Grant: Project Grant

Medulloblastoma is the most common primary brain tumour in children. While medulloblastomas can have different molecular properties that determine how treatable the tumour is, as a whole, survival is only around 60%. For those classified as Group 3 the survival outcome is even poorer. Treatment consists of surgical removal of as much of the tumour mass as possible and either radiation or chemotherapy. Unfortunately, those who do survive are left with life-changing losses in brain function as a result of the treatment. Studies demonstrate that genes controlling the amount of apoptosis (programmed cell death) inhibitory proteins (IAPs), are increased in medulloblastoma. New drugs that can block the effects of various IAPs are available, but have limited activity against brain tumours due to the inability to cross the specialized blood vessels of the brain that form the blood-brain barrier. These studies will use a method my laboratory has developed and tested to selectively and reversibly open the blood-brain barrier to increase brain and tumor levels of chemotherapeutics and the XIAP sensitizing drugs to allow both radiation and chemotherapeutic agents to more effectively kill the tumour cells in the brain. Using peptides that target cadheren, an adhesion molecule that helps capillary endothelial cells stick together, we will temporarily loosen the connections between the brain capillary endothelial cells to allow increased delivery of drugs and sensitizing agents to the brain tumour. We will examine our approach using medulloblastoma cells in cell culture or implanted in the brain of a mouse. In the mouse brain tumour model we will examine both survival and cognitive functions to identify improvements in treatment. We believe this approach will translate to increased numbers of children who can be cured of this cancer while decreasing the resulting adverse effects on brain development and cognition caused by the treatments used.