Karajannis Matthias A, Mauguen Audrey, Maloku Ekrem, Xu Qingwen, Dunbar Erin M, Plotkin Scott R, Yaffee Anna, Wang Shiyang, Roland J Thomas, Sen Chandranath, Placantonakis Dimitris G, Golfinos John G, Allen Jeffrey C, Vitanza Nicholas A, Chiriboga Luis A, Schneider Robert J, Deng Jingjing, Neubert Thomas A, Goldberg Judith D, Zagzag David, Giancotti Filippo G, Blakeley Jaishri O
Pediatric Neuro-Oncology Service, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
Mol Cancer Ther. 2021 Sep;20(9):1584-1591. doi: 10.1158/1535-7163.MCT-21-0143. Epub 2021 Jun 17.
Inhibition of mTORC1 signaling has been shown to diminish growth of meningiomas and schwannomas in preclinical studies, and clinical data suggest that everolimus, an orally administered mTORC1 inhibitor, may slow tumor progression in a subset of patients with neurofibromatosis type 2 (NF2) with vestibular schwannoma. To assess the pharmacokinetics, pharmacodynamics, and potential mechanisms of treatment resistance, we performed a presurgical (phase 0) clinical trial of everolimus in patients undergoing elective surgery for vestibular schwannoma or meningiomas. Eligible patients with meningioma or vestibular schwannoma requiring tumor resection enrolled on study received everolimus 10 mg daily for 10 days immediately prior to surgery. Everolimus blood levels were determined immediately before and after surgery. Tumor samples were collected intraoperatively. Ten patients completed protocol therapy. Median pre- and postoperative blood levels of everolimus were found to be in a high therapeutic range (17.4 ng/mL and 9.4 ng/mL, respectively). Median tumor tissue drug concentration determined by mass spectrometry was 24.3 pg/mg (range, 9.2-169.2). We observed only partial inhibition of phospho-S6 in the treated tumors, indicating incomplete target inhibition compared with control tissues from untreated patients ( = 0.025). Everolimus led to incomplete inhibition of mTORC1 and downstream signaling. These data may explain the limited antitumor effect of everolimus observed in clinical studies for patients with NF2 and will inform the design of future preclinical and clinical studies targeting mTORC1 in meningiomas and schwannomas.
在临床前研究中，mTORC1信号通路的抑制已被证明可减少脑膜瘤和神经鞘瘤的生长，临床数据表明，口服mTORC1抑制剂依维莫司可能会减缓2型神经纤维瘤病（NF2）伴前庭神经鞘瘤患者亚组中的肿瘤进展。为了评估依维莫司的药代动力学、药效学及治疗耐药的潜在机制，我们对接受前庭神经鞘瘤或脑膜瘤择期手术的患者进行了依维莫司的术前（0期）临床试验。符合条件的需要进行肿瘤切除的脑膜瘤或前庭神经鞘瘤患者在术前10天每天接受10mg依维莫司治疗。在手术前后即刻测定依维莫司血药浓度。术中收集肿瘤样本。10名患者完成了方案治疗。发现依维莫司术前和术后血药浓度中位数处于高治疗范围（分别为17.4ng/mL和9.4ng/mL）。通过质谱法测定的肿瘤组织药物浓度中位数为24.3pg/mg（范围为9.2 - 169.2）。我们观察到在治疗的肿瘤中磷酸化S6仅部分受到抑制，表明与未治疗患者的对照组织相比，靶点抑制不完全（P = 0.025）。依维莫司导致mTORC1及其下游信号传导的抑制不完全。这些数据可能解释了在NF2患者的临床研究中观察到的依维莫司抗肿瘤作用有限的原因，并将为未来针对脑膜瘤和神经鞘瘤中mTORC1的临床前和临床研究设计提供参考。
