Understanding how myelodysplasia (MDS) forms from normal cells is the goal of a Leukaemia Foundation-funded* research project led by Dr Steven Lane at QIMR Berghofer Medical Research Institute (Brisbane).

“MDS is a very common disease; we see it a lot, and it can turn into acute leukaemia,” said Dr Lane, Principal Investigator of the study titled, Understanding the pathways that regulate transformation of normal stem cells to myelodysplasia and leukaemia.

Azacitidine is the only specific treatment for MDS in Australia and while a lot of people with MDS try azacitidine, more than 50% of them don’t benefit from the drug. Azacitidine is unpredictable as to which patients it will and won’t work on, and information about how it works in patients is limited.

The only other treatment option for MDS is transfusion support to keep people’s blood counts up.

“We can’t offer good treatment to a lot of patients and there’s nothing available to people with low-risk MDS, so this is an area of very high need in the community,” said Dr Lane.

“MDS is a group of diseases that is poorly understood, and the genetics of all the myelodysplasias might all be quite different.

“We know that for patients with high-risk genetic features such as changes in the chromosomes, or changes in a particular gene such as P53, the survival and outcomes from myelodysplasia is extremely poor, and very similar to acute myeloid leukaemia (AML).

“There also are patients with low-risk MDS who may live for many years without any treatment.

“It’s important to understand how the genetic factors found in a patient’s blood cancer, and other clinical factors such as their age and other illnesses, contribute to their overall prognosis,” said Dr Lane.

In normal blood formation, there is a tightly regulated process where the blood stem cells in the bone marrow mature into functioning cells such as neutrophils and red blood cells, and these are the cells that are reduced in patients with myelodysplasia.

Research at Dr Lane’s lab concentrates on understanding the disease-causing cells in MDS, AML and MPN, and how these disease stem cells drive the transformation to disease, as well as looking into resistance to treatment.

“We’ve generated a new, unique model** that we use in the lab to understand the transformation from normal blood formation to myelodysplasia,” said Dr Lane.

“With the Leukaemia Foundation grant, we will use this model to better understand how azacitidine works, to get a better idea of the processes regulating the response, and then use the model to test how new drugs might be used in MDS.

“The model develops low blood counts, particularly in the platelets, which then progresses to low counts in other cells as well, then transforms into acute leukaemia after 6-12 months.

“It is a step-wise progression from normal blood through to myelodysplasia, through to acute leukaemia, so we can look at all the different stages of the disease.

“Azacitidine is an epigenetic therapy and we know its mechanism of action changes the methylation of DNA. Put simply, that means it turns genes back ‘on’ that have been switched ‘off’ in the myelodysplasia cells. Turning those genes back on, allows the cells to progress back to normal blood formation.

“We’ve shown that the MDS stem cells are very responsive to azacitidine, by taking those cells before and after azacitidine treatment to look at how the genetics of the cells might change and what signals they are putting out,” said Dr Lane.

“By doing that, we can understand the biological processes that drive the response to azacitidine.

“Now we are going back to the original model to understand if particular pathways might be different in these cells compared to normal cells.

“One of those pathways is apoptosis, which is basically the way a cell dies, and we’ve seen a difference in apoptosis between the model and normal blood stem cells.

“Therefore, we’re using new drugs that might target apoptosis to see if they work in this myelodysplasia model.

“We think this is really important research at the international level,” said Dr Lane.

“If we can show that this apoptosis process is different or abnormal in the model with myelodysplasia, and we can show the best way of combining treatments, we hope these can then be used in a clinical trial, and in the clinic moving forward.

“We’re keeping our eyes open for other drugs that work, but the predominant focus of this project is to improve the response to azacitidine.

“Some people have a spectacular response to azacitidine and do really well. We want to improve on that treatment, so most people do really well, not just a small percentage.”

The protocol Dr Lane is testing is azacitidine combined with venetoclax***.

“We hope we can use these drugs together to improve responses in all MDS patients,” he said.

“There’s a published trial using azacitidine and venetoclax in AML and we would hope this drug combination can be used in myelodysplasia as well.

“One of the difficulties will be getting around the toxicity of these drugs.”

Azacitidine is given daily for one week by injection, followed by three weeks with no treatment.

“We have shown in our model that by giving azacitidine continuously (every day) at a much lower dose, there’s an improved response rate, and the response is a little more specific for the MDS cells. So, this protocol may be better,” said Dr Lane.

On this project, Dr Lane’s lab is working with collaborators in Germany, at the National Centre for Tumour Diseases (Heidelberg), the German Cancer Research Centre (Heidelberg), and Professor Andrew Perkins’ group at Monash University (Melbourne).

* $160,000 over two years, as one of the Leukaemia Foundation’s Strategic Ecosystem Research Partnerships (SERP) to support high impact research. This project has been part funded through the estates of Rina Chow and Professor Patrick Quilty AM and the generous support of individuals in the community.

** Therese Vu was the postdoctoral researcher who worked on this project.

*** The Leukaemia Foundation provided funding for early work on the precursor to ABT-199 (now known as venetoclax). This research, undertaken by Dr Kylie Mason, Professor Andrew Roberts and collaborators at the Walter & Eliza Hall Institute (Melbourne) through the Leukaemia Foundation’s National Research Program Grants-in-Aid 2012 and 2012, assisted in the development of venetoclax.

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