| Project title | The Involvement of the Kynurenine Pathway in Glioma Pathogenesis |
|---|---|
Grant Amount | $384,090 |
Institution | Macquarie University |
Investigator Team | Principal investigators A/Prof. Gilles Guillemin and Dr. Seray Adams |
Years | 2013 – 2015 |
Brain cancer patients have impaired immune system function, which promotes cancer growth. One metabolic pathway which impairs the immune system in brain cancer patients is the kynurenine pathway. A/Prof. Guillemin and Dr. Adams’ research will investigate novel therapeutics that target the kynurenine pathway to restore normal immune system function to halt brain cancer growth.
This research project involves (1) measuring the whole kynurenine pathway metabolic repertoire in brain cancer patient blood and correlating these levels with tumour progression and brain cancer subtype and; (2) assessing the effect of novel kynurenine pathway inhibitors on brain cancer cell growth using cells grown in the laboratory. If this approach is successful, the next step will be to move this work into preclinical models.
“Our proposed research will advance the knowledge base of kynurenine pathway involvement in cancer pathology, which will promote new treatment options for patients.”
Dr. Seray Adams
Progress: Final report (2015)
Our research has made significant developments in understanding the mechanisms of how the kynurenine pathway interferes with normal immune system function. Our study has assessed the effect of certain kynurenine pathway toxic metabolites on the function of immune cells (the cells that make up the immune system) using a particular type of microscope to track the life of the immune cell real-time (over a number of days). To our knowledge, this study was the first to assess the effect of toxic metabolites using human immune cells in a time-course study.
We have demonstrated that specific toxic metabolites caused immune cells to stop growing and eventually lead to their death. We are currently in the process of assessing which of the many types of immune cells have died and what specific mechanism lead to their death. This process requires extensive optimisation of ‘colour’ combinations using a specialised machine called a flow cytometer. This machine can analyse the physical and chemical characteristics of immune cells and tell us exactly which immune cells have died.
The knowledge gained from our studies has enabled a better understanding of the mechanisms that control immune system dysfunction in brain cancer. A better understanding of these mechanisms will allow the harnessing of immunity for cancer therapy, which may have long-standing and durable significant improvements in patient survival. If we can better understand exactly how the kynurenine pathway interferes with normal immune system function and know which specific metabolites have greater effects on immune cells, then we can better develop more specific therapies for brain cancer patients, aimed at reversing immune cell death.
Blocking the kynurenine pathway at specific points may represent a novel molecular weapon in the treatment of brain cancer, which may slow the growth of the brain cancer through blocking the production of kynurenine pathway toxic metabolites.