1区 · 医学
Article
作者: Golfinos, John G. ; Sen, Namita ; Placantonakis, Dimitris G. ; Wakimoto, Hiroaki ; Zagzag, David ; Tsirigos, Aristotelis ; Chi, Andrew S. ; Riina, Howard A. ; Tateishi, Kensuke ; Shen, Guomiao ; Nicolaides, Theodore P. ; Zeck, Briana ; Cahill, Daniel P. ; Jain, Rajan ; Frenster, Joshua D. ; Isse, Kumiko ; Vasudevaraja, Varshini ; Kurz, Sylvia C. ; Chiriboga, Luis ; Sulman, Erik P. ; Spino, Marissa ; Snuderl, Matija ; Serrano, Jonathan ; Patel, Seema ; Suryadevara, Carter M. ; Saunders, Laura R.
Purpose::Isocitrate dehydrogenase (IDH)-mutant glioma is a distinct glioma molecular subtype for which no effective molecularly directed therapy exists. Low-grade gliomas, which are 80%–90% IDH-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 IDH-mutant glioma.
Experimental Design::We evaluated DLL3 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 IDH 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 IDH-mutant glioma tumorspheres was determined by cell viability assay.
Results::Compared to IDH wild-type glioblastoma, IDH-mutant gliomas have significantly higher DLL3 RNA (P < 1 × 10−15) and protein by IHC (P = 0.0014 and P < 4.3 × 10−6 in the discovery and validation set, respectively). DLL3 immunostaining was intense and homogeneous in IDH-mutant gliomas, retained in all recurrent tumors, and detected in only 1 of 20 nontumor brains. Patient-derived IDH-mutant glioma tumorspheres overexpressed DLL3 and were potently sensitive to Rova-T in an antigen-dependent manner.
Conclusions::DLL3 is selectively and homogeneously expressed in IDH-mutant gliomas and can be targeted with Rova-T in patient-derived IDH-mutant glioma tumorspheres. Our findings are potentially immediately translatable and have implications for therapeutic strategies that exploit cell surface tumor-associated antigens.