Cell Surface Notch Ligand DLL3 is a Therapeutic Target in Isocitrate Dehydrogenase–mutant Glioma

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 Â 10 À15) and protein by IHC (P ¼ 0.0014 and P < 4.3 Â 10 À6 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.

A Bispecific DLL3/CD3 IgG-Like T-Cell Engaging Antibody Induces Antitumor Responses in Small Cell Lung Cancer

“…According to the DLL3-expression profile, the DLL3/CD3 ITE has the potential to be developed in additional indications with high unmet medical need, such as glioma (33), medullary thyroid cancer (34), gastrointestinal neuroendocrine malignancies (35), dispersed neuroendocrine tumors of the pancreas (34), small cell bladder cancer (36), Merkel-cell carcinoma (37), and neuroendocrine prostate cancer (38).…”

<p>The Role of DLLs in Cancer: A Novel Therapeutic Target</p>

“…52,54 DLL3 expression in IDH mutant gliomas, particularly in 1p/19q co-deleted subsets is higher than that of IDH wild-type glioblastoma. 55 The treatment of IDH mutant glioma cell lines with Rova-T can effectively induce the cytotoxicity of DLL3-expressing cells. 55 In IDH wild-type glioblastoma, DLL3 is mainly expressed in the tumor lesions contacting the subventricular zone (SVZ) but not involving the cortex, which is a prognostic marker of poor PFS.…”

“…55 The treatment of IDH mutant glioma cell lines with Rova-T can effectively induce the cytotoxicity of DLL3-expressing cells. 55 In IDH wild-type glioblastoma, DLL3 is mainly expressed in the tumor lesions contacting the subventricular zone (SVZ) but not involving the cortex, which is a prognostic marker of poor PFS. 56 However, in high-grade gliomas, DLL3 is defined as a proneural signature gene that is associated with longer survival, with DLL3/Notch signaling a major determinant of tumor growth.…”

“…6,7 In tumors, a range of DLL3 functions have been described (Figure 2). DLL3 is not expressed on the surface of normal cells, but is highly expressed on the surface of tumor cells, particularly those with histopathologic features of neuro-or neuro-endocrine origin, including IDH wild-type and mutant gliomas, 55,56 neuroendocrine lung cancer, 28 neuroendocrine prostate cancer (NEPC), 111 gastrointestinal neuroendocrine cancer (GI-NEC) 112 and small cell bladder cancer (SCBC). 113 DLL3 is upregulated at the transcriptional level in neuroendocrine tumors by the ASCL1 oncogenic driver, and is predominantly expressed in metastatic and aggressive disease phenotypes.…”

IDH-Mutant Gliomas

“…Since Notch ligand DLL-3 is overexpressed in IDH-mutant gliomas, anti-DLL3 antibody-drug conjugate (ADC), rovalpituzumab tesirine (Rova-T), is a potent therapeutic agent for IDH-mutant gliomas [164].…”