Cell surface notch ligand dll3 is a therapeutic target in isocitrate dehydrogenase–mutant glioma

Abstract

Purpose: Isocitrate dehydrogenase (IDH)-mutant glioma is a Results: Compared to IDH wild-type glioblastoma, distinct glioma molecular subtype for which no effective molec-IDH-mutant gliomas have significantly higher DLL3 RNA ularly directed therapy exists. Low-grade gliomas, which are (P < 1 10 15 ) and protein by IHC (P ¼ 0.0014 and P < 4.3 80%–90% IDH-mutant, have high RNA levels of the cell surface 10 6 in the discovery and validation set, respectively). Notch ligand DLL3. We sought to determine DLL3 expression by DLL3 immunostaining was intense and homogeneous in IHC in glioma molecular subtypes and the potential efficacy of IDH-mutant gliomas, retained in all recurrent tumors, and an anti-DLL3 antibody–drug conjugate (ADC), rovalpituzumab detected in only 1 of 20 nontumor brains. Patient-derived tesirine (Rova-T), in IDH-mutant glioma. IDH-mutant glioma tumorspheres overexpressed DLL3 and Experimental Design: We evaluated DLL3 expression by were potently sensitive to Rova-T in an antigen-dependent RNA using TCGA data and by IHC in a discovery set of 63 manner. gliomas and 20 nontumor brain tissues and a validation set of Conclusions: DLL3 is selectively and homogeneously 62 known IDH wild-type and mutant gliomas using a mono-expressed in IDH-mutant gliomas and can be targeted with clonal anti-DLL3 antibody. Genotype was determined using a Rova-T in patient-derived IDH-mutant glioma tumorspheres. DNA methylation array classifier or by sequencing. The effect Our findings are potentially immediately translatable and of Rova-T on patient-derived endogenous IDH-mutant glioma have implications for therapeutic strategies that exploit cell tumorspheres was determined by cell viability assay. surface tumor-associated antigens.