Lay Summary

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.

Executive Summary

Pediatric high-grade gliomas (pHGGs), including diffuse intrinsic pontine gliomas (DIPGs), are among the most aggressive and lethal central nervous system (CNS) tumors in children. Despite treatment, nearly all children with pHGGs succumb to their disease within two years of diagnosis. Factors that contribute to the dismal prognosis of these patients include the infiltrative nature and anatomic location in an eloquent area of the brain, which precludes surgical resection, and the presence of the blood-brain barrier (BBB), which limits the distribution of systemically administered agents. While some small molecules are delivered systemically to the brain by crossing the BBB, high doses are needed to achieve therapeutic levels, which can lead to substantial toxicity. Therefore, therapeutic approaches that facilitate drug delivery bypassing the BBB are desperately needed to improve outcomes for pHGG patients.

Intranasal delivery (IND) is a practical, noninvasive method of bypassing the BBB to deliver anti-cancer agents to the brain. Intranasally administered drugs reach the CNS within minutes of administration by using unique anatomic connection between nasal cavity and CNS along with the olfactory and trigeminal neural pathways. This technique has been used to enhance the delivery of a wide range of chemotherapeutic agents into the brain and showed promising results in the treatment of human CNS neurological disorders without obvious toxicity. In the recent clinical trials, IND of temozolomide (NCT04091503) and perillyl alcohol (NCT02704858) are being tested in adult patients with glioblastoma. This promising approach could potentially improve drug delivery, and hence clinical outcomes, for pediatric patients. However, given the distinct biology of pHGG, relative to the adult disease, preclinical evaluation of biologically appropriate agents, using pediatric glioma models, is needed prior to testing IND-associated treatment in children with brain tumors.

Unlike adult glioma, pHGG is uniquely characterized by distinct epigenetic features including histone modifications, which in turn, have profound effects on gene expression. pHGG models have shown sensitivity to epigenetic-targeted therapies, including those targeting EZH2, the enzymatic subunit of polycomb repressive complex 2 (PRC2) that acts as a histone methyltransferase. Unfortunately, the clinical efficacy of systemically administered 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 rigorous pre-clinical study of IND bypassing the BBB for the effect on EZH2 inhibitor delivery to, and biologic activity, against pHGG.

The effectiveness of IND can be further optimized by using liposomal drug carriers which provide stable encapsulation for anticancer agents. Nanoiposomes (LS) improve delivery properties across the nasal mucosa by increasing residence time of the formulation in the nasal cavity, leading to improve nasal penetration. IND of LS enables to deliver higher concentration of encapsulated drugs into the brain tumor. We have recently demonstrated the effects of IND of nanoliposomal CPT-11 (LS-CPT-11) in human brainstem xenograft models. IND of LS-CPT-11 increased survival benefit relative to IND of LS-control. However, IND of LS-CPT-11 has modest activity at best in vivo due to the limitation of hepatic metabolism to its active metabolite SN-38. LS-SN-38 increases the solubility of SN-38, which is a relatively insoluble compound, and improves the pharmacodynamics profile, in parallel with safety and efficacy profile when compared with the pro-drug version. Indeed, IND of LS-SN-38 significantly increased survival of animals bearing DIPG patient-derived xenografts (PDXs), outperforming IND of LS-CPT-11, without systemic toxicity.

The specificity of liposomes can be enhanced by using immunoliposome (iLS) formulation, which are coated with antibodies specific to the tumor cells on the surface of liposomes, leading to increase the transcytosis and delivering the drugs to the tumor cells, and reducing systemic toxicity to normal cells. Platelet-derived growth factor receptor alpha (PDGFRA) potentially plays a role in DIPG oncogenesis and expresses in as much as 70% of DIPG patients using immunohistochemistry (IHC). While PDGFRA inhibitors show promising results in preclinical studies, early clinical trials using these inhibitors did not exhibit significant benefit in patients (NCT01393912, NCT1229644). The failure of the clinical trials with PDGFRA inhibitors was in part due to the impermeability of the BBB, and the delicate location of DIPG. In this proposal, we will test IND of anti-PDGFRA monoclonal antibody conjugated immunoliposome (PDGFRA-iLS) to bypass the BBB and facilitate selective drug delivery to PDGFRA-expressing pHGGs.

The primary goal of this project is to integrate an efficient and noninvasive drug delivery system, IND, with the targeted iLS formulation of therapeutics that can be evaluated in a clinical trial setting for the treatment of children with HGGs. We will test the hypothesis that IND of PDGFRA-iLS-Tazemetostat, an FDA approved EZH2 inhibitor, will increase targeting specificity and internalization, which increase intracellular drug concentration, thereby achieving heightened anti-tumor activity in pHGG cells and PDX models.  Furthermore, we will test an innovative intranasal platform, SipNose, which has recently approved by FDA and being tested in clinical trials in adult and pediatric patients. Finally, our long-term goal is to use IND of PDGFRA-iLS-Tazemetostat in combination with radiation which is used routinely for the treatment of pHGG patients. The successful completion of proposal study has significant impact on clinical practice, and accumulating data from this research could therefore lay the foundation for phase I/II clinical trials of this approach. The ultimate goal of this research is to improve the clinical care and survival of children with pHGGs. This new therapeutic approach may benefit not only children that are afflicted with highly aggressive brain cancers but also perhaps those afflicted with multifocal brain tumors, such as metastatic brain tumors from other cancers.

Description of Research Proposal

Budget

Collaborations and Conflicts of Interest