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Characterisation of a novel DCAF factor as a blood cancer therapy

Jake Shortt

 

 

 

 

 

Associate Professor Jake Shortt, Monash University (Melbourne).
Funding period: 2019-2021.

This project is kindly supported by the estate of Davina Sickerdick.

Multiple myeloma is one of the most common blood cancers. Unfortunately, despite a number of remarkable advances in myeloma treatment, most patients ultimately experience disease progression on currently available therapies and new treatment approaches are urgently required.

Myeloma is a cancer of the plasma cell – a cell which normally functions as a protein factory to generate antibodies for the immune system. In Myeloma patients these cancerous plasma cells produce large amounts of antibodies which are not active, these antibodies are known as ‘M-protein’ or ‘paraprotein’. As these cells are producing large amounts of protein this feature seems to make myeloma particularly vulnerable to treatments that disrupt protein processing and regulation within the cell. Indeed, the two most active and frequently used myeloma treatments – proteasome inhibitors (e.g. Velcade) and IMiDs (e.g. Revlimid) – work in this way.

The beginnings of Prof Shortt’s project lay in trying to discover if cell protein regulation could be targeted in a different way to the existing therapies of proteasome inhibitors and IMiDs. Performing a sophisticated genetic screen, using a new technology called ‘CRISPR’, has allowed Prof Shortt and his team to identify a new myeloma target within the same protein machinery that is disrupted by IMiDs. A series of small ‘drug-like’ molecules have been identified that in the laboratory which can kill myeloma cells. The mode by which these new molecules kill the myeloma cells is very different to existing IMiD drugs and preliminary tests have shown that these molecules can even kill myeloma cells which are resistant to existing treatments such as the IMiD drug Revlimid.

This project will now develop lead drug candidates in a series of translational experiments designed to accelerate progression to human trials. In tandem the medicinal chemistry team will further optimise these drug-like molecules in order to maximise potency against blood cancers while avoiding non-specific side-effects. These new drugs will be tested in combination with existing myeloma therapies and across a number of pre-clinical myeloma models. These molecules will also be tested against other blood cancers – including lymphoma and leukaemia.