Holy grail: Peter Mac researcher’s work on non-genetic therapeutic resistance mechanisms in AML

Can you sum up the aim of your research in 10 words?

To understand the non-genetic processes governing treatment response in cancer.

What led you to this line of research?

I study cancer epigenetics with a particular focus on haematological malignancies such as acute myeloid leukaemia (AML). AML is characterised by a high rate of relapse following clinical remission, often without a clear genetic cause. Previous work in our lab showed that drug resistance can arise in the absence of new DNA mutations and that this was due to a genetically identical but functionally distinct subset of malignant cells that are able to survive treatment and seed relapse. These cells are difficult to isolate and study and so our current line of research is focussed on developing tools to be able to track changes within leukaemic cells as they adapt to and survive drug pressure and through this, identify the defining features of this rare cell subset. This will allow us to prospectively isolate and study them in greater detail which will provide novel opportunities to specifically target them with novel therapeutics.

What aspect of your research excites you the most?

My research requires a single-cell resolution understanding of cancer behaviour. Single-cell sequencing approaches have revolutionised our ability to study individual cells and understand differences between them. The pace of technological innovation in this field is breathtaking, and it is very exciting to be working in an area that is at the bleeding-edge of an intersection between biomedical, molecular and computational biology.

What have you already discovered about non-genetic mechanisms of cancer resistance? 

Using a method known as cellular barcoding in which thousands of cancer cells are individually labelled with a unique and heritable DNA barcode, we could track the fates of individual malignant cells as they encounter and adapt to drug treatment. We found that the progeny of the same few barcoded cells would almost invariably be the ones to drive disease and seed relapse suggesting that there is an intrinsic priming of cellular behaviour. We went on to show that these “primed” cells comprise a rare population within the total pool of barcoded cancer cells and that they display a gene expression profile that distinguishes them from the malignant cells that do not contribute to the disease. By studying the gene expression profiles of these primed cells we were also able to identify and validate factors that are required for this priming behaviour.

You recently won a research grant. How will this spur your research? 

I was awarded an early career special fellowship from the Leukemia and Lymphoma society in the USA. This three-year fellowship will support my research into non-genetic mechanisms of leukaemia development and treatment resistance and allow me the opportunity to further develop these insights into new knowledge and therapeutic opportunities.

How and when could your findings impact patient care?

If you look across genetic profiling studies of AML patients one thing that is clear is that up to 40% of patients in some cohorts show no clear relapse-specific driver mutations, suggesting it is a non-genetic process that is driving tumour progression in a significant proportion of cases. The biological processes behind this are poorly understood. Our cellular barcoding methodology can identify the key factors that control non-genetic tumour evolution and therapeutic resistance. We hope that within the next 3–5 years this method can be further applied in a variety of cancer contexts to identify biomarkers that can better monitor residual disease in patients alongside current methods focussed on tracking DNA mutations. Further down the line, we hope to develop our insights into novel therapeutics to inhibit this non-genetic route to relapse.

What’s your Holy Grail — the one thing you’d like to achieve in your research career?

The holy grail of epigenetics is to understand how two cells which share the same DNA can behave differently when faced with the same stimulus. In cancer this translates into understanding 1) how genetically identical cancer cells can transition between different states and what factors define these states, 2) how cells become fixed in certain states following drug pressure or other stimuli without changes to the DNA and finally, 3) how we can inhibit or circumvent this process to provide more durable treatment responses.

What is your biggest research hurdle?

COVID-19 has impacted almost every aspect of laboratory research. While access to laboratory facilities is now less of an issue, supply chains are still under massive pressure and acquiring reagents necessary to do experiments remains a challenge.

Who has inspired you in work or life? 

I am inspired most by my parents, family, and kids who help me maintain perspective on what is most important in life and who are relentlessly supportive of my endeavours.

What new hobby have you picked up during COVID?

Reading for pleasure is something that I have refocussed on during COVID. Also making the most of lockdowns by playing with my kids at every opportunity. I have become pretty good at LEGO.

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