NanoPROTACs: a New Blood-Brain Barrier Penetrating Therapeutic Approach to Drug the ‘Undruggable’ in DIPG/DMG

Background: The blood-brain barrier (BBB) is one of the greatest barriers to treatment of brain tumors, including H3K27-altered diffuse midline glioma (DMG), a near universally fatal childhood brain cancer. We have developed a clinically-compatible fucoidan nanoparticle (Fi- NP) that homes to P-selectin on tumor vasculature after low-dose radiation (RT) to breach the BBB and deliver several classes of targeted therapies.

Objectives/Hypothesis: We propose to use this strategy in DMG to target BET proteins BRD2/3/4, which are powerful transcriptional co-activators of oncogenic pathways implicated in tumor proliferation and radiation therapy resistance. However, BRD4 inhibitors that have been in clinical development over the past decade have been hindered by their systemic toxicity profiles. We have recently expanded the encapsulation capabilities of fucoidan nanoparticles to include delivery of Proteolysis targeting chimeras, or PROTACs, to degrade several ‘undruggable’ targets found in pediatric brain tumors. We will use Fi-NP to encapsulate and deliver dBET6, a promising PROTAC degrader of BRD2/3/4 proteins but with limited CNS penetration and common dose-limiting toxicities. We hypothesize that Fi-encapsulation of dBET6 (Fi-dBET6) PROTAC will have improved therapeutic indices, reduced systemic side- effect profile, and improved BBB penetration. 

Specific Aims: (1) Optimization of Fi-dBET6 tumor delivery across the BBB in DMG genetically engineered mouse models and (2) determine in vivo Fi-dBET6 therapeutic efficacy and toxicity. 

Study Design: In our preliminary data, in our RCAS-TVA DMG mouse, tumor vasculature exclusively expresses P-selectin, and low-dose RT (2 Gy) significantly enhances it at 24h. Importantly, we have also been to localize, after a single dose, near-infrared labelled Fi-dBET6 specifically into the tumor space while sparing healthy brain after this RT priming dose. We will confirm the timepoint and dose of optimal p-selectin expression, then characterize Fi-dBET6 localization, drug effect, PK, and biodistribution. We will establish therapeutic benefit and toxicities after a defined treatment course eight doses with RT priming, given in alternating days. 

Significance and potential impact to patients: Our findings will provide the critical foundation for our Fi-NP approach delivering dBET6 to be evaluated in much-needed clinical trials for children with DMG, and also for other aggressive childhood CNS tumors driven by BET transcriptional activation.