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Spino, Marissa; Kurz, Sylvia C; Chiriboga, Luis; Serrano, Jonathan; Zeck, Briana; Sen, Namita; Patel, Seema; Shen, Guomiao; Vasudevaraja, Varshini; Tsirigos, Aristotelis; Suryadevara, Carter M; Frenster, Joshua D; Tateishi, Kensuke; Wakimoto, Hiroaki; Jain, Rajan; Riina, Howard A; Nicolaides, Theodore P; Sulman, Erik P; Cahill, Daniel P; Golfinos, John G; Isse, Kumiko; Saunders, Laura R; Zagzag, David; Placantonakis, Dimitris G; Snuderl, Matija; Chi, Andrew S
Clinical cancer research, 02/2019, Letnik: 25, Številka: 4Journal Article
Isocitrate dehydrogenase ( )-mutant glioma is a distinct glioma molecular subtype for which no effective molecularly directed therapy exists. Low-grade gliomas, which are 80%-90% -mutant, have high RNA levels of the cell surface Notch ligand DLL3. We sought to determine DLL3 expression by IHC in glioma molecular subtypes and the potential efficacy of an anti-DLL3 antibody-drug conjugate (ADC), rovalpituzumab tesirine (Rova-T), in -mutant glioma. We evaluated expression by RNA using TCGA data and by IHC in a discovery set of 63 gliomas and 20 nontumor brain tissues and a validation set of 62 known wild-type and mutant gliomas using a monoclonal anti-DLL3 antibody. Genotype was determined using a DNA methylation array classifier or by sequencing. The effect of Rova-T on patient-derived endogenous -mutant glioma tumorspheres was determined by cell viability assay. Compared to wild-type glioblastoma, -mutant gliomas have significantly higher RNA ( < 1 × 10 ) and protein by IHC ( = 0.0014 and < 4.3 × 10 in the discovery and validation set, respectively). DLL3 immunostaining was intense and homogeneous in -mutant gliomas, retained in all recurrent tumors, and detected in only 1 of 20 nontumor brains. Patient-derived -mutant glioma tumorspheres overexpressed DLL3 and were potently sensitive to Rova-T in an antigen-dependent manner. DLL3 is selectively and homogeneously expressed in -mutant gliomas and can be targeted with Rova-T in patient-derived -mutant glioma tumorspheres. Our findings are potentially immediately translatable and have implications for therapeutic strategies that exploit cell surface tumor-associated antigens.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Vir: Osebne bibliografije
in: SICRIS
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