Genotype-targeted local therapy of glioma.
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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
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Journal | Proc Natl Acad Sci U S A
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Volume | 115
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Issue | 36
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Pages | E8388-E8394
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Date Published | 2018 09 04
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ISSN | 1091-6490
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DOI | 10.1073/pnas.1805751115
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PubMed ID | 30082399
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PubMed Central ID | PMC6130372
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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
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