Game Changer Grant Awarded to James Rutka

Diffuse intrinsic pontine glioma (DIPG) is a devastating tumor that primarily affects children 5 - 7 years of age and is universally fatal. The location of these tumors within the brainstem prevents surgical removal, as this region controls essential functions like breathing and heart rate. Additionally, due to the significance of this area, a blood-brain barrier (BBB) acts as a cellular shield, protecting the brain from toxins, pathogens and drugs in the circulation. Consequently, chemotherapies fail because many drugs cannot effectively cross the BBB to reach the tumor. Previously, we successfully demonstrated the safety of using MR-guided focused ultrasound (MRgFUS) to temporarily open the BBB, creating a window of opportunity for administering cancer treatment.

Excitingly, Health Canada approved our Phase I clinical trial testing MRgFUS-enhanced delivery of the BBB-excluded chemotherapy drug doxorubicin in patients with DIPG, which is currently in progress. Furthermore, our clinical team now routinely performs robot-assisted brainstem biopsies of DIPG tumors in children, enabling us to characterize genetic and molecular pathway alterations and to design tumor biology-based precision therapy regimens in real-time. While we are investigating the use of doxorubicin to treat human DIPG using MRgFUS in our clinical trial, we wish to extend our preliminary experience using single, non-targeted chemotherapy to combinatorial strategies. This can only be achieved by testing novel treatment approaches in preclinical mouse models. In the first part of our proposal, we will use our genetically engineered DIPG mouse model, which closely mirrors the tumor’s key mutations and maintains an intact immune system, thereby providing a more accurate representation of the human disease. We will refine the MRgFUS procedure in this model to ensure it both increases drug delivery and helps stimulate the body’s immune defenses within the tumor. Next, we will develop a proof-of-principle combination strategy that precisely targets DIPG tumors by integrating molecular insights from individual patient biopsies with MRgFUS-enhanced delivery of both targeted agents and immunotherapies. This will allow us to identify the most effective combinations to achieve the most durable anti-cancer response and to inform future clinical trials. Our studies will ultimately advance a precision medicine approach that offers better outcomes for children with this aggressive brain tumor.