A Phase 2 Study of Neo-adjuvant Metformin and Temozolomide followed by Hypofractionated Accelerated RadioTherapy (HART) with Concomitant and Adjuvant Metformin and Temozolomide (TMZ) in Patients with Glioblastoma

Shenouda, George; Souhami, Luís; Petrecca, Kevin; Panet-Raymond, Valérie; Owen, Scott; Diaz, Roberto J.; Hall, Jeffery A.; Guiot, Marie Christine; Carvalho, T.; Abdulkarim, Bassam

doi:10.1016/j.ijrobp.2020.07.2107

Cited by 8 publications

(7 citation statements)

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“…A recent clinical trial assessed MET efficacy as neo-adjuvant compound together with TMZ and hypofractionated accelerated radio-therapy (HART) in 33 patients with glioblastoma. The study confirmed no adverse effects after the use of MET, confirming its safety and tolerability and validating previous results on favorable outcomes of glioblastoma patients, particularly those with low methylation levels of MGMT (NCT02780024) [56]. However, Seliger et al observed that MET does not succeed in increasing glioblastoma patient survival, neither alone nor in combination with other drugs [57].…”

Section: Discussionsupporting

confidence: 84%

Effects of Metformin as Add-On Therapy against Glioblastoma: An Old Medicine for Novel Oncology Therapeutics

Guarnaccia

Navone

Masseroli

et al. 2022

Cancers

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Background: Glioblastoma is the most aggressive primary brain malignancy in adults, with a poor prognosis of about 14 months. Recent evidence ascribed to metformin (MET), an antihyperglycemic drug, the potential to reduce cancer incidence and progression, but the molecular mechanisms underlying these effects need to be better investigated. Methods: Here, we tested the efficacy of MET on n = 10 primary glioblastoma endothelial cells (GECs), by viability and proliferation tests, as MTT and Live/Dead assays, apoptosis tests, as annexin V assay and caspase 3/7 activity, functional tests as tube-like structure formation and migration assay and by mRNA and protein expression performed by quantitative real-time PCR analysis (qRT-PCR) and Western Blot, respectively. Results: Data resulting revealed a time- and μ-dependent ability of MET to decrease cell viability and proliferation, increasing pro-apoptotic mechanisms mediated by caspases 3/7. Also, MET impacted GEC functionality with a significant decrease of angiogenesis and invasiveness potential. Mechanistically, MET was able to interfere with sphingolipid metabolism, weakening the oncopromoter signaling promoted by sphingosine-1-phosphate (S1P) and shifting the balance toward the production of the pro-apoptotic ceramide. Conclusions: These observations ascribed to MET the potential to serve as add-on therapy against glioblastoma, suggesting a repurposing of an old, totally safe and tolerable drug for novel oncology therapeutics.

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Section: Discussionsupporting

confidence: 84%

Effects of Metformin as Add-On Therapy against Glioblastoma: An Old Medicine for Novel Oncology Therapeutics

Guarnaccia

Navone

Masseroli

et al. 2022

Cancers

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“…Of relevance, a recent clinical trial assessed the efficacy of metformin as neo-adjuvant compound together with TMZ and hypofractionated accelerated radio-therapy (HART) in 33 patients with glioblastoma. The study confirmed no adverse effects after the use of metformin, confirming its safety and tolerability and validating previous results on favorable outcomes of glioblastoma patients, particularly those with low methylation levels of MGMT (NCT02780024) [ 127 ].…”

Section: Metforminsupporting

confidence: 86%

Frontiers in Anti-Cancer Drug Discovery: Challenges and Perspectives of Metformin as Anti-Angiogenic Add-On Therapy in Glioblastoma

Guarnaccia

Marfia

Masseroli

et al. 2021

Cancers

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Glioblastoma is the most common primitive tumor in adult central nervous system (CNS), classified as grade IV according to WHO 2016 classification. Glioblastoma shows a poor prognosis with an average survival of approximately 15 months, representing an extreme therapeutic challenge. One of its distinctive and aggressive features is aberrant angiogenesis, which drives tumor neovascularization, representing a promising candidate for molecular target therapy. Although several pre-clinical studies and clinical trials have shown promising results, anti-angiogenic drugs have not led to a significant improvement in overall survival (OS), suggesting the necessity of identifying novel therapeutic strategies. Metformin, an anti-hyperglycemic drug of the Biguanides family, used as first line treatment in Type 2 Diabetes Mellitus (T2DM), has demonstrated in vitro and in vivo antitumoral efficacy in many different tumors, including glioblastoma. From this evidence, a process of repurposing of the drug has begun, leading to the demonstration of inhibition of various oncopromoter mechanisms and, consequently, to the identification of the molecular pathways involved. Here, we review and discuss metformin’s potential antitumoral effects on glioblastoma, inspecting if it could properly act as an anti-angiogenic compound to be considered as a safely add-on therapy in the treatment and management of glioblastoma patients.

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“…Unexpectedly, an in silico study has identified 1348 FDA-approved medications as prospective candidates for targeted therapy in glioma (Chen and Xu, 2016). Chloroquine (Sotelo et al, 2006), metformin (Hong, 2021;Shenouda, 2022), ritonavir (Case Comprehensive Cancer Center, 2013, and donepezil are a few non-cancer medications that have so far entered GBM Phase II/III clinical trials. Itraconazole, minocycline, sertraline, captopril, aprepitant (Halatsch, 2021), and auranofin are other non-cancer medications that are undergoing phase I clinical trials in glioma.…”

Section: Introductionmentioning

confidence: 99%

A combination of metformin and epigallocatechin gallate potentiates glioma chemotherapy in vivo

et al. 2023

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Glioma is the most devastating high-grade tumor of the central nervous system, with dismal prognosis. Existing treatment modality does not provide substantial benefit to patients and demands novel strategies. One of the first-line treatments for glioma, temozolomide, provides marginal benefit to glioma patients. Repurposing of existing non-cancer drugs to treat oncology patients is gaining momentum in recent years. In this study, we investigated the therapeutic benefits of combining three repurposed drugs, namely, metformin (anti-diabetic) and epigallocatechin gallate (green tea-derived antioxidant) together with temozolomide in a glioma-induced xenograft rat model. Our triple-drug combination therapy significantly inhibited tumor growth in vivo and increased the survival rate (50%) of rats when compared with individual or dual treatments. Molecular and cellular analyses revealed that our triple-drug cocktail treatment inhibited glioma tumor growth in rat model through ROS-mediated inactivation of PI3K/AKT/mTOR pathway, arrest of the cell cycle at G1 phase and induction of molecular mechanisms of caspases-dependent apoptosis.In addition, the docking analysis and quantum mechanics studies performed here hypothesize that the effect of triple-drug combination could have been attributed by their difference in molecular interactions, that maybe due to varying electrostatic potential. Thus, repurposing metformin and epigallocatechin gallate and concurrent administration with temozolomide would serve as a prospective therapy in glioma patients.

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A Phase 2 Study of Neo-adjuvant Metformin and Temozolomide followed by Hypofractionated Accelerated RadioTherapy (HART) with Concomitant and Adjuvant Metformin and Temozolomide (TMZ) in Patients with Glioblastoma

Cited by 8 publications

References 0 publications

Effects of Metformin as Add-On Therapy against Glioblastoma: An Old Medicine for Novel Oncology Therapeutics

Effects of Metformin as Add-On Therapy against Glioblastoma: An Old Medicine for Novel Oncology Therapeutics

Frontiers in Anti-Cancer Drug Discovery: Challenges and Perspectives of Metformin as Anti-Angiogenic Add-On Therapy in Glioblastoma

A combination of metformin and epigallocatechin gallate potentiates glioma chemotherapy in vivo

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