ID #105 nanoPROTACs – a new approach to enhanced blood-brain barrier delivery of EZH2-targeting therapies with tumor-specific localization in DMG/DIPG
Bryan Li, Raashed Raziuddin, Kristen Vogt, Daniel Heller, G Praveen RajuAbstract
Background
The blood-brain barrier (BBB) is a major challenge to the treatment of CNS tumors, including diffuse midline glioma (DMG), a near universally fatal childhood brain cancer. Small molecule inhibitors of EZH2, a key catalytic subunit of the PRC2 complex driving DMG proliferation, have been proposed but have poor BBB penetration with additional acquired treatment resistance concerns. New proteolysis-targeting chimera (PROTAC) molecules use the ubiquitin-proteasome system to degrade oncoproteins like EZH2, disrupting both its catalytic and non-catalytic functions, and destabilize other PRC2 subunits (i.e. EED and SUZ12) to overcome the emergence of secondary mutations and treatment resistance. However, their macromolecular structures also limit BBB penetration.
Methods
We are advancing a clinically-compatible fucoidan (Fi) nanoparticle that can encapsulate several classes of anti-cancer drugs, homes to P-selectin on tumor vasculature after low-dose radiation (RT) to breach the BBB through active transcytosis and localize to tumor areas. We have used this strategy to Fi-encapsulate EZH2 inhibitor tazemetostat (EPZ-6438) and EZH2 PROTAC MS8815 (Fi-EPZ and Fi-MS8815, respectively). Optimal treatment regimen for tumor-specific delivery, efficacy, and side-effect profile will be determined in robust RCAS-tva DMG mouse models with a tight BBB.
Results
Mouse DMG models are amenable to Fi-based nanoparticle delivery as tumor vasculature exclusively expresses P-selectin, and that low-dose RT (2 Gy) enhances its expression further at 24h. Fi-EPZ and Fi-MS8815 form nanoparticles of uniform size and stability by zeta potential. We have been able to localize Fi-EPZ and Fi-MS8815 after a single RT priming dose specifically to the DMG tumor region while sparing normal brain. We hypothesize that Fi-encapsulation will improve therapeutic indices, while reducing systemic side-effects.
Significance
Our findings will provide the critical foundation for Fi-EPZ and Fi-MS8815 to be evaluated in clinical trials for children with DMG, and other brain tumors dependent by EZH2 and the PRC2 complex.