Working to understand and improve MDS drug

Dean and colleagues at the Dawson lab

Azacitidine (Vidaza®) is the only drug available for treating myelodysplastic syndrome (MDS), and is also used to treat several other blood cancers. Unfortunately, the drug is only effective in about half of MDS cases, and its exact mode of action isn’t understood.

With funding support from the Leukaemia Foundation, Dean Tyler at the University of Melbourne and Peter MacCallum Cancer Centre  is using new techniques to discover how azacitidine interacts within cells at the molecular level, hoping to enable researchers to improve its effectiveness.

Small molecules might offer big insight

To answer questions about the drug’s molecular activity, Dean is using a novel technique that involves chemically adapting the small molecules that make up azacitidine. This allows Dean to label and then visualise the molecules using a specialised microscope to see where in a cell the drug is distributed. He can also isolate the cellular proteins targeted by the drugs.

“We also believe this methodology extends to assessing the amount of the drug that is present within cancerous and normal tissues,” Dean said.

“This level of data will provide an unprecedented understanding of the mechanism of action of azacitidine.”

What is azacitidine?

Azacitidine belongs to a class of drugs known as epigenetic therapies. The drug appears to be absorbed by cancer cells, where it interacts with several targets to restore normal cell behaviour.

Critically, the drug is thought to turn off a protein called DNA methyltransferase. This in turn switches on genes that stop cancer from making the RNA and DNA they need to grow and divide. Treatment with the drug also leads to cancer cell death, which is believed to be caused by the reactivation of the cell death cycle.

A test to identify who will benefit from treatment

In a separate project at St Vincent’s Hospital in Melbourne, Dr Meaghan Wall (pictured left) has been developing a clinical prognostic tool to identify MDS patients who are most likely to benefit from treatment with azacitidine.

Dr Wall and her team have been scanning MDS cells from 40 patients for genetic abnormalities associated with favourable and unfavourable response to azacitidine.

“In the long-term, this tool has the potential to be used by clinicians to give people a more accurate way to estimate their chances of responding to azacitidine and help them make treatment decisions,” Dr Wall said.

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