Gemcitabine in Recurrent Meningioma

Khaddar, Satvik; Bhelekar, Arti; Dale, Ochin; Varghese, Litty; Patil, Vijay

doi:10.1055/s-0040-1721178

Cited by 4 publications

(2 citation statements)

References 4 publications

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“…Although further randomized studies are warranted to confirm the findings obtained, this study revealed the anti-tumor activity and tolerability of everolimus [ 6 ]. On the other hand, a recent study on a small group of patients with meningioma documented the efficacy and safety of treatment with gemcitabine, and a phase II clinical trial is now underway [ 9 ]. As a reflection of these findings, everolimus and gemcitabine are listed as candidate drugs for meningioma in the latest version of the EANO guidelines [ 3 ].…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, the guidelines of the European Association of Neuro-Oncology (EANO) listed gemcitabine as one of the candidate drugs for the treatment of meningioma [ 3 ]. A phase II clinical trial is currently underway after confirmation of the safety and efficacy of gemcitabine in the treatment of recurrent high-grade meningioma in a small population of patients [ 9 ]. Furthermore, we demonstrated that gemcitabine enhanced the effects of radiation together with navitoclax, an inhibitor of anti-apoptotic BCL-2 family proteins [ 10 ], suggesting a role for gemcitabine as an enhancer of treatments for malignant meningioma.…”

Section: Introductionmentioning

confidence: 99%

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Gemcitabine Cooperates with Everolimus to Inhibit the Growth of and Sensitize Malignant Meningioma Cells to Apoptosis Induced by Navitoclax, an Inhibitor of Anti-Apoptotic BCL-2 Family Proteins

Yamamoto

Togashi

Sugai

et al. 2022

Cancers

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Despite several clinical trials with encouraging findings, effective standard systemic therapies have yet to be established for malignant meningioma and the prognosis of these patients remains poor. Accumulating preclinical and clinical evidence suggests that gemcitabine is effective against malignant meningioma. To identify drugs with therapeutic effects that may be enhanced in combination with gemcitabine, we screened drugs that have been tested in preclinical and clinical trials for meningioma. In IOMM-Lee and HKBMM malignant meningioma cells, gemcitabine enhanced the growth inhibitory effects of the mTOR inhibitor everolimus, the clinical benefits of which have been demonstrated in patients with meningioma. The synergistic growth inhibitory effects of this combination were accompanied by cellular senescence characterized by an increase in senescence-associated β-galactosidase activity. To enhance the effects of this combination, we screened senolytic drugs that selectively kill senescent cells, and found that navitoclax, an inhibitor of anti-apoptotic BCL-2 family proteins, effectively reduced the number of viable malignant meningioma cells in combination with everolimus and gemcitabine by inducing apoptotic cell death. The suppression of tumor growth in vivo by the combination of everolimus with gemcitabine was significantly stronger than that by either treatment alone. Moreover, navitoclax, in combination with everolimus and gemcitabine, significantly reduced tumor sizes with an increase in the number of cleaved caspase-3-positive apoptotic cells. The present results suggest that the addition of gemcitabine with or without navitoclax to everolimus is a promising strategy that warrants further evaluation in future clinical trials for malignant meningioma.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gemcitabine Cooperates with Everolimus to Inhibit the Growth of and Sensitize Malignant Meningioma Cells to Apoptosis Induced by Navitoclax, an Inhibitor of Anti-Apoptotic BCL-2 Family Proteins

Yamamoto

Togashi

Sugai

et al. 2022

Cancers

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Will mastering ferroptosis allow treating refractory meningiomas?

Marosi

2021

Neuro-Oncology

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Gemcitabine radiosensitization primes irradiated malignant meningioma cells for senolytic elimination by navitoclax

Yamamoto

Sanomachi

Togashi

et al. 2021

Neuro-Oncology Advances

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Background Malignant meningioma is an aggressive tumor that requires adjuvant radiotherapy after surgery, yet there has been no standard systemic therapy established so far. We recently reported that malignant meningioma cells are highly sensitive to gemcitabine; however, it remains unknown whether or how gemcitabine interacts with ionizing radiation (IR) in malignant meningioma cells. Methods We examined radiosensitization effects of gemcitabine using malignant meningioma cell lines and xenografts and explored the underlying mechanisms. Results Gemcitabine sensitized malignant meningioma cells to IR through the induction of senescence both in vitro and in vivo. Gemcitabine augmented the intracellular production of reactive oxygen species (ROS) by IR, which, together with cell growth suppression/senescence induced by this combination, was inhibited by N-acetyl-cysteine, suggesting a pivotal role for ROS in these combinatorial effects. Navitoclax, a senolytic drug that inhibits Bcl-2 proteins, further enhanced the effects of the combination of gemcitabine and IR by strongly inducing apoptotic cell death in senescent cells. Conclusion These results not only indicate the potential of gemcitabine as a candidate radiosensitizer for malignant meningioma, but also reveal a novel role for gemcitabine radiosensitization as a means to create a therapeutic vulnerability of senescent meningioma cells to senolytics.

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Gemcitabine in Recurrent Meningioma

Cited by 4 publications

References 4 publications

Gemcitabine Cooperates with Everolimus to Inhibit the Growth of and Sensitize Malignant Meningioma Cells to Apoptosis Induced by Navitoclax, an Inhibitor of Anti-Apoptotic BCL-2 Family Proteins

Gemcitabine Cooperates with Everolimus to Inhibit the Growth of and Sensitize Malignant Meningioma Cells to Apoptosis Induced by Navitoclax, an Inhibitor of Anti-Apoptotic BCL-2 Family Proteins

Will mastering ferroptosis allow treating refractory meningiomas?

Gemcitabine radiosensitization primes irradiated malignant meningioma cells for senolytic elimination by navitoclax

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