Abstract
Diffuse intrinsic pontine glioma is the most common and deadliest pediatric brainstem tumor and is difficult to treat with chemotherapy in part due to the blood-brain barrier (BBB). Focused ultrasound (FUS) and microbubbles (MBs) have been shown to cause BBB disruption (BBBD), allowing larger chemotherapeutics to enter the parenchyma. Panobinostat is an example of a promising in vitro agent in DIPG with poor BBB penetrance. In this study, we hypothesized that using FUS to disrupt the BBB allows higher concentrations of panobinostat to accumulate in the tumor, providing a therapeutic effect. Mice were orthotopically injected with a patient-biopsied DIPG cell line, BT-245. After two weeks of growth, MR images guided FUS targeting to the tumor location. Microbubbles (25µl/kg, IV) and FUS (Frequency: 1.515 MHz, PNP: 0.77MPa, PRF: 1Hz, PL: 10ms, treatment time: 3 minutes) were applied to half the mice. Passive cavitation data (PCD) was collected and analyzed. Panobinostat was given (10mg/kg IP) to all mice. After 1.5 hours, a subset of mice were sacrificed to determine the concentration of panobinostat in tumor and cortex areas. We showed a 3-fold drug concentration increase in the tumor region while only slightly increasing the concentration in the forebrain. The remaining mice received three weekly treatments. Half were treated with FUS/MB and panobinostat, while others received panobinostat only. MRI was taken weekly to evaluate BBBD extent and tumor growth. PCD during treatments showed ideal cavitation of microbubbles illustrating safety and consistency across all treatments. The combination of panobinostat and FUS exhibited a tumor size decrease of 71% on MRI compared to panobinostat alone. Furthermore, FUS/MB improved the mean survival from 21 to 31.5 days (p=0.0001). Our study demonstrates that FUS-mediated BBBD can increase the delivery of panobinostat to an orthotopic DMG tumor, providing a strong therapeutic effect and increased survival.