5-Azacitidine in patients with IDH1/2-mutant recurrent glioma

Federici, Laetitia; Laurent, Césari; Annereau, Maxime; Bielle, Franck; Willekens, Christophe; Dehais, Caroline; Laigle‐Donadey, Florence; Hoang-Xuân, Khê; Delattre, Jean‐Yves; Idbaïh, Ahmed; Lemare, François; Botton, Stéphane de; Sanson, Marc; Touat, Mehdi

doi:10.1093/neuonc/noaa074

Cited by 20 publications

(14 citation statements)

References 10 publications

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“…5-Azacytidine, on the other hand, has been studied individually in glioma and GB xenografts 16 , 17 , and in patients with recurrent glioma bearing mutations of isocitrate dehydrogenase genes 57 , as the latter frequently exhibit DNA hypermethylation. Despite stratification of patients, no conclusive results regarding the efficiency of azacytidine monotherapy could be achieved 57 . In our viability assay with resazurin, 48 h treatment with azacytidine resulted in 8 µM and 10 µM IC 50 values in U-251 MG and T98-G, respectively (Table 1 ).…”

Section: Discussionmentioning

confidence: 99%

Viability fingerprint of glioblastoma cell lines: roles of mitotic, proliferative, and epigenetic targets

Lavõgina

Laasfeld

Vardja

et al. 2021

Sci Rep

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Despite the use of multimodal treatment combinations, the prognosis of glioblastoma (GB) is still poor. To prevent rapid tumor recurrence, targeted strategies for the treatment of GB are widely sought. Here, we compared the efficacy of focused modulation of a set of signaling pathways in two GB cell lines, U-251 MG and T98-G, using a panel of thirteen compounds targeting cell cycle progression, proliferation, epigenetic modifications, and DNA repair mechanism. In parallel, we tested combinations of these compounds with temozolomide and lomustine, the standard chemotherapy agents used in GB treatment. Two major trends were found: within individual compounds, the lowest IC50 values were exhibited by the Aurora kinase inhibitors, whereas in the case of mixtures, the addition of DNA methyltransferase 1 inhibitor azacytidine to lomustine proved the most beneficial. The efficacy of cell cycle-targeting compounds was further augmented by combination with radiation therapy using two different treatment regimes. The potency of azacytidine and lomustine mixtures was validated using a unique assay pipeline that utilizes automated imaging and machine learning-based data analysis algorithm for assessment of cell number and DNA damage extent. Based on our results, the combination of azacytidine and lomustine should be tested in GB clinical trials.

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Section: Discussionmentioning

confidence: 99%

Viability fingerprint of glioblastoma cell lines: roles of mitotic, proliferative, and epigenetic targets

Lavõgina

Laasfeld

Vardja

et al. 2021

Sci Rep

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“…Despite these promising preclinical results, the first clinical use of azacitidine given as therapy of 12 heavily pretreated patients with IDH1/2-mut recurrent gliomas with astrocytic or oligodendroglial histology showed only minimal activity: no patient achieved a radiographic response, while five (41.7%) had disease stabilization, of whom 2 (16.7%) lasting for more than 18 months [ 68 ]. Other clinical trials, testing 5-azacytidine as single agent or in combination with IDH-mut inhibitors (Olutasidenib), are now ongoing (NCT03666559, NCT03684811) ( Table 3 ).…”

Section: Epigenetic Approachesmentioning

confidence: 99%

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

Persico

Lorenzi

Losurdo

et al. 2022

Cancers

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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.

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“…DNA methylation is the most commonly studied epigenetic modification in cancer ( 285 ), and methylation signatures are included in glioma classification ( 288 ). Gliomas harboring mutant IDH1 display high levels of DNA hypermethylation in CpG rich domains, which are associated with increased tumor progression and altered gene expression ( 289 , 290 ). Inhibitors of mutated IDH1/2 enzymes entered clinical trials and represent a novel drug class for targeted therapy of gliomas.…”

Section: Novel Targets and Strategies To Stimulate Anti-glioma Immune Responsementioning

confidence: 99%

“…Early studies have shown anti-glioma efficacy of DNMT inhibitors in vivo and in vitro ( 294 , 295 ). Despite the preclinical successes, a representative DNMT inhibitor, 5-aza-2′-deoxycytidine, has been shown to have minimal efficacy in early clinical trials ( 290 ). Recent studies showed a strong connection between epigenetics and cytokine production in tumor cells.…”

Section: Novel Targets and Strategies To Stimulate Anti-glioma Immune Responsementioning

confidence: 99%

Genetic Alterations in Gliomas Remodel the Tumor Immune Microenvironment and Impact Immune-Mediated Therapies

et al. 2021

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High grade gliomas are malignant brain tumors that arise in the central nervous system, in patients of all ages. Currently, the standard of care, entailing surgery and chemo radiation, exhibits a survival rate of 14-17 months. Thus, there is an urgent need to develop new therapeutic strategies for these malignant brain tumors. Currently, immunotherapies represent an appealing approach to treat malignant gliomas, as the pre-clinical data has been encouraging. However, the translation of the discoveries from the bench to the bedside has not been as successful as with other types of cancer, and no long-lasting clinical benefits have been observed for glioma patients treated with immune-mediated therapies so far. This review aims to discuss our current knowledge about gliomas, their molecular particularities and the impact on the tumor immune microenvironment. Also, we discuss several murine models used to study these therapies pre-clinically and how the model selection can impact the outcomes of the approaches to be tested. Finally, we present different immunotherapy strategies being employed in clinical trials for glioma and the newest developments intended to harness the immune system against these incurable brain tumors.

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5-Azacitidine in patients with IDH1/2-mutant recurrent glioma

Cited by 20 publications

References 10 publications

Viability fingerprint of glioblastoma cell lines: roles of mitotic, proliferative, and epigenetic targets

Viability fingerprint of glioblastoma cell lines: roles of mitotic, proliferative, and epigenetic targets

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

Genetic Alterations in Gliomas Remodel the Tumor Immune Microenvironment and Impact Immune-Mediated Therapies

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