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Exploiting Metabolic Defects in Glioma with Nanoparticle-Encapsulated NAMPT Inhibitors
Matthew A Murray1,2, Katelyn J Noronha3, Yazhe Wang4
1Department of Therapeutic Radiology, Yale University, New Haven, Connecticut.
Abstract:
The treatment of primary central nervous system tumors is challenging due to the blood-brain barrier and complex mutational profiles, which is associated with low survival rates. However, recent studies have identified common mutations in gliomas [isocitrate dehydrogenase (IDH)-wild-type and mutant, WHO grades II-IV; with grade IV tumors referred to as glioblastomas (GBM)]. These mutations drive epigenetic changes, leading to promoter methylation at the nicotinic acid phosphoribosyl transferase (NAPRT) gene locus, which encodes an enzyme involved in generating NAD+. Importantly, NAPRT silencing introduces a therapeutic vulnerability to inhibitors targeting another NAD+ biogenesis enzyme, nicotinamide phosphoribosyl transferase (NAMPT), rationalizing a treatment for these malignancies. Multiple systemically administered NAMPT inhibitors (NAMPTi) have been developed and tested in clinical trials, but dose-limiting toxicities-including bone marrow suppression and retinal toxicity-have limited their efficacy. Here, we report a novel approach for the treatment of NAPRT-silenced GBMs using nanoparticle (NP)-encapsulated NAMPTis administered by convection-enhanced delivery (CED). We demonstrate that GMX1778 (a NAMPTi) can be formulated in degradable polymer NPs with retention of potency for NAMPT inhibition and anticancer activity in vitro, plus sustained drug release in vitro and in vivo. Direct injection of these drugs via CED into the brain is associated with reduced retinal toxicity compared with systemic administration. Finally, we show that CED of NP-encapsulated GMX1778 to NAPRT-silenced intracranial GBM xenografts in mice exhibit significant tumor growth delay and extends survival. These data support an approach to treat gliomas harboring defects in NAD+ metabolism using CED of NP-encapsulated NAMPTis to greatly improve the therapeutic index and treatment efficacy for this class of drugs.
Insights
This study introduces nanoparticle-encapsulated NAMPT inhibitors delivered via convection-enhanced delivery for treating gliomas with defective NAD+ metabolism, improving efficacy and reducing toxicity.
Area of Science:
- Neuro-oncology
- Cancer Therapeutics
- Molecular Biology
Background:
- Primary central nervous system tumors, including glioblastomas (GBMs), present treatment challenges due to the blood-brain barrier and complex mutations.
- Specific mutations in gliomas lead to epigenetic changes, including silencing of the nicotinic acid phosphoribosyl transferase (NAPRT) gene, creating a vulnerability to NAMPT inhibitors.
- Systemic administration of NAMPT inhibitors (NAMPTi) shows promise but is limited by dose-limiting toxicities like bone marrow and retinal toxicity.
Purpose of the Study:
- To develop and evaluate a novel therapeutic strategy for NAPRT-silenced GBMs.
- To investigate the use of nanoparticle (NP)-encapsulated NAMPT inhibitors delivered via convection-enhanced delivery (CED).
- To assess the efficacy and toxicity profile of this novel approach compared to systemic administration.
Main Methods:
- Formulation of GMX1778 (a NAMPTi) into degradable polymer nanoparticles (NPs).
- Evaluation of NP-encapsulated GMX1778's potency, drug release kinetics, and anticancer activity in vitro and in vivo.
- Administration of NP-encapsulated GMX1778 via CED in intracranial GBM xenograft models in mice.
Main Results:
- NP-encapsulated GMX1778 retained potency for NAMPT inhibition and anticancer activity, with sustained drug release.
- CED of NP-encapsulated GMX1778 demonstrated reduced retinal toxicity compared to systemic administration.
- CED of NP-encapsulated GMX1778 significantly delayed tumor growth and extended survival in mice with intracranial GBM xenografts.
Conclusions:
- CED of NP-encapsulated NAMPT inhibitors represents a promising strategy for treating gliomas with defects in NAD+ metabolism.
- This approach has the potential to significantly improve the therapeutic index and efficacy of NAMPT inhibitors for brain tumors.
- Further development of this localized drug delivery system could offer a more effective treatment option for challenging brain malignancies.
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