Khalid Alhreish

Introduction: Gliomas represent the most common primary brain tumor in adults¹. They remain incurable despite current therapies, which are plagued by high morbidity and mortality. The isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) genes are mutated in 50-80% of astrocytomas, oligodendrogliomas or oligoastrocytomas of grades II and III, and secondary glioblastomas². Patients that IDH mutations are present are younger at diagnosis and live longer. IDH (Isocitrate dehydrogenase) mutation occur in association and may represent early genetic alterations in the development of gliomas. However, the prognostic value still requires further investigation. Studies have identified IDH mutations in acute myelogenous leukemia (AML), cholangiocarcinoma, cartilaginous tumors, prostate cancer, papillary breast carcinoma, melanoma, acute lymphoblastic leukemia, angioimmunoblastic T cell lymphoma, and primary myelofibrosis indicating that these genes may be important players in multiple tumor types¹.  Methods: To evaluate the roles of genes in glioma development, a mouse model system has been used based on the RCAS/TVA retroviral vector system to induce malignant gliomas in vivo. NADPH consumption and 2-HG, glioma formation was measures in cell lines. Methylation landscape was measured using microarray and H&P staining. Results: In the presence of isocitrate, cells expressing WT IDH1 generated significantly higher levels of NADPH compared to cells expressing IDH1R132H¹. IDH1R132H expression alone is insufficient to initiate glioma development². Therefore, IDH mutant must be paired with other genetic factors to induce tumor formation. Significant cooperativity and necessity of combined genetic alterations is required in promoting tumor development and that IDH1R132H promotes glioma formation³. A decrease in 5hmC staining was observed in the WT IDH1 tumors compared to the PDGFA and Cre-only tumors⁴. This may be explained by the finding that wild-type IDH1 can also catalyze the conversion of α-KG to 2-HG less efficiently than mutant IDH². Combination of TMZ and olaparib resulted in a significant reduction in cell viability suggesting that this is an effective therapeutic strategy for treatment¹. Conclusion: The main course of action is currently tumor resection followed by radiation and cytotoxic chemotherapy. Mutant IDH cells are sensitive to olaparib. A selective inhibitor of mutant IDH1 inhibited the production of 2-HG and the growth of cells expressing IDH1R132H. Demonstration of in vivo efficacy of these and other therapies in a relevant glioma model would further support translation to the clinic.

1. Philip, D.X. Yu, M.R. Silvis, C.H. Shin, J.P. Robinson, G.L. et al. Mutant IDH1 promotes glioma formation in vivo. Cell Rep., 23 (2018), pp. 1553-1564
2. Lu Y, Kwintkiewicz J, Liu Y, Tech K, Frady LN, Su YT, et al. Chemosensitivity of IDH1-mutated gliomas due to an impairment in PARP1-mediated DNA repair. Cancer Res. (2017) 77:1709–18. doi: 10.1158/0008-5472.CAN-16-2773
3. Cai J, et al. Detection of ATRX and IDH1-R132H immunohistochemistry in the progression of 211 paired gliomas. Oncotarget. 2016;7:16384–16395.
4. Cancer Genome Atlas Research Network. Comprehensive, Integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med. 2015;372(26):2481–98.