A new approach to treat acute myeloid leukaemia

Apr 15 2020

Dr Matt Dun and Associate Professor Nikki Verrills

Researchers from the University of Newcastle, Hunter Medical Research Institute and Hunter Cancer Research Alliance have published research outlining the discovery of a new cellular mechanism that promotes the development of acute myeloid Leukaemia (AML).

AML is a devastating blood cancer. Despite the use of intensive combination chemotherapy, only one in four AML patients survive their disease.

The growth and spread of cancer occurs due to a number of important cellular changes. One of the most common and important change is switching off the cells natural ability to suppress cancer formation; known as tumour suppression. Activating tumour suppressor proteins has traditionally been viewed as an unassailable goal, however this discovery provides clear evidence that it can be done.

Dr Matt Dun and Associate Professor Nikki Verrills paper, published in Leukemia, the leading international blood cancer journal, identifies SBDS as the protein in leukaemia cells that inhibits an important tumour suppressor protein, called PP2A. 

“In normal, healthy cells, PP2A acts as a stop switch – telling cells to stop dividing and to undergo controlled cell death,” lead author, Dr Dun says. “However in cancer cells, and in particular in blood cancers like AML, the activity of PP2A is switched off, freeing the cells to continually grow and to avoid cell death signals.”

By discovering that the protein SBDS contributes to the switching off of PP2A in AML, the team are able to target this protein using drugs to restore PP2A activity, killing the tumour cells. Importantly it was found that SBDS depletion had no effect on normal healthy cells, suggesting that SBDS could be a good target for anti-cancer therapy.

“We found that the chemical compound, AAL(S), binds directly to SBDS, blocking the interaction with PP2A, boosting PP2A activity and killing the leukaemia cells,” Associate Professor Verrills adds.

“Excitingly, early indications suggest that SBDS is also present at high levels in many other types of cancer. Therefore the development of new SBDS inhibitors will likely be an important contribution to future anti-cancer therapies.”

There is a lot more to be done, with the team modelling the interaction between AAL(S) and SBDS, providing a powerful platform for the future development of new, even better SBDS inhibitors.

This work has been a collaboration between members of the Hunter Cancer Research Alliance from the University of Newcastle, Hunter Medical Research Institute, the Newcastle Calvary Mater Hospital and John Hunter Children’s Hospital together with medicinal chemists at the University of NSW and leukaemia researchers at the Children’s Cancer Institute Australia.

Paper title: “Shwachman–Bodian–Diamond syndrome (SBDS) protein is a direct inhibitor of protein phosphatase 2A (PP2A) activity and overexpressed in acute myeloid leukaemia”

* HMRI is a partnership between the University of Newcastle, Hunter New England Health and the community.