well, that treatment is not very good’. But the other way to look at it is… we get up to 80% of patients into a complete remission.

“The problem is, that is not sustained. It [AML] comes back. And, even though you can’t see it or detect it, doesn’t mean it’s gone.

Remission is the first step to cure

“That is a concept that, for a lay person to understand, is very difficult. The way I describe how AML is treated, to patients in my clinic, is that ‘remission is the first step to cure’.

“But remission, sadly, does not equal cure. And cure is only measured with time, and we know most patients with AML relapse within the first two years.

“Of the 80% of people who go into remission, only less than half, probably only 40% of them actually ultimately get cured.”

Prof. Dawson’s research focus is on the other 60%.

“If we can change that in some way, then what a massive difference that makes,” he said.

“From a consumer’s perspective, this is the important question and answering this question could potentially change the way we deal with this disease.

Searching for new strategies to prevent resistance

“Our aim is to identify future therapeutic strategies to prevent these different forms of resistance.”

A prevailing concept Prof. Dawson thinks needs to be challenged, is that when cancers come back, they come back because they develop new mutations.

“I think cancers are lucky, but I’m not sure they’re that lucky that in a short period of time – a year or two – they develop the exact right mutation to become resistant to your treatment.

“Some of these mutations exist in a patient for decades before they actually manifest as leukaemia. The fact that that leukaemia cell would suddenly, miraculously develop the right mutation to come back, I think is pretty unclear if that’s really what’s driving it.”

Prof. Dawson’s lab is to trying to understand a more dynamic process; that cells can change their gene expression in minutes to hours.

“If you were to take a cell and expose it to any kind of pressure, such as low oxygen, low nutrients, a drug… it’ll change its gene expression program almost immediately, to try and adapt to that,” Prof. Dawson explained.

Changes in gene expression and relapse

“And what we have underappreciated for a long time is how important these changes in gene expression are in bringing about the relapse that we get from AML.

“This research, which will take several years, really wants to look at single cell resolution, to identify the major principles of this adaptive process and uncover how much of this is driven by genetic adaption (getting new mutations) and how much of this is non-genetic (driven by changes in gene expression).

“We will collect leukaemia cells at the time a person presents [at diagnosis] and we will characterise them in a really granular way, to understand – what are the mutations that this cell has? And what is the gene expression program these cells have at the time they present.

“Then, we’ll do the same thing at a time when they are in complete remission, even if we find one or two or 10 cells that still remain, to understand the properties of those cells and how they differed from before this cancer saw chemotherapy.

“Sadly, we know that ultimately, in quite a lot of these patients, the cancer comes back.

“When their cancer comes back, again we will ask – what is it in their cancer that came back. How does this differ to what the cancer started as? And is there something in this journey that we could learn, to stop it from coming back.

“Could we have done something at the time when you were in remission, with only residual disease, and can we do something [in the future] to stop the adaptive process?”

This process has already been modelled and Prof. Dawson said the results suggest relapse is not driven by new mutations and is driven by an adaptive process where the cancer adapts to this pressure by changing the way it expresses genes to enable fitness during therapy.

“That adaptive process requires epigenetic* machinery and, potentially, using epigenetic drugs at the time of that adaption, to change the outcome of the ultimate disease” said Prof. Dawson.

“What we did was model how resistance to an epigenetic drug develops and the results were published in Nature Communications in July last year [2019].

“What we don’t know is whether the principles we found in the resistance process to the epigenetic drug applies to other types of therapies or is this peculiar to an epigenetic drug. That’s why we need to now look at this in humans,” he said.

*  Professor Dawson describes epigenetics as “the study of the processes that go into place to change the way our DNA is accessed. Our DNA is accessed for three major purposes – to replicate itself, to repair itself, and to express the genes that are contained in it. This is a highly dynamic process”.

The difference a Senior Research Fellowship made

The Leukaemia Foundation awarded Professor Mark Dawson with a five-year Senior Research Fellowship, from 2013-2017, with annual funding of $200,000.

His research project title was Understanding how abnormal regulation of DNA contributes to leukaemia and his research was to understand the role epigenetic regulators play in the initiation of cancer and the maintenance of cancer, then how therapies can be used to alter the natural history of some of these cancers.

“The first thing to say is how grateful I am to the Leukaemia Foundation for that scholarship,” said Prof. Dawson.

“It played a critical role in me deciding to come back to Australia*.

“It provided the financial security to expand the research I was about to do, to build a research team, and ask some of the questions that we have answered over the last five years”.

At the time Prof. Dawson was conducting his research at the University of Cambridge (UK) where he was supported by a Wellcome Trust Beit Fellowship.