From Laboratory Studies to Clinical Trials: Temozolomide Use in IDH-Mutant Gliomas

Sun, Xueyuan; Turcan, Şevin

doi:10.3390/cells10051225

Cited by 19 publications

(14 citation statements)

References 201 publications

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“…However, GSCs are known to exhibit resistance towards temozolomide treatment, a standard care for glioblastoma. GSCs were shown to express multidrug resistance-related proteins (MGMT) [ 3 , 31 , 32 , 34 , 35 , 36 ] and to produce extracellular vesicles, which are disseminating factors of therapy resistance [ 31 ]. Furthermore, standard treatment with temozolomide promotes drug-induced tumorigenicity, i.e., de-differentiation of non-GSCs tumor cells into GSCs [ 5 , 33 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

“…Despite numerous studies that have appointed Lyn as a key molecule of tumorigenesis, specific inhibitors for this kinase are still lacking. Several inhibitors can potently block the kinase activity of Lyn as part of a pan-SFK inhibition through their interaction with the catalytic domain, but all have wide spectra of additional targets, most likely due to the homolog of the fold of the kinase domain, which is similar to all other known protein kinases [ 3 , 4 ]. This can partially explain the limited efficacy of dasatinib in some tumor entities including glioblastoma, despite its high potency to induce tumor cell death [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

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In Vitro Validation of the Therapeutic Potential of Dendrimer-Based Nanoformulations against Tumor Stem Cells

Knauer

Arkhipova

et al. 2022

IJMS

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Tumor cells with stem cell properties are considered to play major roles in promoting the development and malignant behavior of aggressive cancers. Therapeutic strategies that efficiently eradicate such tumor stem cells are of highest clinical need. Herein, we performed the validation of the polycationic phosphorus dendrimer-based approach for small interfering RNAs delivery in in vitro stem-like cells as models. As a therapeutic target, we chose Lyn, a member of the Src family kinases as an example of a prominent enzyme class widely discussed as a potent anti-cancer intervention point. Our selection is guided by our discovery that Lyn mRNA expression level in glioma, a class of brain tumors, possesses significant negative clinical predictive value, promoting its potential as a therapeutic target for future molecular-targeted treatments. We then showed that anti-Lyn siRNA, delivered into Lyn-expressing glioma cell model reduces the cell viability, a fact that was not observed in a cell model that lacks Lyn-expression. Furthermore, we have found that the dendrimer itself influences various parameters of the cells such as the expression of surface markers PD-L1, TIM-3 and CD47, targets for immune recognition and other biological processes suggested to be regulating glioblastoma cell invasion. Our findings prove the potential of dendrimer-based platforms for therapeutic applications, which might help to eradicate the population of cancer cells with augmented chemotherapy resistance. Moreover, the results further promote our functional stem cell technology as suitable component in early stage drug development.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In Vitro Validation of the Therapeutic Potential of Dendrimer-Based Nanoformulations against Tumor Stem Cells

Knauer

Arkhipova

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…Taking into account the relevance of the epigenetic landscape in gliomas and, in particular, in the prediction of treatment sensitivity, in recent years, pharmacological research is increasingly considering the possibility of including epidrugs in therapeutic options for GBM, with particular regard to personalized therapy ( Zang et al, 2018 ; Phillips et al, 2020 ). Several clinical trials are currently evaluating the effect of different epigenetic modulators, including DNA-methyltransferase inhibitors (DNMTi), used alone or in combined therapies with TMZ or radiations ( ClinicalTrials.gov, 2021 ; Wu et al, 2021 ), and various studies have proposed epidrugs and DNMTi, among other, to optimize the use of TMZ for personalized medicine in GBM ( Seelan et al, 2018 ; Yamashita et al, 2019 ; Belter et al, 2020 ; Gallitto et al, 2020 ; Moon et al, 2020 ; Sun and Turcan, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Modified Adenosines Sensitize Glioblastoma Cells to Temozolomide by Affecting DNA Methyltransferases

et al. 2022

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Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor, and due to its unique features, its management is certainly one of the most challenging ones among all cancers. N6-isopentenyladenosine (IPA) and its analog N6-benzyladenosine (N6-BA) are modified nucleosides endowed with potent antitumor activity on different types of human cancers, including GBM. Corroborating our previous finding, we demonstrated that IPA and N6-BA affect GBM cell line proliferation by modulating the expression of the F-box WD repeat domain-containing-7 (FBXW7), a tumor suppressor with a crucial role in the turnover of many proteins, such as SREBPs and Mcl1, involved in malignant progression and chemoresistance. Luciferase assay revealed that IPA-mediated upregulation of FBXW7 translates in transcriptional inactivation of its oncogenic substrates (Myc, NFkB, or HIF-1α). Moreover, downregulating MGMT expression, IPA strongly enhances the killing effect of temozolomide (TMZ), producing a favorable sensitizing effect starting from a concentration range much lower than TMZ EC50. Through DNA methyltransferase (DNMT) activity assay, analysis of the global DNA methylation, and the histone modification profiles, we demonstrated that the modified adenosines behave similar to 5-AZA-dC, known DNMT inhibitor. Overall, our results provide new perspectives for the first time, suggesting the modified adenosines as epigenetic tools able to improve chemo- and radiotherapy efficacy in glioblastoma and potentially other cancers.

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“…However, these mutations occur in only up to 12% of GBMs [ 31 ]. Increasingly, IDH mutation and malignant transformation are being linked to numerous alterations at the cellular level [ 32 ], e.g., cellular epigenetics, DNA repair pathways, and redox homeostasis [ 33 ]. This could provide potential opportunities for targeting these pathways [ 34 ] or complementing currently available approved therapeutic protocols [ 33 , 35 , 36 ].…”

Section: Introductionmentioning

confidence: 99%

Radiogenomic Predictors of Recurrence in Glioblastoma—A Systematic Review

Corr

Grimm

Saß

et al. 2022

JPM

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Glioblastoma, as the most aggressive brain tumor, is associated with a poor prognosis and outcome. To optimize prognosis and clinical therapy decisions, there is an urgent need to stratify patients with increased risk for recurrent tumors and low therapeutic success to optimize individual treatment. Radiogenomics establishes a link between radiological and pathological information. This review provides a state-of-the-art picture illustrating the latest developments in the use of radiogenomic markers regarding prognosis and their potential for monitoring recurrence. Databases PubMed, Google Scholar, and Cochrane Library were searched. Inclusion criteria were defined as diagnosis of glioblastoma with histopathological and radiological follow-up. Out of 321 reviewed articles, 43 articles met these inclusion criteria. Included studies were analyzed for the frequency of radiological and molecular tumor markers whereby radiogenomic associations were analyzed. Six main associations were described: radiogenomic prognosis, MGMT status, IDH, EGFR status, molecular subgroups, and tumor location. Prospective studies analyzing prognostic features of glioblastoma together with radiological features are lacking. By reviewing the progress in the development of radiogenomic markers, we provide insights into the potential efficacy of such an approach for clinical routine use eventually enabling early identification of glioblastoma recurrence and therefore supporting a further personalized monitoring and treatment strategy.

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From Laboratory Studies to Clinical Trials: Temozolomide Use in IDH-Mutant Gliomas

Cited by 19 publications

References 201 publications

In Vitro Validation of the Therapeutic Potential of Dendrimer-Based Nanoformulations against Tumor Stem Cells

In Vitro Validation of the Therapeutic Potential of Dendrimer-Based Nanoformulations against Tumor Stem Cells

Modified Adenosines Sensitize Glioblastoma Cells to Temozolomide by Affecting DNA Methyltransferases

Radiogenomic Predictors of Recurrence in Glioblastoma—A Systematic Review

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