Data from Cell Surface Notch Ligand DLL3 is a Therapeutic Target in Isocitrate Dehydrogenase–mutant Glioma
Year: 2023
Type: other
Abstract: 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.
Authors: Marissa Spino, Sylvia C. Kurz, Luis Chiriboga, Jonathan Serrano, Briana Zeck, Namita Sen, Seema Patel, Guomiao Shen, Varshini Vasudevaraja, Aristotelis Tsirigos, Carter M. Suryadevara, Joshua D. Frenster, Kensuke Tateishi, Hiroaki Wakimoto, Rajan Jain, Howard A. Riina, Theodore P. Nicolaides, Erik P. Sulman, Daniel P. Cahill, John G. Golfinos, Kumiko Isse, Laura R. Saunders, David Zagzag, Dimitris G. Placantonakis, Matija Snuderl, Andrew S. Chi
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4361958154