Quest to better understand MDS and find out more effective therapies
When someone with MDS is treated with azacitidine (Vidaza®), it takes six months to find out if they are responding to the drug.
This “really is a wait and watch scenario”, according to Dr Ashwin Unnikrishnan, Group Leader and Senior Research Fellow of the Adult Cancer Program at Lowy Cancer Research Centre (Sydney).
But he hopes to change that with his latest translational research building on discoveries in his lab.
This research, co-funded* by the Leukaemia Foundation, Leukemia & Lymphoma Society (U.S.) and Snowdome Foundation over the next three years, involves collaborators in Australia and overseas working closely together to solve the problem of MDS.
“My work focuses on how we can improve the treatment of MDS. We need to develop more effective and durable therapies,” said Dr Unnikrishnan, who chose to investigate MDS when he was a basic science researcher, for both personal and professional reasons.
Dr Unnikrishnan’s personal interest in MDS
“My great uncle succumbed to this disease exactly 20 years ago, when I was in high school. He’d be rushed off to hospital in the middle of the night with a nosebleed. Then he’d get transfusions and all the conglomerate problems that went with that.
“I saw how MDS affected his health and its impact on the person he was. This was prior to azacitidine being available, when the mode of treatment was sub-optimal,” said Dr Unnikrishnan whose PhD was in epigenetics.
“I realised that epigenetics is one of the major things that goes wrong in a number of cancers including MDS.
“Epigenetic mutations are different to DNA mutations, and epigenetic alterations underlie a lot of what’s going wrong with MDS,” he said.
Understanding how azacitidine works
“Azacitidine is an epigenetic modifying drug and the best available treatment for people with MDS.
“There are individuals who benefit from azacitidine, even if it isn’t lifelong, and some people are almost cured; they’ve been on azacitidine for 10+ years and are still healthily tolerating the drug.
“But it only works in about 50% of the patients exposed to the drug, and we don’t understand why.”
This means around half of all azacitidine recipients will never respond to the treatment for MDS, and a significant fraction of those who do respond to azacitidine will relapse within two years.
“That’s the sad reality. And the prognosis for people who fail azacitidine treatment is quite poor,” said Dr Unnikrishnan.
“We’re trying to work out why azacitidine only works for a period of time before patients then relapse on the treatment.”
Dr Unnikrishnan has identified what is happening in patients who do respond to this treatment.
“Azacitidine isn’t eliminating the MDS cells that contain the mutation, so these mutated cells continue to exist in the bone marrow but the patient’s ability to produce blood improves, which is why they are identified as being responders to azacitidine treatment,” he explained.
“This reservoir of ‘bad cells’ in the bone marrow is the foundation for eventual relapse.”
Developing more effective therapies for MDS
Dr Unnikrishnan’s ongoing research has two goals – to better understand how azacitidine works and to use that information to develop more effective therapies, “because azacitidine isn’t a cure and most people eventually will relapse”.
“We need to do a better job of identifying how we can target the cells that cause MDS in the first place and aren’t being eliminated by azacitidine treatment,” he said.
“Then alternative therapies could be used to eliminate those abnormal cells and hopefully improved treatment options may lead to longer life spans as well.
“We have tantalising hints on what might be happening and what we can potentially do,” said Dr Unnikrishnan.
“But these findings are preliminary at this stage and need to be validated and confirmed. This will be done using samples collected in clinical trials and those banked in the past, and that’s where funding for this project is absolutely essential.
Validating initial discoveries
“We have applied advanced technologies, such as next generation sequencing, to make these initial discoveries and this new funding helps us follow up on those initial discoveries, with experiments to validate our hypotheses and to generate high quality pre-clinical data which is essential to move our discoveries forward to early stage clinical trials.
“We have collected bone marrow [samples] from MDS patients before they receive treatment and at different stages when they’ve received treatment.
“From those samples, we extract the hematopoietic stem cells and early progenitor cells that sit in the bone marrow. We think MDS arises from those stem cells or progenitor cells, so our investigations are focused on those cell populations.
“A lot of our pre-clinical work involves using these patient samples to work out what’s different about them, compared to healthy individuals; what’s happening in those cell populations in an individual as they get treatment, and what’s changing or not changing in individuals based on whether they do or don’t respond to treatment?
“We generate hypotheses based on that, then utilise the samples in lab experiments to validate whether our hypotheses are correct or not correct.”
Identifying responders and non-responders
Dr Unnikrishnan also has started to uncover reasons why people don’t respond to azacitidine.
“They have a baseline molecular characteristic that is quite different to the responders,” he said.
“Molecular pathways seem to distinguish individuals, even before they begin treatment, identifying those who will become responders and those who won’t.
“One striking discovery is that bone marrow cells in people who don’t respond to this treatment are more cell cycle quiescent; their bone marrow cells don’t go through the cell cycle (dividing and replicating) as healthy cells should.
“We also identified molecular pathways that we think are linked to this increased cell cycle quiescence.
“Emerging from that work, through the technologies we are developing, we hope to identify pre-existing differences up front – before treatment is started – about whether individuals will respond or be resistant to azacitidine.
“Predicting that a person won’t respond to treatment is one of the things we’re trying to work on,” he said.
“A bone marrow transplant is the best therapy for people with MDS who have a matched donor and whose age and health suggests they can tolerate a transplant,” said Dr Unnikrishnan.
“And at some stage a clinical decision might be made for these individuals, rather than waiting six months on a futile treatment (if they turn out to be non-responders to azacitidine).”
However, Dr Unnikrishnan said it was important for patients to understand that was being worked on and was not yet in the clinic.
“It would be unethical to deny people treatment if we couldn’t make that prediction with a high level of confidence.
“We hope to find alternative ways to rectify these aberrant molecular pathways and we might be able to target the MDS more effectively than azacitidine currently does,” said Dr Unnikrishnan.
“We will investigate molecular mechanisms within MDS cells affected by azacitidine, as a means to develop new treatment options for MDS.”
Boosting azacitidine with an alternative therapy to make it more effective, or that works separately, may be an option.
And there may be drugs already on the Pharmaceutical Benefits Scheme or approved by the Federal Drug Administration (in the U.S.) that need to be tested on clinical trials as possible alternative therapies for MDS.
Collaborative partnerships interstate and internationally
Dr Unnikrishnan said new collaborations over the last two years, in Melbourne, interstate and overseas, had brought new insights into the problem he has been thinking about for many years.
“To look at MDS in a different light and mindset, to discover new things and solve this disease, you need to bring in a team of collaborators with different skill sets and expertise in different areas, including immunology, mathematics and biology, to complement one’s own.
“It’s exciting to work on multi-disciplinary research in this manner, and that integrates Australian research with the research community across the world.”
* Beyond Azacitidine: Investigating new therapeutic strategies for the treatment of MDS? University of NSW, (Sydney). Collaborating institutes: UNSW (NSW), St Vincent’s (Vic), Technical University of Denmark. Funding: USD600,000, co-funded through LLS (USD300,000), Leukaemia Foundation (USD150,000), Snowdome Foundation (USD150,000).
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