Precision Oncology in Lower-Grade Gliomas: Promises and Pitfalls of Therapeutic Strategies Targeting IDH-Mutations

Abstract

Mutations in isocitrate dehydrogenase (IDH)1 and its homolog IDH2 are considered an earliest “driver” genetic event during gliomagenesis, representing now the molecular hallmark of lower-grade gliomas (LGGs). IDH-mutated genes encode for a neomorphic enzyme that converts α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate (2-HG), which accumulates to high concentrations and alters cellular epigenetics and metabolism. Targeting IDH mutations is the first attempt to apply “precision oncology” in LGGs. Two distinct strategies have been proposed so far and are under intense clinical investigation: (i) reducing the amount of intratumoral 2-HG by directly blocking the function of mutant IDH enzyme; (ii) exploiting the selective epigenetic and metabolic cellular vulnerabilities as a consequence of 2-HG accumulation. The present review describes the physiopathological mechanisms by which IDH mutations lead to tumorigenesis, discussing their prognostic significance and pivotal role in the gliomas diagnostic classification system. We critically review preclinical evidence and available clinical data of first-generation mutant-selective IDH inhibitors and novel IDH-targeted vaccines. Finally, as an alternative and attractive approach, we present the rationale to take advantage of selective 2-HG related epigenetic and metabolic weaknesses. The results of ongoing clinical trials will help us clarify the complex scenario of IDH-targeted therapeutic approaches in gliomas.

MGMT and Whole-Genome DNA Methylation Impacts on Diagnosis, Prognosis and Therapy of Glioblastoma Multiforme

“…Mutations in the Isocitrate Dehydrogenase (IDH) 1 and 2 genes are early driver genetic events during glial tumor development [65]. Accordingly, IDH1/2 mutations are a hallmark of lower-grade gliomas, up to 90% of WHO grade II and up to 70% of WHO grade III gliomas harboring mutations in these genes [66].…”

“…Accordingly, IDH1/2 mutations are a hallmark of lower-grade gliomas, up to 90% of WHO grade II and up to 70% of WHO grade III gliomas harboring mutations in these genes [66]. Moreover, nearly all 1p-19q codeleted oligodendrogliomas bear an IDH1/2 mutation, along with Telomerase Reverse Transcriptase (TERT) promoter mutation and MGMT gene methylation [65]. Finally, mutations in the IDH1/2 genes are frequently found in a distinct subtype of glioblastomas, characterized by the younger age of onset and longer survival.…”

“…Importantly, among the 263 genes found significantly downregulated and hypermethylated within G-CIMP tumors, many were associated, upon gene ontology analysis, with tumor invasion [69]. Indeed, IDH1/2 mutations have been established as the most powerful positive prognostic factor for glioma patient survival, followed by age, tumor grade and MGMT gene methylation status [65]. Moreover, typically, G-CIMP tumors have a distinct profile of copy number variation when compared to non-G-CIMP tumors [69].…”

Genetically modified IL-2 bone marrow-derived myeloid cells reprogram the glioma immunosuppressive tumor microenvironment

“…In the last decade, immunotherapy was considered a major advance for the treatment of several tumor types, but it has shown very limited efficacy in glioma [22]. This failure is thought to be mainly due to the presence of the blood brain barrier (BBB), which hampers the ability of these drugs to reach the TME, and to immune-escape mechanisms mediated by cancer cells and immunosuppressive myeloid cells [23, 24].…”

The Significance of MGMT Promoter Methylation Status in Diffuse Glioma

“…Moreover, IDH mutations are detected in many other malignancies, such as chondrosarcoma (50%), acute myeloid leukemia (AML; 30%), cholangiocarcinoma (20%), angioimmunoblastic T-cell lymphoma (AITL), solid papillary carcinoma with reverse polarity (SPCRP), melanoma, breast cancer, etc. [ 9 ].…”