Research And Grants
Hospital for Sick Children - $50,000
Dr. Saira Alli
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.