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Mr Dean Sydney Tyler

PhD Scholarship top up grant

Researcher:          Dean Sydney Tyler

Institute:               The University of Melbourne & Peter MacCallum Cancer Centre (VIC)

Project title:          Visualising the mechanism of action of cancer therapies

Disease focus:     Myelodysplastic syndrome

Annual Funding:  $4,717

Funding period:   2015-2017


Project summary  

In this PhD project, Dean is using new techniques to discover how the anti-cancer drug, azacitidine (Vidaza®) interacts within cells.

Azacitidine is the only drug available for treating myelodysplastic syndrome (MDS), and is also used to treat several other cancers including chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia (AML).

The drug is only effective in about half of MDS cases, and its exact mode of action isn’t understood. By defining how the drug acts at a molecular level within the cells, Dean hopes to enable researchers to improve its effectiveness.

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. He also can isolate the cellular proteins targeted by the drugs.

“We’re able to directly assess where in a cell the drug is distributed, as well as isolate in a cellular context the protein/RNA and DNA it associates with in the cell,” said Dean.

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

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

The methodologies Dean is using were developed by his supervisor Associate Professor Mark Dawson – Consultant Haematologist and Head of the Cancer Epigenetics Laboratory, Peter MacCallum Cancer Centre – in collaboration with leading chemist, Dr Raphael Rodriguez and his laboratory at the CNRS, Paris.

The Leukaemia Foundation also awarded a 2015 Postdoctoral Fellowship to Dr Omer Gilan, who is working in Associate Professor Dawson’s laboratory. Dr Gilan is investigating the use of combination therapies, including BET inhibitors, in treating AML.