McKean William B, Yang Jingye, Boucher Kenneth, Shrieve Dennis C, Suneja Gita, Salzman Karen, Jensen Randy, Colman Howard, Cohen Adam L
Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
Division of Medical Oncology, University of Utah School of Medicine, Salt Lake City, Utah, USA.
Neurooncol Adv. 2024 Apr 23;6(1):vdae063. doi: 10.1093/noajnl/vdae063. eCollection 2024 Jan-Dec.
Standard treatment for newly diagnosed high-grade gliomas remains suboptimal. Preclinical data indicate that mesenchymal transition and radiation resistance in glioblastoma are driven by NF-κB and microglia activation, which can be inhibited by minocycline. We assessed the safety and efficacy of minocycline combined with standard radiation and temozolomide in newly diagnosed high-grade gliomas.
Adults with newly diagnosed high-grade glioma were eligible. Minocycline was given with concurrent and adjuvant temozolomide. Minocycline doses were escalated using a 3 + 3 design and expanded to identify the maximum tolerated dose (MTD) and adverse event profile. Individual progression-free survival (PFS) was compared to predicted PFS based on RTOG RPA class using a binomial test. The relationships between mesenchymal and microglial biomarkers were analyzed with immunohistochemistry.
The MTD of minocycline was 150 mg twice per day ( = 20); 1 patient (5%) experienced CTCAE grade 3 + nausea and dizziness, and 2 patients (10%) demonstrated thrombocytopenia requiring temozolomide interruptions. Twelve patients exceeded their predicted PFS (60%), which did not meet the predefined efficacy endpoint of 70%. Symptoms increased during post-radiation treatment but remained mild. No significant correlation was seen between biomarkers and PFS. Expression levels of P-p65, a marker of NF-κB activation, were correlated with the microglia marker IBA-1.
Minocycline at 150 mg twice per day is well tolerated with standard chemoradiation in patients with newly diagnosed high-grade gliomas. PFS was not significantly increased with the addition of minocycline when compared to historical controls. NF-κB activation correlates with microglia levels in high-grade glioma.
新诊断的高级别胶质瘤的标准治疗效果仍不理想。临床前数据表明，胶质母细胞瘤中的间充质转化和放射抗性由核因子κB（NF-κB）和小胶质细胞激活驱动，而米诺环素可抑制这一过程。我们评估了米诺环素联合标准放疗和替莫唑胺治疗新诊断的高级别胶质瘤的安全性和疗效。
符合条件的为新诊断的高级别胶质瘤成年患者。米诺环素与同步和辅助替莫唑胺联合使用。米诺环素剂量采用3+3设计递增，并扩大样本量以确定最大耐受剂量（MTD）和不良事件特征。使用二项式检验将个体无进展生存期（PFS）与基于美国放射肿瘤学会（RTOG）递归分区分析（RPA）分级预测的PFS进行比较。采用免疫组织化学分析间充质和小胶质细胞生物标志物之间的关系。
米诺环素的MTD为每日两次，每次150毫克（n=20）；1例患者（5%）出现3级以上美国国立癌症研究所常见不良反应事件评价标准（CTCAE）的恶心和头晕，2例患者（10%）出现血小板减少症，需要中断替莫唑胺治疗。12例患者的PFS超过了预测值（60%），未达到预先设定的70%的疗效终点。放疗后症状有所增加，但仍较轻微。生物标志物与PFS之间未发现显著相关性。NF-κB激活标志物P-p65的表达水平与小胶质细胞标志物离子钙结合衔接分子1（IBA-1）相关。
新诊断的高级别胶质瘤患者每日两次服用150毫克米诺环素，与标准放化疗联合使用时耐受性良好。与历史对照相比，添加米诺环素后PFS未显著增加。高级别胶质瘤中NF-κB激活与小胶质细胞水平相关。
