Research And Grants

MRI Guided Focused Ultrasound: Targeted Drug Delivery in Diffuse Intrinsic Pontine Glioma

Hypothesis & Anticipated Results

Diffuse Intrinsic Pontine Glioma, (DIPG) is a fatal cancer and the leading cause of death from  brain tumours in young children. Despite numerous existing chemotherapeutic agents and  promising new molecular therapies, one overriding challenge remains: to overcome the blood  brain barrier (BBB) and achieve effective delivery of these agents to the tumour site. We  propose to use MRI guided focused ultrasound (MRIgFUS) to achieve non-invasive, focal and  reversible disruption of the BBB thereby creating a window of opportunity for drug delivery.  We believe that not only will MRIgFUS of the brainstem be safe but it will significantly enhance  drug concentrations within the tumour and in turn confer improved survival.     ii) Specific Aims Aim 1: To determine the safety of transient disruption of the BBB of the murine brainstem by  MRIgFUS  Aim 2: To develop and optimize preclinical models of DIPG for delivery of known and novel  chemotherapeutics using MRIgFUS.    iii)! Background!and!Rationale:!   a)! Diffuse Intrinsic Pontine Glioma (DIPG): A devastating cancer  Primary brain tumours occur across all age groups and confer a poor prognosis in the majority.  Gliomas are the predominant tumour type, constituting 65% of all primary brain tumours.  Diffuse Intrinsic Pontine Glioma is a high grade glioma that arises in the pons and occurs  almost exclusively in young children. Its eloquent location and aggressive nature results in a  near 100% fatality rate within 2 years of diagnosis and as such, is a truly devastating diagnosis  for families of afflicted patients1. The diffuse growth pattern of these tumours precludes  surgical resection and current treatment is confined to radiotherapy which provides only  transient remission.  Numerous clinical trials assessing a multitude of chemotherapeutic  agents have failed to demonstrate an improvement in survival2. As such, DIPG is now the  leading cause of brain tumour deaths in children3.    b) Molecular Developments & Preclinical Models  Through  a  combination  of  autopsy  samples  and  the  advent  of  safe  brainstem  biopsy  techniques, significant strides have been made in elucidating the underlying molecular drivers  of DIPG. The most commonly found mutation is now known to be that of a Lys27met (K27M)  substitution in histone H3 (70-84%) with resultant local hypomethylation4-7. Mutations and  copy number alterations have also been identified in TP53 (42 – 71%) and ACVR1 (20-32%)  which encodes the activin A receptor type 12,8. Identification of these genes has not only led  to the determination of pathways leading to tumorigenesis and subsequent new targets for  therapy but has also helped advance the sophistication of pre-clinical models.