Engineering an in vitro model of the central nervous system leukaemic niche to improve treatments for childhood leukaemia.

Cancer is the leading cause of death for children aged 1-14 years. Acute lymphoblastic leukaemia (ALL) is the commonest childhood cancer. The largest advance in survival rates for ALL came with the recognition that it often spreads to involve the central nervous system (CNS) and therefore all patients require CNS-directed treatment to achieve long-term cure. This involves children requiring intensive treatment, including direct injection of toxic chemotherapy into the cerebrospinal fluid to achieve long-term cure and to prevent ALL recurrence within the brain/CNS. Although successful, this treatment causes significant side-effects, especially with IQ, learning and memory, which affects 20-40% of survivors treated for ALL. There is therefore an urgent need to develop more effective, and less-toxic, treatments for CNS-leukaemia. In order to discover novel drugs for CNS leukaemia, it is essential to accurately model the unique cellular and environmental components of the CNS-niche. The current lack of in vitro models is a major barrier to progress in this field. This project will use tissue engineering to develop a physiologically relevant model of the CNS niche incorporated into a microfluidic device suitable for drug discovery. Cells (leukaemia cells and meningeal stromal cells), will be cultured on an engineered membrane, with controlled properties (stiffness, thickness, porosity), which will provide an interface between the CNS niche and normal blood plasma conditions. It will also incorporate key components of the CNS niche including a low nutrient environment (low lipid, low glucose) and enable important cell-to-cell interactions to be modelled as these are known to confer resistance to current chemotherapy treatment. This system will enable investigations into how leukaemia cell behaviour changes when they transit from the blood to the CNS and provide a unique model to investigate drug responses in ALL. This project will provide training and develop expertise in biomaterials, tissue bioengineering, complex fluids and rheology. It will involve the design of advanced bio-interfaces, incorporating growth factors, extracellular matrix and cancer cell/stromal cell interactions, as well as the use of microfluidic approaches and design of systems suitable for drug discovery. Developing preclinical pipelines to identify less-toxic CNS-active agents is a major unmet clinical need.