Research And Grants
The University of Alabama at Birmingham – $100,000
Dr. Rintaro Hashizume
DIPG / DMG
Intranasal Delivery of Targeting Nanotherapeutics for DIPG
Pediatric gliomas are one of the most common cause of cancer-related death in children, and diffuse intrinsic pontine gliomas (DIPGs) are the most rapidly fatal of these tumors. No significant advances in the survival of patients with DIPG have been made over the last few decades, and new therapeutic approaches are desperately needed.
The infiltrative nature together with delicate tumor location in the brainstem precludes surgical resection, and the blood-brain barrier (BBB) prevents to deliver most drugs to the brain. To overcome this barrier, we will employ an innovative and effective drug delivery, intranasal delivery. Intranasal delivery is a practical, noninvasive method of bypassing the BBB to deliver drugs to the brain using unique anatomic (nerve) connection between nose to the brain, reducing unwanted systemic toxicity, and is amenable to self-administration by patients.
Intranasal delivery (IND) can be optimized by using nanoliposomal drug carriers which provide stable encapsulation of the drug and improve nasal penetration. To increase the specificity of liposomal drug delivery, immunoliposomes, which coated with antibodies on the surface of liposomes, can increase delivery of the drugs into the tumor cells, and reduce toxicity to normal cells. The primary goal of this project is to integrate IND with the targeted nanotherapeutics, leading to increase drug concentration in brainstem tumor without harming healthy brain tissues.
We have generated PDGFRA-antibody coated nanoimmunoliposome, because PDGFRA (Platelet-Derived Growth Factor Receptor Alpha) plays a role in DIPG growth and expresses in as much as 70% of DIPG. We found greater uptake of PDGFRA coated nanoliposome into the DIPG cells than that of non-coated nanoliposome.
Unlike adult glioma, DIPG is uniquely characterized by histone gene mutation, which causes enzymatic modification in the histone protein, which in turn, increases gene expression. DIPG has shown sensitivity to enzyme-targeted therapies, those targeting EZH2, the enzyme increases histone methylation. Unfortunately, the clinical efficacy of systemically administered (i.e., intravenous injection) EZH2 inhibitors in children has been disappointing due to poor penetrance across the BBB. For this reason, we consider it of high importance to perform a pre-clinical study of IND bypassing the BBB for the effect on EZH2 inhibitor delivery to, and biological activity, against DIPG.
In this proposal, we will test the efficacy of IND of PDGFRA-naoimmunoliposomal-Tazemetostat, an FDA approved EZH2 inhibitor, using patient-derived DIPG animal models. In our preliminary study, PDGFRA-nanoimmunoliposomal-Tazemetostat showed greater inhibition of DIPG cell growth in compared to empty immunolipsome. We hypothesize that this new therapeutic approach will reduce systemic toxicity and increase drug distribution and efficacy for treating brainstem tumor in patient-derived DIPG animal model,
Furthermore, we will test a new intranasal device, SipNose, which has recently approved by FDA and being tested in clinical trials in children. Finally, our long-term goal is to use IND of nanotherapeutics in combination with radiation which is used routinely for the treatment of DIPGs. The data generated through this study could lay the foundation for a clinical trial of this approach in children, with the goal to improve clinical care and outcomes for children with this devastating pediatric brain tumor.