First multicentric real-life experience with the combination of CCNU and temozolomide in newly diagnosed <i>MGMT</i> promoter methylated <i>IDH</i> wildtype glioblastoma

Lazaridis, Lazaros; Bumes, Elisabeth; Spille, Dorothee Cäcilia; Schulz, Tim; Heider, Sina; Agkatsev, Sarina; Schmidt, Teresa; Blau, Tobias; Oster, Christoph; Feldheim, Jonas; Stummer, Walter; Keßler, Almuth F.; Seidel, Clemens; Grauer, Oliver; Hau, Peter; Sure, Ulrich; Keyvani, Kathy; Herrlinger, Ulrich; Kleinschnitz, Christoph; Stuschke, Martin; Herrmann, Ken; Deuschl, Cornelius; Breuer, Stella; Hattingen, Elke; Scheffler, Björn; Kebir, Sied; Glas, Martin

doi:10.1093/noajnl/vdac137

Cited by 10 publications

(9 citation statements)

References 16 publications

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“…The study reported the safety, feasibility, and initial efficacy of this treatment protocol. A recent multi-center analysis of real-world evidence corroborated those findings, demonstrating a survival benefit for TTFields with TMZ plus CCNU [ 22 ]. These studies were the basis for expanding the CE Mark to include CCNU concomitant with TTFields and maintenance TMZ for newly diagnosed GBM patients.…”

Section: Introductionmentioning

confidence: 73%

“…The primary aim of this work was to study in cell cultures the effects of adding TTFields to the CeTeG regimen, a strategy with a recently identified potential clinical benefit [ 21 , 22 ]. The work described herein focused on the involvement of TTFields in DNA damage and repair as the other modalities used for treatment of GBM involve generation of DNA damage.…”

Section: Discussionmentioning

confidence: 99%

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Tumor Treating Fields (TTFields) increase the effectiveness of temozolomide and lomustine in glioblastoma cell lines

Fishman¹,

Monin²,

Dor-On³

et al. 2023

J Neurooncol

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Purpose Tumor Treating Fields (TTFields) are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression, ultimately leading to cell death. TTFields therapy is approved for treatment of newly-diagnosed glioblastoma (GBM) concurrent with maintenance temozolomide (TMZ). Recently, the benefit of TMZ in combination with lomustine (CCNU) was demonstrated in patients with O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. The addition of adjuvant TTFields to TMZ plus CCNU further improved patient outcomes, leading to a CE mark for this regimen. The current in vitro study aimed to elucidate the mechanism underlying the benefit of this treatment protocol. Methods Human GBM cell lines with different MGMT promoter methylation statuses were treated with TTFields, TMZ, and CCNU, and effectiveness was tested by cell count, apoptosis, colony formation, and DNA damage measurements. Expression levels of relevant DNA-repair proteins were examined by western blot analysis. Results TTFields concomitant with TMZ displayed an additive effect, irrespective of MGMT expression levels. TTFields concomitant with CCNU or with CCNU plus TMZ was additive in MGMT-expressing cells and synergistic in MGMT-non-expressing cells. TTFields downregulated the FA-BRCA pathway and increased DNA damage induced by the chemotherapy combination. Conclusions The results support the clinical benefit demonstrated for TTFields concomitant with TMZ plus CCNU. Since the FA-BRCA pathway is required for repair of DNA cross-links induced by CCNU in the absence of MGMT, the synergy demonstrated in MGMT promoter methylated cells when TTFields and CCNU were co-applied may be attributed to the BRCAness state induced by TTFields.

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Section: Introductionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Tumor Treating Fields (TTFields) increase the effectiveness of temozolomide and lomustine in glioblastoma cell lines

Fishman¹,

Monin²,

Dor-On³

et al. 2023

J Neurooncol

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“…Median PFS of 14.4 months and median OS of 33.8 months were observed in 70 patients. 70 TTFields are a promising candidate radiosensitizer which induced an abnormal increase in mitotic catastrophe and DNA damage of cells. 32 A prospective, single-arm study that recruited 10 patients with ndGBM was conducted to assess the feasibility and safety of combined RT and TTFields therapy with maintenance TMZ and TTFields.…”

Section: New Diagnosed Glioblastomamentioning

confidence: 99%

“…A new publishment reported that the combination of TTFields and TMZ plus CCNU can provide additional survival benefits for newly diagnosed MGMT promoter methylated glioblastoma patients. Median PFS of 14.4 months and median OS of 33.8 months were observed in 70 patients 70 …”

Section: Clinical Studies Of Ttfields In Malignant Brain Tumorsmentioning

confidence: 99%

Therapeutic potential of tumor treating fields for malignant brain tumors

et al. 2023

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Background Malignant brain tumors are among the most threatening diseases of the central nervous system, and despite increasingly updated treatments, the prognosis has not been improved. Tumor treating fields (TTFields) are an emerging approach in cancer treatment using intermediate‐frequency and low‐intensity electric field and can lead to the development of novel therapeutic options. Recent Findings A series of biological processes induced by TTFields to exert anti‐cancer effects have been identified. Recent studies have shown that TTFields can alter the bioelectrical state of macromolecules and organelles involved in cancer biology. Massive alterations in cancer cell proteomics and transcriptomics caused by TTFields were related to cell biological processes as well as multiple organelle structures and activities. This review addresses the mechanisms of TTFields and recent advances in the application of TTFields therapy in malignant brain tumors, especially in glioblastoma (GBM). Conclusions As a novel therapeutic strategy, TTFields have shown promising results in many clinical trials, especially in GBM, and continue to evolve. A growing number of patients with malignant brain tumors are being enrolled in ongoing clinical studies demonstrating that TTFields‐based combination therapies can improve treatment outcomes.

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“…None of the clinical trials of these combination therapies have, so far, shown sufficient patient benefit to merit phase III trials for any tumor type or dosage regime for reasons that have yet to be established. Whether or not AGT inactivators that specifically target tumor cells [ 158 , 159 , 160 ] or other means of attenuating AGT activity, for example, tumor treating fields [ 161 ], alkylating drug combinations [ 162 ], or antisense strategies [ 163 ], will prove to be more successful remains to be seen.…”

Section: Agt In Cancer Chemotherapymentioning

confidence: 99%

The DNA Alkyltransferase Family of DNA Repair Proteins: Common Mechanisms, Diverse Functions

Tessmer,

Margison

2023

IJMS

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DNA alkyltransferase and alkyltransferase-like family proteins are responsible for the repair of highly mutagenic and cytotoxic O6-alkylguanine and O4-alkylthymine bases in DNA. Their mechanism involves binding to the damaged DNA and flipping the base out of the DNA helix into the active site pocket in the protein. Alkyltransferases then directly and irreversibly transfer the alkyl group from the base to the active site cysteine residue. In contrast, alkyltransferase-like proteins recruit nucleotide excision repair components for O6-alkylguanine elimination. One or more of these proteins are found in all kingdoms of life, and where this has been determined, their overall DNA repair mechanism is strictly conserved between organisms. Nevertheless, between species, subtle as well as more extensive differences that affect target lesion preferences and/or introduce additional protein functions have evolved. Examining these differences and their functional consequences is intricately entwined with understanding the details of their DNA repair mechanism(s) and their biological roles. In this review, we will present and discuss various aspects of the current status of knowledge on this intriguing protein family.

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First multicentric real-life experience with the combination of CCNU and temozolomide in newly diagnosed MGMT promoter methylated IDH wildtype glioblastoma

Cited by 10 publications

References 16 publications

Tumor Treating Fields (TTFields) increase the effectiveness of temozolomide and lomustine in glioblastoma cell lines

Tumor Treating Fields (TTFields) increase the effectiveness of temozolomide and lomustine in glioblastoma cell lines

Therapeutic potential of tumor treating fields for malignant brain tumors

The DNA Alkyltransferase Family of DNA Repair Proteins: Common Mechanisms, Diverse Functions

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