Investigating the therapeutic effect of a ketogenic diet in a xenogeneic (PDX) mouse model of chronic lymphocytic leukaemia

This project is suitable for a PhD student or Honours followed by a PhD.

BACKGROUND

Chronic lymphocytic leukaemia (CLL) is a blood and bone marrow cancer that slowly worsens over time. CLL is one of the most common types of leukaemia in adults and typically occurs during or after middle age. Most patients have a form of CLL that develops slowly and remain stable for many years without treatment, while others develop aggressive disease hallmarks.

CLL patients have too many abnormal B lymphocytes, along with poor responses to infections and low anti-tumour immunity. Infections are a major cause of death in CLL patients; current treatments used to reduce the number of tumour cells further compromise patient immune systems, and resistance/intolerance to treatment adds to the disease burden. Restoring immune system functions in CLL patients is currently an unmet need and developing new drugs and treatments is critical.

Using a mouse model of CLL, we have recently discovered that mice fed a ketogenic diet are protected against developing disease. However, the clinical relevance of this dietary intervention has not been tested. The protective molecular mechanisms that are triggered by the ketogenic diet are also unknown. However, it is likely that the protection provided by the diet against CLL is associated with a set of metabolites with a potentially anti-leukaemic effect, creating hypotheses for exploration.

This project will create a patient-derived xenogeneic (PDX) model of CLL, using blood cells from CLL patients injected into mice without T, B or NK cells, which allows for the engraftment of human cells. The mice will then be fed a range of diets, and CLL progression will be monitored using flow cytometry and other biochemical assays.

AIMS

The aims of this project are to:

• Evaluate the therapeutic effect of diet in a patient-derived xenogeneic (PDX) model of CLL.
• Identify the metabolites associated with the ketogenic diet-mediated protection against CLL in the PDX model.
• Test the anti-leukaemic function of the metabolites in-vitro.
• Understand the molecular function of these metabolites (such as receptors, target cells, and signalling).
• Evaluate the anti-leukaemic metabolites in mouse and PDX models of CLL.

The identification of anti-leukaemic metabolite/s will facilitate development of a new class of drugs, with a novel mechanism of action and minimal side effects. Through these studies, the student will gain significant expertise in mouse models of disease, cell culture, flow cytometry, immunohistochemistry, and metabolomics. This project has a high potential for translation and interaction with industry.

PROJECT POTENTIAL

The development of first in class metabolite-based therapies for CLL, a much-needed source of treatments for patients with CLL developing resistance to existing and recently introduced new treatments for CLL.