Proceedings of the National Academy of Sciences of the United States of America · 2018
Genotype-targeted local therapy of glioma.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Shankar Ganesh M, Kirtane Ameya R, Miller Julie J, Mazdiyasni Hormoz, Rogner Jaimie, Tai Tammy, Williams Erik A, Higuchi Fumi, Juratli Tareq A, Tateishi Kensuke, Koerner Mara V A, Tummala Shilpa S, Fink Alexandria L, Penson Tristan, Schmidt Stephen P, Wojtkiewicz Gregory R, Baig Aymen, Francis Joshua M, Rinne Mikael L, Batten Julie M, Batchelor Tracy T, Brastianos Priscilla K, Curry William T, Barker Fred G, Jordan Justin T, Iafrate A John, Chi Andrew S, Lennerz Jochen K, Meyerson Matthew, Langer Robert, Wakimoto Hiroaki, Traverso Giovanni, Cahill Daniel P
Аннотация
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.