Professor Pimanda is incredibly curious. His observations around why cells behave in certain ways and respond variably to stimuli led him down a cell biology research path. He was particularly drawn to blood stem cell development and maturation and the disruption of this orderly process in blood cancers.
In 2008, when John was setting up his lab at the University of NSW, he was drawn to a clinical conundrum, Myelodysplastic Syndrome (MDS), a blood stem cell disorder where normal cell maturation is disrupted and patients fail to make mature blood cells in sufficient quantities to support life. At that time, there were no effective treatments for MDS on the pharmaceutical benefits scheme (PBS) in Australia, despite FDA approval for azacitidine (AZA) for the treatment of MDS in 2004. An idea for a clinical study to understand why half of all treated MDS patients didn’t respond to AZA was conceived, but just as importantly, this trial enabled MDS patients in NSW and the ACT to access AZA through the manufacturer, Celgene on a compassionate access scheme.
The trial highlighted that patients who responded had features in their blood stem cells that allowed for the uptake of AZA, whilst non-responders did not have sufficient uptake of AZA. In vitro studies showed that if AZA resistant cells were exposed to AZA combined with α5/ITGA5 and focal adhesion kinase (FAK) inhibitors, you could induce more drug uptake.
With the grant John has received from Leukemia Lymphoma Society-Snowdome Foundation-Leukaemia Foundation (LLS-SF-LF) for his Translational Research Project, he will try to uncover what treatments could be used to enable AZA uptake in resistant cells. The aim is to identify new drugs that improve AZA efficacy using a chemical genome screening to identify targets and pharmacological treatments that will interact with specific molecular pathways.
John is also the recipient of a Medical Research Future Fund (MRFF) grant which is enabling him to take the laboratory research he started twelve years ago into a clinical trial. John will be treating MDS patients with a combination of AZA and a FAK inhibitor. He will be monitoring the patients’ response to the treatment and measuring AZA uptake into their cells. The cells that John collects from this patient clinical trial will be used to create mice carrying human cells (xenografts) that will enable him to perform pre-clinical testing with pharmacological treatments that are discovered from the chemical genome screen.
One day John hopes to have a new treatment for MDS that is the result of his research into drug resistance to AZA. With the availability of more treatment options, he believes that in the future we will be able to determine the best combination of treatment for every MDS patient by performing laboratory tests on their bone marrow cells to offer them the best possible choice and outcome.