SCIDOT-48. EVALUATING THE THERAPEUTIC EFFICACY AND CONVECTION ENHANCED DELIVERY (CED) TOXICITY ANALYSIS OF CDK4/6 INHIBITOR PALBOCICLIB FOR DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

Abstract DIPG is a devastating, aggressive brain tumor of childhood. No chemotherapeutic agent has so far shown significant clinical efficacy and focal radiation therapy provides only temporary relief. Recent studies on the genomic aberrations of pediatric gliomas have shown that a subset of these tumors harbor focal gains in proteins of the cyclin-dependent kinase (CDK) 4/6 cell cycle pathway. H3.3K27M mutation, associated with >80% of DIPGs, has also been associated with epigenetic silencing of p16 tumor suppressor, an important effector in regulating CDK4/6 pathway. In this study, we characterized and confirmed through immunoblot analysis that proteins involved in CDK 4/6 pathway, including Rb1, are intact in multiple patient derived DIPG (SU-DIPG-IV, SU-DIPG-XIII, SU-DIPG-XVIII, SF8628) and wild type (SF9428) cell lines. Expression of p16 was decreased or undetectable in DIPG cells compared to normal astrocytes. In addition, pharmacologic inhibition of CDK4/6 with palbociclib showed dose dependent reduction in DIPG cell proliferation with IC50 ranging from 5.42uM to 21.35uM between different cell lines. However, major problems of palbociclib are that it does not readily cross the blood-brain-barrier (BBB) and has major systematic toxicities, such as myelosuppression, which limits oral dosing. One solution to overcome the BBB is convection enhanced delivery (CED) which is a form of local delivery that bypasses the BBB by placement of small diameter catheters directly into the brain tumor. With this approach, high regional drug concentration can be achieved with negligible systemic toxicity. In this study, we also observed no significant short- or long-term neurotoxicity of palbociclib delivered via CED in a mouse model. We hypothesize that the CDK4/6 cell cycle pathway has an important role in DIPG tumorigenesis and progression and that existing therapies targeting these pathways, which are already in clinical use for other cancers, can be rapidly repurposed for the treatment of DIPG through CED.