Combination Therapy with Mtor Inhibition and Ionizing Radiation in Meningioma Results In Superior Cytostatic Effect than Monotherapy

Introduction: Adjuvant therapy for recurrent and progressive meningioma remains a challenge. Radiotherapy shows a varied clinical response, particularly among WHO grade II-III meningiomas. Mammalian target of rapamycin (mTOR)-inhibition has been suggested as a potential medical adjuvant agent for growth arrest. There is a paucity of data on the efficacy and mechanism of radiation and mTOR inhibition combination therapy.

Methods: Patient-derived grade 2 meningioma primary cultures were treated with single fraction radiation at 4Gy, mTOR inhibitor (rapamycin, 1nM) or a combination. Cells were counted (Celigo, Nexelcom) to assess for growth after 7-days. Separately, BenMen1 meningioma cell line was treated with monotherapy versus combination therapy, stained for DAPI after 48 hours and a cell cycle analysis was performed via flow cytometry (Attune NxT). For experiments lasting >2 days, rapamycin was re-dosed every 2 days.

Results: Both radiation and rapamycin treatment significantly inhibited growth in a panel of grade 2 primary meningioma cultures. Combination therapy was significantly more effective than either monotherapy in isolation (p < 0.05 vs. rapamycin, p < 0.001 vs. 4 Gy; [Fig. 1]—sample growth curve; [Fig. 2]—group analysis).

Cell cycle analysis demonstrates that cell cycle distribution was similar for control and monotherapy treated cells (ANOVA p = ns, [Fig. 3]), whereas those treated with combination therapy stall in S-phase (%S phase Ctl: 10.2% vs. Rapamycin + 4 Gy: 41.2%, p < 0.01; [Fig 4]), and do not progress through the cell cycle.

Fig. 1

Conclusions: We identified the potential cytostatic utility of combination therapy with mTOR inhibition and radiation in atypical meningioma. The interaction of these treatment modalities appears to be associated with disruption of cell cycle progression. Notably, the radiation dose used here (4 Gy) is low relative to clinical doses, suggesting possible applicability of combination therapy (low dose radiation + mTOR inhibition) in patients in whom previous radiotherapy precludes further full radiotherapy course due to dose limits. Further work is needed to ascertain any cytotoxic effects and validate these findings in an animal model.