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Genotype-targeted Local Therapy of Glioma

Genotype-targeted Local Therapy of Glioma

Ganesh M Shankar, Ameya R Kirtane, Julie J Miller, Hormoz Mazdiyasni, Jaimie Rogner, Tammy Tai, Erik A Williams, Fumi Higuchi, Tareq A Juratli, Kensuke Tateishi, Mara V A Koerner, Shilpa S Tummala, Alexandria L Fink, etc.

Proc Natl Acad Sci U S A. 2018 Sep 4;115(36):E8388-E8394.

PMID: 30082399

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 (IDH1) or IDH2 mutations, which sensitize to metabolism-altering agents. To improve local control of IDH 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 IDH-directed nicotinamide phosphoribosyltransferase (NAMPT) inhibitor (GMX-1778). We validated our genetic diagnostic tool on clinically annotated tumor specimens. GMX-1778 MPs showed mutant IDH genotype-specific toxicity in vitro and in vivo, inducing regression of orthotopic IDH 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP200484113	GMX1778		200484-11-3	Price

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