New therapeutic target for IDH-positive glioma - DLL3

Mutations that encode isocitric acid dehydrogenase IDH1/IDH2 occur in low-grade gliomas and secondary glioma stomasThe mutation of IDH is generally considered an early event of glioma, and the mutation of IDH causes tumor tissue metabolites 2-HG to accumulate and makes the tumor genome have highmethylated phenotypesThe standard treatment stoadded for idh-positive glioma patients is surgically assisted radiotherapy and PCV chemotherapyAlthough the program significantly improves the survival of patients, many patients will eventually relapse and dieThis result may be due to the fact that there is no target treatment for the target of the IDH mutation, and immunotherapy for the IDH mutation needs further clinical trialsAndrew SChi, director of the Langone Brain Tumor Center at New York University, and others have made new breakthroughs in targeted immunotherapy for IDH mutant gliomas, which found that DLL3 is highly expressive in IDH mutant gliomas, and that tumor cells with the source of this type of molecular characteristic glioma can be targeted by Rova-T drugs, a study that provides a new direction for targeted and immunotherapy for IDH-positive glioma patientsthe authors collected tissue samples from 62 glioma patients, 26 of which were IDH wild and 36 were IDH positive; Expression was also high in the tissues of glioma patients; then, molecular lymes were made in patients with gliomas, and DLL3 expression was then counted and analyzed; and finally, the authors developed tumor cells from IDH-positive, DLL3 high-expression glioma patients, and tested the tumor cells with anti-DLL3 drugsThe TCGA database and RNA-seq experiments showed that DLL3 was highly expressed in gliomas with IDH mutations (Figure 1), and through a series of data analysis, the authors found that the high expression of DLL3 in glioma was not caused by DLL3 gene mutations or gene amplificationFigure 1. DLL3 is highly expressive in low-grade gliomas, especially in high expression of gliomas with IDH mutationin order to determine the expression of DLL3 proteins in different levels of glioma, the authors tested immune groupation experiments on tissues of different levels, IDH positive and wild patientsThe experimental results showed that most IDH-positive glioma patients had strong and homogeneous DLL3 protein expression in tissues, while there was no or small amount of DLL3 protein expression in IDH-negative gliomas (Figure 2)Figure 2Immune histology detects DLL3 protein expression in gliomasANegative control, HEK-293T cell line B Positive control, HEK-293T cell line , hDLL3 C Positive control, derived from the PDX model of non-small cell lung cancer D Non-tumor samples E.IDH Wild GBM, inter-charged subtype F.IDH Wild GBM, RTKII subtype G.IDH mutant astrocyma H IDH mutation slowers glioblastoma I-L initial and paired recurrent tumors the authors found that DLL3 RNA and proteins were highly expressed in the large number of IDH-positive gliomas, and to explore whether DLL3 could be a molecular therapeutic target for treating idh positive glioma patients, the team first trained the glioma cell line MGG119 and MGG119 (from tumor tissue in patients with IDH mutant glioma) and used immunoimprint to detect dLL3 expression in cell lines The authors then used the molecular drugs Rova-T for DLL3 to treat MGG119 and MGG152 cell lines, and the results showed that Rova-T drugs were able to specifically kill MGG119 and MGG119 and MGG152 cell lines with IDH mutations, DLL3 high expression, in an antigen-dependent manner (Figure 3) Figure 3 Antibody drug sensitivity derived from the patient's endogenous IDH-mutant glioma tumor sphere targeting DLL3 (Rova-T) the study identified DLL3 as a target for cell surface therapy in tumor-related antigens and IDH mutant gliomas The findings of this study are of great significance for the development of gliomas and new treatment strategies for the use of cell surface tumor-related antigens