Genotype-targeted local therapy of glioma.

Proc Natl Acad Sci U S A
Authors
Keywords
Abstract

Aggressive neurosurgical resection to achieve sustained local control is essential for prolonging survival in patients with lower-grade glioma. However, progression in many of these patients is characterized by local regrowth. Most lower-grade gliomas harbor isocitrate dehydrogenase 1 () or mutations, which sensitize to metabolism-altering agents. To improve local control of mutant gliomas while avoiding systemic toxicity associated with metabolic therapies, we developed a precision intraoperative treatment that couples a rapid multiplexed genotyping tool with a sustained release microparticle (MP) drug delivery system containing an -directed nicotinamide phosphoribosyltransferase (NAMPT) inhibitor (GMX-1778). We validated our genetic diagnostic tool on clinically annotated tumor specimens. GMX-1778 MPs showed mutant genotype-specific toxicity in vitro and in vivo, inducing regression of orthotopic mutant glioma murine models. Our strategy enables immediate intraoperative genotyping and local application of a genotype-specific treatment in surgical scenarios where local tumor control is paramount and systemic toxicity is therapeutically limiting.

Year of Publication
2018
Journal
Proc Natl Acad Sci U S A
Volume
115
Issue
36
Pages
E8388-E8394
Date Published
2018 09 04
ISSN
1091-6490
DOI
10.1073/pnas.1805751115
PubMed ID
30082399
PubMed Central ID
PMC6130372
Links
Grant list
R01 EB000244 / EB / NIBIB NIH HHS / United States
R01 CA227821 / CA / NCI NIH HHS / United States
K12 CA090354 / CA / NCI NIH HHS / United States
R37 EB000244 / EB / NIBIB NIH HHS / United States
P50 CA165962 / CA / NCI NIH HHS / United States